Gene expression, biological effects and clinical aspects of lymphokines

Critical Reviews in Oncology/Hematology 26 (1997) 175 – 213

Gene expression, biological effects and clinical aspects of lymphokines Leonore M.L. Tuyt, Willem H.A. Dokter, Edo Vellenga * Department of Hematology, Uni6ersity Hospital, Hanzeplein 1, 9713 GZ Groningen, Netherlands Accepted 13 October 1997

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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2. Interleukin-1 . . . . . . . . . . . . . . . . . . . 2.1. History . . . . . . . . . . . . . . . . . . 2.2. IL-1 gene architecture . . . . . . . . . . 2.3. IL-1b gene expression . . . . . . . . . . 2.4. The IL-1 receptor . . . . . . . . . . . . 2.5. Biochemical pathways of IL-1b action 2.6. In vitro effects of IL-1 . . . . . . . . . 2.7. Clinical application of IL-1 . . . . . . .

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3. Interleukin-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. IL-3 gene architecture . . . . . . . . . . . . . . . . . . . . 3.3. IL-3 gene expression . . . . . . . . . . . . . . . . . . . . . 3.4. The IL-3 receptor . . . . . . . . . . . . . . . . . . . . . . 3.5. Biochemical pathways of IL-3 action . . . . . . . . . . . 3.6. In vitro effects of IL-3 . . . . . . . . . . . . . . . . . . . 3.7. Clinical application of IL-3 . . . . . . . . . . . . . . . . . 3.7.1. In vivo effects of IL-3. . . . . . . . . . . . . . . . 3.7.2. IL-3 in standard chemotherapy . . . . . . . . . . 3.7.3. IL-3 in autologous bone marrow transplantation 3.7.4. IL-3 for peripheral stem cell mobilization . . . . 3.7.5. IL-3 in AML and myelodysplasia . . . . . . . . .

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4. Interleukin-4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. IL-4 gene architecture . . . . . . . . . . . . . . . . . . . . . . 4.3. IL-4 gene expression . . . . . . . . . . . . . . . . . . . . . . . 4.4. The IL-4 receptor . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Biochemical pathways of IL-4 action . . . . . . . . . . . . . 4.6. In vitro effects of IL-4 . . . . . . . . . . . . . . . . . . . . . 4.6.1. IL-4 effect on myeloid and erythroid progenitors . . 4.6.2. IL-4 effect on the myeloid leukemic progenitor cell . 4.6.3. IL-4 effect on monocyte functions. . . . . . . . . . . 4.7. Clinical application of IL-4 . . . . . . . . . . . . . . . . . . .

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5. Interleukin-6 . . . . . . . . . . . 5.1. History . . . . . . . . . . 5.2. IL-6 gene architecture . . 5.3. IL-6 gene expression . . . 5.4. The IL-6 receptor . . . . 5.5. Biochemical pathways of

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* Corresponding author. Tel.: + 31 50 3612354; fax: + 31 50 3614862; e-mail: [email protected] 1040-8428/97/$32.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 1 0 4 0 - 8 4 2 8 ( 9 7 ) 1 0 0 0 6 - 3

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L.M.L. Tuyt et al. / Critical Re6iews in Oncology/Hematology 26 (1997) 175–213 5.6. In vitro effects of IL-6 . . . . . . . . . . . . . . . . . . . . . . 5.6.1. IL-6 effect on erythroid, myeloid and megakaryocytic 5.6.2. IL-6 effect on AML . . . . . . . . . . . . . . . . . . . . 5.7. Clinical application of IL-6 . . . . . . . . . . . . . . . . . . . .

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6. Interleukin-9 . . . . . . . . . . . 6.1. History . . . . . . . . . . 6.2. IL-9 gene architecture . . 6.3. IL-9 gene expression . . . 6.4. The IL-9 receptor . . . . 6.5. Biochemical pathways of 6.6. In vitro effects of IL-9 .

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7. Interleukin-10 . . . . . . . . . . 7.1. History . . . . . . . . . . 7.2. IL-10 gene architecture . 7.3. IL-10 gene expression . . 7.4. IL-10 receptor . . . . . . 7.5. Biochemical pathways of 7.6. In vitro effects of IL-10 .

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Reviewer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Appendix A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction

2. Interleukin-1

The large amount of data published over the last decade has drastically expanded our knowledge on the biology of human cytokines. Moreover, more insight has been gained on the mechanism of action of cytokines, stretching from cytokine receptor binding to induction of gene transcription and the signaling routes in between. As a consequence, the involvement of cytokines in malignant disease has been further acknowledged, and much attention has been focused on aberrant cytokine and cytokine receptor expression in malignancies. The gain of insight in cytokine-induced intracellular pathways also contributed to the identification of aberrantly activated signaling routes in malignancies, although its involvement in the process of leukemogenesis/carcinogenesis is still largely unknown. In this paper we review biological and clinical aspects of six lymphokines, namely interleukin-1 (IL-1), IL-3, IL-4, IL-6, IL-9 and IL-10. For the sake of clarity we will mainly focus on the normal biological function of cytokines and refrain from discussing disregulated cytokine expression in hematological malignancies. For every cytokine the gene architecture and control of gene expression are discussed. Then the cytokine receptor, its expression and the signal transduction pathways which are mediated from the receptor into the cytoplasm are described. Some of the in vitro effects of these lymphokines are also discussed. For this purpose we concentrated on the effects of these lymphokines on the myeloid, lymphoid and erythroid immature and mature cells. Finally, an overview will be given of studies that describe the clinical application of the respective lymphokine. The latter is only done for IL-1, IL-3, IL-4 and IL-6 since IL-9 and IL-10 are not used in clinical studies yet.

2.1. History With the cloning of the IL-1a and IL-1b molecules, 13 years ago, it appeared remarkable that a single polypeptide could evoke such a wide variety of biological effects [1,2]. At present, three members of the IL-1 gene family have been identified: IL-1a, IL-1b and IL-1 receptor anatagonist (IL-1Ra)[3]. IL-1a and IL-1b are for the largest part agonists, whereas IL-1Ra serves as a specific Ra [4–6]. The naturally occurring IL-1Ra appears to be a unique feature in cytokine biology. IL-1b is generally considered a systemic, hormonal mediator intended to be released from cells, whereas IL-1a is primarily regarded as a regulator of intracellular events and mediator of local inflammation [4]. Thus, since IL-1b is functionally the most relevant of the three IL-1 gene family members, this chapter will mainly focus on the actions of IL-1b.

2.2. IL-1 gene architecture IL-1a and IL-1b are encoded by two different genes, which are both located on chromosome 2: locus 2q13 for IL-1a and 2q13–q21 for IL-1b [7,8]. The IL-1a and IL-1b genes are 12 and 9.7 kB in length, respectively [9–11]. Both genes display similar organization comprising of seven exons. The gene encoding the IL-1Ra is located in the vicinity of the two IL-1 genes, on 2q14– q21 [12]. IL-1a and IL-1b are both synthesized as 31 kDa precursors without leader sequences [13,14]. Processing of these precursors to the mature forms of 17 kDa

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requires a specific cellular protease; the protease for IL-1b is termed the IL-1b-converting enzyme (ICE) [15,16]. ICE does not cleave the IL-1a precursor [16]. The intracellular precursors of IL-1a and IL-1b do not contain recognizable hydrophobic secretory signal sequences, which is unusual for cytokines [14]. This secretory signal sequence would allow secretion of the protein by classical secretory pathways involving the endoplasmic reticulum (ER)/Golgi system. Instead, both molecules are translated in the cytosol associated with cytoskeletal rather than ER structures. At protein level IL-1a and IL-1b display 27% homology, mainly restricted to the carboxyterminal region [9,13]. The three-dimensional structure of the two IL-1 forms, however, is almost identical [17,18]. Both forms are spherical proteins of all b-sheets and, more importantly, both forms bind to the same receptor [19]. In contrast, IL-1Ra evolved containing a signal peptide and is transported out of the cells by the classical pathways, and subsequently termed soluble IL-1Ra (sIL-Ra) [16].

2.3. IL-1b gene expression Several levels of control of gene expression exist. At each stage between the DNA and the production of a particular protein the gene expression can be regulated. It seems that two mechanisms are most important with regard to cytokine expression. The first important level is gene transcription i.e. the speed by which the DNA is transcribed into a primary RNA transcript. The relative rate by which a given gene is transcribed can be measured by nuclear run-on experiments. The second level of control of cytokine gene expression is post-transcriptional control. The rate by which cytoplasmic degradation of cytokine mRNAs occurs may vary resulting in half-lives of a few minutes to several hours. Actinomycin-D pulse chase experiments are used to determine the half-life of a given mRNA in control and stimulated conditions. Monocytes are the main source of secreted IL-1b, although the cytokine can also be produced by macrophages from different sources as well as peripheral neutrophil granulocytes [20 – 23]. IL-1b transcripts are generally absent in unstimulated cells. The IL-1b regulation is investigated with respect to the large and complex nature of the IL-1b promoter, interference at the level of mRNA splicing processes, phosphorylation of proteins required for translation and the stabilization of the 3%-untranslated region of IL-1b mRNA. The most studied cells are freshly isolated human monocytes and monocytic cell lines derived from myelo-monocytic leukemia cell lines [24 – 41]. The expression of IL-1b can be enhanced by other cytokines and growth factors such as tumor necrosis factor-a (TNF)-a, interferon-g (IFN-g), IL-6, and gran-

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ulocyte-macrophage colony-stimulating factor (GMCSF), but also by IL-1 itself [23,30,31]. Phorbolesters, bacterial endotoxins, viruses, mitogens and antigens are also potent stimulators of IL-1 synthesis [25,26,34–36]. Of the bacterial endotoxins, the activation of monocytes by the bacterial wall breakdown product from gram negative bacteria, lipopolysaccharide (LPS), is most extensively described. Both the phorbolester, phorbol myristate acetate (PMA), and LPS have been shown to exert their activating functions by increasing protein kinase C (PKC) activity [29,34–36]. LPS stimulation of monocytes triggers transient transcription of the IL-1b gene and increases the half-life of IL-1b mRNA, which thus accumulates during the first 4–6 h after which a rapid decrease is observed [30,32]. This decline is thought to be due to the synthesis of a transcriptional repressor and/or a decrease in mRNA half-life [27]. G(Anh)MTetra, a naturally occurring breakdown product of peptidoglycan that is produced by soluble lytic transglycosylase of Escherichia coli, has also been shown to induce IL-1b expression in human monocytes [37]. Steady-state IL-1b mRNA levels were optimal after 2 h of stimulation, and the extent of induction was similar to that observed after LPS treatment and, at least, in part due to up-regulation of the transcription rate of the IL-1b gene. When stimulating with agents which enhance intracellular cAMP levels, such as prostaglandin E2 (PGE2) and histamine, the IL-1b mRNA levels are sustained for over 24 h [32,38]. Similar duration of IL-1b mRNA levels are observed when treating monocytes to IL-1b itself [30,32]. In contrast, LPS-induced IL-1b mRNA is down-regulated by cAMP elevating agents [39]. Recombinant IL-1a (rIL-1a)-stimulated peripheral blood mononuclear cells (PBMC) cultures secrete high levels of IL-1b, which could be inhibited to the level of unstimulated controls by co-incubation with rIL-13 [40]. IL-1b synthesis is also inhibited by lipoproteins, lipids and a2-microglobulin [32a]. Over the past few years much progress has been made with respect to the involvement of protein phosphatases in the signal transduction pathways leading to gene expression [33,43]. Opposite to protein kinases, phosphatases exert their effect by dephosphorylating and thus inactivating proteins. Recently, it was described that the protein serine /threonine (Ser/Thr) phosphatase inhibitor okadaic acid (OA) and the protein tyrosine (Tyr) phosphatase inhibitor diamide elevated IL-1 expression, at least partly by up-regulating the IL-1 gene transcription rate [33,41]. Characteristic for IL-1b, but also for TNF-a, is the observed dissociation between the production of mRNA and the generation of protein [28,29]. Stimulants such as the complement factor C5a, hypoxia, adherence to surfaces or blood clotting induce vigorous IL-1b gene transcription in monocytes and thus large

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amounts of IL-1b mRNA, without significant translation into the IL-1b protein [42]. Thus, some stimuli are not capable of providing a signal which is sufficient to initiate translation, despite the strong transcriptional effect on the IL-1b gene. When the translation process does not take place, the mRNA is rapidly degraded. However, when bacterial endotoxin or IL-1 is added to the cells with high levels of IL-1b mRNA, the translation rate is enhanced [42]. One explanation which could account for the observed translation is an enhanced stabilization of the AU-rich 3%-untranslated region of the transcript, which has been observed after treatment of monocytes with LPS [27]. The AU-rich elements (AREs) in the 3% noncoding region of many short-living mRNAs are shown to be the target of a pathway for mRNA degradation and a AUUUA-specific mRNA binding protein has been identified [39,44 – 46]. Many cytokine transcripts share these AU-rich sequences in their 3% noncoding regions, which might explain the high turnover rate of these mRNAs. After synthesis of the pro-IL-1b molecule, the protein remains primarily cytosolic until it is cleaved by ICE and transported out the cell [30]. In cells of the monocytic lineage activated ICE is required for pro-IL1b to be processed into its mature form and subsequently secreted. Studies into the T-cell signal(s) that mediates the cell contact-dependent induction of IL-1b mRNA by monocytes revealed that CD2 is required for T-cell induction of IL-1b through interaction with LFA-3 on the monocytes [47]. Moreover, the generation of soluble IL-1b is regulated by CD69, since addition of antiCD69 antibody was shown to inhibit the generation of sIL-1b. In line with these findings are studies into the production of IL-1b and IL-1Ra by the monocytic cell line THP-1 upon contact with either T helper 1 cells (Th1) or Th2 type cell clones [48]. It was observed that Th1 clones induced higher levels of IL-1b production by THP-1 cells than did Th2 type cells. In contrast, lower levels of IL-1Ra were observed after stimulation of THP-1 cells with Th1 clones than with Th2 cells. This would suggest that activated Th1 and Th2 cells express different molecules on the cell surface, which enables them to induce distinct pro-inflammatory (IL1b) or anti-inflammatory (IL-1Ra) responses in monocytes. IL-1b again distinguishes itself from other cytokines by the size of its promoter and enhancer regions: studies in which IL-1b promoter constructs were transfected into human monocytic cell lines demonstrated that the IL-1b regulatory sequences can be found distributed over several thousand basepairs (bp) upstream and a few bp downstream from the transcriptional start site [49]. The first described regulatory region is a 187-bp region located between positions −2982 and − 2795, and is designated a PMA-inducible enhancer element

[50]. Potential binding sites for the transcription factors activator protein 1 (AP-1) and positive regulatory domain 1-binding protein are located within this region. After deletion of other enhancer sequences, the positive regulatory effect of AP-1 and positive regulatory domain 1-binding protein appeared not sufficient to elicit inducibility, indicating the existence of other regulatory sequences [51]. Subsequently, a LPS-inducible element was identified, which overlapped the PMA-inducible region and extended further upstream to position −3757 [51]. In this enhancer region binding sites were identified for the C/EBP family member nuclear factor IL-6 (NF-IL6) and two novel factors termed NF-b1 and NF-b2. NF-IL6 and NF-b1 were shown to act as positive regulators after LPS stimulation, whereas NFb2 appeared unaffected by LPS. An 80-bp fragment between − 2782 and − 2729 is shown to be required for transcription in response to LPS. In addition to an NF-kB-like site in this fragment, a CRE (cAMP responsive element)/ATF-like site was identified at position − 2762 to − 2755, which later was demonstrated to be essential for maximal induction of the IL-1b enhancer [52]. The IL-1b cap site proximal promoter (CSP), which stretches from − 131 to +14, also contains several regulatory factor binding elements [51,53,54]. Binding sites are identified for the novel nuclear factors NF-bA (− 49/− 38), NF-bC (−12/ +8) and NF-IL6 ( − 90/− 82 and − 40/− 32). Recently, the nucleotide binding sequences for NF-bA were found to be identical to those of the transcription factor Spi-1/PU.1, a well-established nuclear factor in cells of myeloid and monocytic lineage [55]. Since the proximal NF-IL6 binding site overlaps the NF-bA site by four bp, studies were undertaken to identify the relevance of each of these binding sites [56]. It was thus shown that the NF-bA-binding element, and not the NF-IL6 binding region, is responsible for mediating the transcriptional activation of the IL-1b CSP in response to for example LPS. Finally, a functional NF-kB site was characterized in the − 300 region of the IL-1b promoter [57]. Mutation of this NF-kB site would result in reduced responsiveness of the IL-1b promoter to various inducers, including PMA and IL-1b itself.

2.4. The IL-1 receptor Two types of IL-1 receptors have been identified so far, which are distinct gene products: the type I receptor (IL-1RI) transduces the signal, whereas the type II receptor (IL-1RII) binds IL-1 but does not transduce a signal [58–63]. In fact, IL-1RII has been proposed to be a ‘decoy’ receptor, which again is unique in cytokine biology [60]. In agreement with this hypothesis were studies in which the IL-1RII gene was transfected into cells which only expressed the type I receptor (8387 fibroblasts) [62]. The IL-1RII-transfected cells showed

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defective responsiveness to IL-1 in terms of cytokine gene expression, cytokine production, but also NF-kB activation. Thus, the IL-1RII, which is regulated by anti-inflammatory signals, functions to capture and block IL-1. The IL-1RI gene is mapped on human chromosome 2q12 [64]. The receptor is an 80 kDa monomeric transmembrane glycoprotein, containing three extracellular immunoglobulin-like domains, and therefore is a member of the immunoglobulin superfamily of proteins [65]. The entire protein has a length of 576 amino acids consisting of an extracellular ligand-binding domain and a cytolasmic domain of 213 amino acids. The IL-1RI contains seven N-glycosylation sites. Neither the extracellular domain nor the transmembrane region of 21 amino acids show any relationship to other proteins. The IL-1RI is not only found on monocytes and T and B-cells, but also on, for example, endothelial cells and fibroblasts [59]. Conversely, IL-1RII is a 68 kDa receptor, very similar to IL-1RI in its extracellular domain, but obviously lacking signal transducing capacity [62,64,66]. In cell lines the number of IL-1RI can reach 5000 per cell, although primary cells generally express less than 200 receptors per cell [65]. In fact, IL-1-mediated signal transduction has even been observed in cells expressing less than ten receptors per cell. After binding of IL-1 to IL-1RI, a complex is formed that subsequently binds to the IL-1R accessory protein (IL-1R-AcP), resulting in high affinity binding [67,68]. Signal transduction mediated by the IL-1/IL-1RI/IL1R-AcP complex appears to require the heterodimerization of IL-1RI with IL-1R-AcP. The low number of IL-1RI required for signal transduction and the discrepancy between binding affinities and biological activities is partly explained by the increased binding affinity of IL-1 in the complex with IL-1R-AcP. This is furthermore underscored by the observation that IL1Ra does not form a complex with IL-1RI/IL-1R-AcP, but binds tightly to the IL-1RI without exhibiting any agonist activity. It is thus concluded that the IL-1/IL1RI/IL-1R-AcP complex triggers the cell and that the IL-1 signal via IL-1RI only is weak or non-existent.

2.5. Biochemical pathways of IL-1b action Once released from cells IL-1b encounters two types of antagonistic molecules: the soluble form of the type II receptor which tightly binds IL-1b, and sIL-1Ra which competes with IL-1b for cell surface receptor occupancy. However, once bound to the type I receptor, IL-1b can initiate a whole cascade of signal transduction pathways. One of the signal transduction pathways which is affected by IL-1b involves adenylate cyclase which transiently increases intracellular cAMP levels [69]. A cAMP-dependent protein kinase A (PKA) and a pertussis toxin-sensitive GTP-binding protein of

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46 kDa are also involved. PKC, calcium, phosphatidyl inositol and related metabolites do not appear to be involved in IL-1-mediated signal transduction [70–73]. Transcription factors which have been shown to be induced by IL-1b include NF-kB, AP-1, NF-IL-6 and CREB [74–76a]. An adapter protein, termed TRAF-6 (TNF-receptor associated factor-6), was demonstrated to be required for IL-1-induced activation of NF-kB, and recently, a novel kinase named NIK, which stands for NF-kB-inducing-kinase, was identified [77,78]. Since the expression of NIK mutants inhibited the activation of NF-kB by IL-1b, it is suggested that, next to TRAF-6, NIK is involved in IL-1-mediated NF-kB activation. It is hypothesized that the activation of NIK by the IL-1 receptor is mediated by IRAK, a Ser/Thr kinase that is recruited to the IL-1 receptor after stimulation, and by TRAF-6, which binds IRAK [79]. In a variety of human cell lines, IL-1b was shown to be a potent activator of the stress-activated protein kinases (SAPK) JUN-terminal kinase 1 (JNK1) and p38 kinase, as well as of the extracellular regulated kinases ERK1 and ERK2 [80–89]. These kinases belong to the family of mitogen-activated protein kinases (MAPKs), which over the past few years has become one of the most important signaling cascades identified. Once activated, the two isoforms ERK1 and ERK2 translocate to the nucleus and phosphorylate transcription factors such as p62Tcf and ELK1 [90]. Both c-JUN and ATF-2 are well-known substrates for JNK [91–93]. c-Jun can function as a homodimer or as a heterodimer with a partner protein such as ATF-2. ATF-2 is also phosphorylated and activated by p38, which therefore serves as one of the integration mechanisms between these two pathways [94–96]. In cell lines the ERK pathway is predominantly linked to cellular proliferation and differentiation, whereas JNK and p38 are associated with stress response, inhibition of cell growth and apoptosis [94,97–100]. Also in monocytes and monocytic cell lines IL-1b has been shown to enhance the activity of ERKs, JNK and p38, as was demonstrated by in vitro kinase assays with their respective substrates (MBP, c-JUN, and ATF-2) [100a,100b]. Recently, IL-1b was shown to enhance the activity of a novel SAPK, SAPK-3 [80]. In fact, in the human KB and 293 cell lines IL-1b induced SAPKK3 (also termed MKK6), which is the upstream kinase of both p38 and SAPK-3: p38 and SAPK-3 phosphorylate a number of proteins at similar rate, including ATF-2, Elk-1 and SAP1. However, IL-1-mediated p38 activity appeared more effective in phosphorylating the downstream MAPKAP kinase-2 and MAPKAP kinase-3 than was SAPK-3. Studies with the pyridinyl imidazol SB203580, which is a potent p38 kinase inhibitor, has given us more insight in the physiological roles of p38 in signaling cascades [101]. SB203580 was shown to inhibit p38 in vitro, which subsequently prevented the phosphory-

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lation of the downstream MAPKAP kinase-2 and heat shock protein 27 (hsp27) by IL-1b [102]. The observation that IL-1b and TNF-a induce many similar signal transduction cascades is underscored by the discovery that both cytokines induce the sphingomyelin turnover and produce ceramide in various cell lines of human origin [103 – 105]. Ceramide may act as a second messenger molecule in an intracellular signaling route. Activation of both acid and neutral sphingomyelinases (SMases) has been suggested [106]. Stimulation of a neutral SMase by IL-1b can lead to the stimulation of a protein kinase CAPK (ceramide-activated protein kinase) and eventually to the activation of the MAPK signaling pathway and phospholipase A2. Ceramide is also capable of activating a cytosolic protein phosphatase termed CAPP (ceramide-activated protein phosphatase). Another lipid second messenger found to transmit IL-1b and TNF-a intracellular signals is 1,2-diacylglycerol (DAG), generated by a phosphatidylcholine-specific phospholipase C [87]. DAG is a well-known activator of the PKC system, which thus appears to mediate various cellular responses to IL-1b and TNF-a. PKC plays a role in the activation of the transcription factor AP-1. Although association of IL-1 with the JAK/STAT (Janus kinase/signal transducers and activators of transcription) pathway remained unresolved for the longest time, a recent report described the existence of a novel STAT-factor which could be immediately induced by LPS and by IL-1, and thus was termed LIL-STAT [107]. LIL-STAT targets an element within the human proIL-1b gene, named LILRE (LPS and IL-1 responsive element). Although LIL-STAT has been shown to exhibit transactivational activity, the exact relevance within the control of IL-1b gene transcription remains to be solved.

2.6. In 6itro effects of IL-1 In many reviews the biological actions of IL-1 have been extensively described [4,5,108]. The main biological activity of IL-1b is the stimulation of T helper cells which are induced to secrete IL-2 and to express IL-2 receptors [109,110]. Furthermore, IL-1b can act directly on B-lymphocytes promoting their proliferation and the synthesis of immunoglobulins [111]. As a priming factor IL-1b renders B-cells responsive to the action of IL-5. IL-1 potentates the effects of colony stimulating factors (CSFs) and promotes the generation of myeloid progenitor cells from stem cells [112,113]. Subsequently, IL-1b synergizes with GM-CSF in macrophage colony growth [114]. By enhancing the expression of receptors for various CSFs, IL-1 is involved in various processes of hematopoiesis. IL-1b also induces the proliferation of pluripotent bone marrow progenitor cells as well as the proliferation and activation of NK cells, thymo-

cytes, fibroblasts and glioblastoma cells [114a]. IL-1b can serve as a strong chemoattractant for leukocytes: in vivo injection of IL-1b leads to the local accumulation of neutrophils at the site of injection [115]. Moreover, the cytokine mediates oxidative metabolism in neutrophils. Treatment of monocytes with IL-1b results in the expression of various cytokines such as IL-1b itself, IL-6, TNF-a, and IL-8, presumably by stimulating the activities of transcription factors such as NF-kB and AP-1 [116,117,117a]. IL-1b plays a role in the short-term suppression of apoptosis both in purified CD34 + /Lin − bone marrow precursors and in the GM-CSF dependent cell line TF-1 [118]. The increase in cell survival after the binding of IL-1 to the type I receptor resulted from the subsequent production of endogenous GM-CSF. A mechanism of autocrine growth control by IL-1b has been suggested for certain cases of acute myeloid leukemia (AML) [119–121]. The uncontrolled, constitutive synthesis of IL-1b in leukemic blasts will lead to the production of other colony stimulating factors, which will promote the proliferation of these cells. This so-called autocrine in vitro proliferation has been shown to be correlated with a poor disease prognosis.

2.7. Clinical application of IL-1 The clinical relevance of IL-1b may be ascribed to its actions as a stimulator of T-cells. It may prove useful after massive immunosuppression and/or therapy with cytostatic drugs. Either alone or combined with other CSFs IL-1b may be useful as a stimulator of hematopoiesis, thereby acting directly on primitive hematopoietic cells and inducing the synthesis of CSFs. A number of studies have proposed that IL-1 combined with lineage specific growth factors may produce synergistic hematological effects and that IL-1b may have a protective effect on chemotherapy-induced myelosuppression [122–124,124a,127]. Patients with aplastic anemia show markedly decreased levels of IL-1b production by PBMC [125,128]. Aplastic patients with low IL-1b levels differ by the severity of their disease and the degree of neutropenia. It is hypothesized that the deficiency of this growth factor contributes to the pathogenesis of some cases of apalastic anemia and furthermore renders those cases more susceptible to infection. IL-1b has been shown to act radioprotective in animal experiments [126]. IL-1b enhances the capacity of allogeneic bonemarrow cells to promote survival of mice given radiation doses that are significantly higher than those generally used for bone marrow ablation. Therefore, IL-1 may prove clinically relevant in promoting bone marrow engraftment. The clinical application of IL-1 is hampered by the very high toxicity profiles of this cytokine. Minute

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amounts of IL-1 can induce septic shock. The use of IL-1Ra appears to be more promising than the use of IL-1 itself [120,121,129].

3. Interleukin-3

3.1. History IL-3 was identified by Ihle and coworkers in 1981 [130,131] by its ability to induce the expression of 20-a hydroxysteroid dehydrogenase in cultures of splenic lymphocytes from nude mice. Later it became clear that IL-3 was a highly pleiotropic lymphokine that appeared similar to multi-CSF, mast cell growth factor, P cellstimulating factor, burst-promoting activity, and WEHI-3 growth factor [132]. IL-3 is generally characterized by its well-established growth stimulatory effects on normal multipotent hematopoietic progenitors [133].

3.2. IL-3 gene architecture The human IL-3 gene has been genetically mapped on chromosome 5 [134], and is part of a cluster of growth factor genes consisting of the GM-CSF, IL-4, IL-5, IL-9 and M-CSF receptor (c-fms) genes [135]. The IL-3 gene contains five exons and four introns [136]. Of special interest is its close proximity to the GM-CSF gene, its similarity with the GM-CSF gene structure and the similarity in biological functions in their common target cells [137]. The IL-3 gene product consists of 152 amino acids [136] and has an apparent molecular weight of 15–30 kDa, reflecting heterogeneity in the carbohydrate component. IL-3 contains two potential N-glycosylation sites [136]. It appears to be very difficult to obtain crystals of IL-3 that could be used to solve the tertiary structure by X-ray crystallography and the solubility of IL-3 is not adequate to allow multi-dimensional NMR studies. Therefore, using homology model building attempts are made to determine the tertiary structure of human IL-3 based on the structures of GM-CSF, IL-4 and IL-5 [138].

3.3. IL-3 gene expression Stimulated T-lymphocytes, megakaryocytes, mast cells and natural killer (NK) cells are the only normal cells in which IL-3 is expressed [139,140,140a]. Human T-cells stimulated with the lectin concanavalin A (conA), anti-CD3 plus IL-1, conA plus PMA, phytohemagglutinin (PHA) plus the calcium ionophore ionomycin express IL-3 mRNA and secrete IL-3 protein [139,141–143]. IL-3 expression has been shown in the CD28 + subset of T-cells as well as in CD4 + and CD8 + cells [141,144]. The so-called T-helper cell population (CD4 + ) can differentiate into two subtypes se-

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creting distinct profiles of cytokines, Th1 and Th2, regulating immunoprotection and different immunopathologies. The Th1 cytokines are IFN-g and IL-2, whereas IL-3, IL-4, IL-5, IL-10 and GM-CSF are considered Th2 cytokines [145,146]. Although Tlymphocytes are regarded as one of the few normal cell types capable of expressing IL-3, IL-3 was demonstrated in infiltrating cells in skin biopsies from atopic patients after allergen challenge. Furthermore, eosinophilic and neutrophilic granulocytes from patients suffering from hay fever release IL-3 upon stimulation with PMA or ionomycin [148]. Studies on the mechanisms that control IL-3 expression were mostly performed using cell lines. In the T-lymphocyte cell line Jurkat and in the gibbon Tlymphocyte cell line MLA-144, it was demonstrated that conA plus PMA-induced IL-3 mRNA expression was at least partly explained by an increase in the rate by which the IL-3 gene was transcribed [149]. Later it was demonstrated that PHA and PHA plus PMA-induced IL-3 mRNA expression in Jurkat cells was due to transcriptional and post-transcriptional mechanisms [150]. Similar findings were obtained in the Th2 clone D10.G4.1, where conA stimulation resulted in increased IL-3 mRNA levels, which was controlled at transcriptional level as well as at the level of mRNA stability [151]. A study into the mechanisms that control IL-3 expression in healthy human T-lymphocytes demonstrated that IL-3 mRNA was undetectable in unstimulated T-cells [152]. Upon activation with conA IL-3 mRNA was expressed. Accumulation of IL-3 mRNA levels peaked 3–6 h after stimulation with conA and was due to a small increase in the IL-3 transcription rate and most likely to an increase of IL-3 message stability. Upon activation with conA, the IL-3 transcripts decayed with a half-life of : 90 min. No IL-3 mRNA expression was induced by the PKC activator PMA alone. However, PMA augmented the conA induced IL-3 mRNA accumulation, which was shown to be mediated at post-transcriptional level by a large increase in the stability of IL-3 mRNA (t1/2 \ 3 h) and at transcriptional level by a further increase in the IL-3 transcription rate [152]. The expression of IL-3 in Tcells is strictly controlled by activators and inhibitors. This is reflected by the fact that mediators of the PKA pathway cAMP or PGE2 down-regulate the conA and conA plus PMA-induced IL-3 expression [153]. The inhibitive effect of cAMP was regulated at both transcriptional and post-transcriptional level [153]. Control of stability of mRNA is poorly understood, but likely the process involves factors interacting with mRNA sequences [154]. The AU-rich elements (ARE’s) in the 3% noncoding region of many short-living mRNAs are shown to be the target of a pathway for mRNA degradation and a AUUUA-specific mRNA binding protein has been identified [155]. Many cytokine transcripts

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share these AU-rich sequences in their 3% noncoding regions, which might explain the high turnover rate of these mRNAs. The IL-3 mRNA ARE region contains six AUUUA-motifs: six binding proteins have been proposed to bind to two overlapping AUUUA-motifs [156]. One of these proteins appears to be the 43 kDa AUF-1 protein. In agreement with the hypothesis that ARE contribute to destabilization, it was found that calcium ionophore, which normally stabilizes IL-3 mRNA, abrogated the formation of the protein –ARE complex [156]. IL-3 mRNA expression in human T-cells is also controlled by growth factors. Costimulation with conA plus IL-4 resulted in a small decrease in IL-3 mRNA accumulation compared to the effects of conA alone [152]. The stromal derived growth factor IL-7, however, up-regulated IL-3 and GM-CSF mRNA levels in activated human T-cells, whereas IL-7 alone did not induce IL-3 mRNA [157]. The IL-7-enhanced expression of IL-3 and GM-CSF mRNA in conA-activated human T-cells was mediated by post-transcriptional mechanisms, affirming that control of mRNA stability is a very important mechanism in the regulation of IL-3 mRNA expression [157]. IL-3 protein release is also regulated via activation of the T-cell CD2 receptor, whereas activation of the CD3 receptor does not result in IL-3 protein secretion [158]. Interestingly however, IL-3 mRNA accumulation is more pronounced after CD3 activation than after CD2 activation. This would suggest that up-regulation of IL-3 protein release following T-cell stimulation via CD2 occurs largely at the translational or post-translational level [158]. Since IL-3 is predominantly expressed in activated T-cells, control of its expression was studied as a model for lineage-specific and stimulation-dependent expression. Analysis of the regulatory elements within the promoter that controls IL-3 gene transcription revealed that several cis-acting DNA sequences within 315 bp of the transcription start site modulate T-cell expression of IL-3 [158a]. The first sequence is an activator protein-1 (AP-1) site at −296 bp proximal from the transcription start site. Studies in human cell lines demonstrated that the presence of the AP-1 site is not sufficient for IL-3 transcriptional activation [149,159] but it seems to enhance expression mediated by another activating region called ACT-1 [159] or NF-IL3-A [149]. The ACT-1 or NF-IL3-A site is shown to bind two distinct proteins. Its 5% end binds an inducible T-cell specific factor that shares functional properties with octamer-1-associated protein and over its 3% end it binds a constitutively expressed octamer-binding protein [160]. Between these two activator regions lies a strong repressor element termed nuclear inhibitory protein (NIP), which is mapped between nucleotides − 271 and− 250. Functional characterization of this element demonstrated

that three distinct complexes interacted with the NIP region, although only one of these complexes correlated with specific repressor activity [161–163]. A study in primary human T-lymphocytes, where physiologic stimulants such as monoclonal antibodies to CD3 and CD2 were used, revealed that indeed AP-1 and octamerbinding proteins are important in the transcriptional activation of the IL-3 gene [164]. A sequence of 49 bp was identified that confers T-cell-restricted expression of IL-3 [162,165]. The fragment contained an Ets family binding site that was found six bp 3% of the AP-1 motif and the AP-1 site itself. The AP-1 and Elf-1 sites in the IL-3 gene can bind their respective protein complexes independently [165]. Characterization of transcriptional regulation of IL-3 in megakaryocytes revealed that IL-3 expression was similar but not identical to normal human T-cells [140a]. Transfections of IL-3 promoter CAT constructs into the human CMK and CMK-6 megakaryocytic cell lines demonstrated two positiveacting transcriptional regulatory regions, one located between bp − 315 and − 284, which contains the consensus AP-1 and ets binding sites, and a second located between bp −173 and − 61 [140a].

3.4. The IL-3 receptor The divergent activities of IL-3 on hematopoietic cells are mediated through binding of IL-3 to the IL-3 receptor (IL-3R). The expression of IL-3R is highly restricted but is not limited to hematopoietic lineages and stages of differentiation that proliferate in respond to IL-3 [166,166a]. The IL-3R is expressed in various lineages with myeloid markers such as CD13+, CD14+, CD15 + , or CD33 + as well as early progenitors with CD34 + . Cells with the T-cell marker CD3 do not express the IL-3R [167]. The high affinity IL-3R is a heterodimer that comprises an IL-3 specific a-chain (ac) and a common b-chain (bc) subunit that is shared with the GM-CSF and IL-5 receptor [168,169]. Common subunits have been identified in various receptor systems, including the bc subunit of the receptors for IL-3, IL-5 and GM-CSF [170,171], the gp130 subunit for the IL-6, IL-11 and LIF receptors [172], and the IL-2 receptor g (IL-2Rg) subunit: the IL-2 common gc is shared by IL-2, IL-4, IL-7, IL-9 and IL-15 [173]. The binding between IL-3 and the IL-3R is one of high affinity, with a dissociation constant of :100 pmol/l. The IL-3Ra as well as the bc subunit are members of the recently described superfamily of cytokine receptors which includes the receptors for IL-2 [174], IL-3 [175], IL-4 [176], IL-5 [177], IL-6 [178], IL-7 [179], IL-9 [180], prolactin [181,182], growth hormone [183], erythropoietin (Epo) [184], GM-CSF [185,186], granulocyte (G)-CSF [187], the gp130 subunit of the IL-6 receptor [188] and the v-mpl oncogene [189]. They share conservation of a four cysteine motif in the

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N-terminal half and a Trp-Ser-X-Trp-Ser motif in the C-terminal half [190]. A very interesting phenomenon known as cross-competition has been reported for the human IL-3, GMCSF and IL-5 receptors. High affinity GM-CSF binding is competed by IL-3 and vice versa [191 –198]. Furthermore, IL-5 binding to its receptor is also competed for by either IL-3 or GM-CSF [194,198]. An explanation for cross-competition was found through the results of a very elegant set of experiments. NIH3T3 cells were stably transfected with cDNAs for GMCSFRa, IL-3Ra and bc subunit. No cross-competition was observed when the expression level of bc exceeded those of the a subunits. Furthermore, the extent of cross-competition varied depending on the expression levels of the subunits [168]. These results indicated that the cross-competition of binding between GM-CSF and IL-3 is caused by the competition for a limiting number of bc by different a subunits. The use of a common b subunit for the IL-3, IL-5 and GM-CSF receptors might explain the similarity in biological functions on their common target cells. Furthermore, the sharing of common subunits might serve as a partial explanation for redundancy, which is characteristic for all cytokines. Binding of IL-3 to IL-3Ra leads to heterodimerization of the a and b subunit which in turn initiates a series of intracellular signaling events [199]. Disulfide linkage of these chains is involved in receptor activation [200]. Data on the exact functional role of the IL-3Ra and bc are still contradictory and under investigation. Experiments in which cell lines were transfected with IL-3Ra and bc subunits and deleted forms of these subunits, suggested that both the IL-3Ra and bc subunits are essential for signal transduction [201]. Deletion of the cytoplasmic region of the IL-3Ra subunit did not affect binding of IL-3 but totally blocked the ability of the receptor to transduce a signal. Other studies indicated that the N-terminal domain is indeed of significant relevance for the binding of IL-3, whereas the bc is the signal transducing subunit [170,202]. Since the receptors for IL-3, IL-5 and GM-CSF share a common bc subunit it is believed that the a subunit is responsible for the induction of cytokine specific signals [201]. Two cytoplasmic regions within the common b subunit have been identified: these include a membraneproximal region that is required for mitogenesis induced by IL-3, IL-5 and GM-CSF, and a membrane-distal region, that is required for the activation of Ras, Raf-1, MAPK and S6-kinase. These proteins are part of a specific signal transduction route which is activated by these cytokines. [201,203]. In fact, one single Tyr residue (Tyr 421) in the bc was shown to be critical for high affinity binding of IL-3, IL-5 and GM-CSF. Furthermore, alanine substitution of the Tyr 421 residue severely impaired the ability of bc to signal, thus suggesting both binding and transducing properties for the bc [170].

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3.5. Biochemical pathways of IL-3 action IL-3R are especially expressed on cells with myeloid markers [167]. Initially it was proposed that IL-3 signals were mediated by activating the PKC dependent pathway [204–207]. Additional evidence has been obtained that shows that upstream proteins such as Tyr phosphorylated proteins play the most important role in IL-3 signal transduction [208]. Two distinct signaling pathways have been described so far: the JAK/STAT pathway and the Ras-mediated signaling pathway. Recently, JAK2 kinase was found to be one of the Tyr kinases activated by IL-3 in target cells [209–213]. Upon activation JAK2 is physically associated with the common b subunit [214]. JAK2 belongs to a family of kinases that act upstream of transcription factors called STATs. STATs exist in the cytoplasm as latent transcriptionally inactive forms until, in response to extracellular signals, they become phosphorylated on Tyr residues. Upon phosphorylation STATs dimerize and translocate to the nucleus where they bind to specific DNA elements. Various studies have shown that the IL-3 family of ligands is able to activate multiple forms of STAT1a and STAT5 [170,213,215]. In addition to JAK2 Tyr kinase, SRC-related kinases have been shown to play a role in IL-3 induced signal transduction. In the myeloid cell line 32Dcl3 it was demonstrated that three SRC-related Tyr kinases were activated following IL-3 stimulation, namely fyn, hck and lyn [209]. In human eosinophils the intracellular kinases lyn and syk are phosphorylated in response to IL-3. Lyn was demonstrated to be proximal of Syk in the Tyr kinase cascade, and both kinases are essential for the activation of the anti-apoptotic pathway by IL-3 in eosinophils [216]. Stimulation of hematopoietic cells with IL-3 triggers Ras activation, which is subsequently followed by the activation of Raf and ERK/MAPK [217–220,220a]. Activation of the so-called MAPK pathway ultimately results in transcriptional activation of a serum response element-containing promoter, for example the c-fos promoter, through the phosphorylation of the transcription facor Elk-1[90,221]. The MAPK signaling pathway is implicated in growth promoting or differentiating events [94,97–100,218]. Recently, it was demonstrated that IL-3 also activates JNK1 in IL-3 dependent hemopoietic cell lines [222]. The JNK/SAPK pathway was previously thought only to be stimulated by various kinds of stresses [223]. Another member of the SAPK family, p38 kinase is also phosphorylated in response to IL-3. The activation of p38 subsequently led to the activation of the downstream MAPKAP kinase-2. Both JNK and p38 kinase are presumed to play an important role in stress responses and apoptosis [97–100].

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Many other Tyr phosphorylated proteins have been described in IL-3-stimulated human cells. The ones that are identified include, among others, the b-subunit itself [224–226], Vav [227], Fps [228], Raf [229,230], Fes[231], Trc[232] and Shc [233,234]. Phosphorylation of these proteins occurs very rapidly between 30 sec and 5 – 15 min and it is thought to act as a signaling cascade. The signaling cascade ultimately leads to the induction of the early response genes c-fos, c-jun, c-myc and early growth response gene-1 (egr-1) [208,221,234– 236].

3.6. In 6itro effects of IL-3 IL-3 exerts its action predominantly on monocytes. Monocytes exposed to IL-3 in vitro secrete different cytokines such as M-CSF and TNF [237,238]. Data concerning the release of IL-6 after IL-3 exposure are conflicting. Several groups have reported that, although in vivo application of IL-3 is associated with the release of IL-6 [239,240], in vitro stimulated human monocytes with IL-3 did not express IL-6 mRNA [241,242]. Other reports have described an enhanced IL-6 expression in IL-3 stimulated monocytes [240,243,244]. The observed difference in IL-3 effects might be related to the state of activation of monocytes resulting from the isolation procedure. IL-3 has also been shown to prime monocytes in enhancing IL-6 mRNA expression when costimulated with LPS [241]. The effects of IL-3 on cytokine expression in monocytes are mediated by the transcription factors AP-1, NF-kB and NF-IL6. NF-kB has been proven especially to be important in the transcription of various cytokine genes [241,245]. In in vitro experiments IL-3 has also been shown to prevent apoptosis of hematopoietic cells [246]. It has been suggested that the IL-3-induced proliferation of hematopoietic cells and the maintenance of viability by IL-3 are initiated through separate signal transduction pathways [246,247]. Upon withdrawal of IL-3 from the human factor-dependent erythroleukemic cell line TF-1, bcl-2 mRNA and protein levels decreased [248]. It is speculated that IL-3 inhibits apoptosis by activating the Ras pathway and thus the expression of the bcl-2 protein [248,249]. IL-3 stimulates in vitro blast cell proliferation in a consistent portion of acute myeloid leukemia cases [250].

3.7. Clinical application of IL-3 3.7.1. In 6i6o effects of IL-3 Phase I/II studies in patients with normal pre-existent bone marrow demonstrated that IL-3 induced a multilineage stimulation of the hematopoiesis in agreement with results obtained with in vitro culture assays. Treatment with IL-3 at dose levels of 0.25 – 10 mg/kg for 7

days showed a moderate effect on the neutrophil and monocyte count whereas the effects on the number of circulating eosinophils and basophils were more pronounced [251]. No effects were observed on the platelet count during this period of observation. Examination of the bone marrow cells demonstrated that IL-3 significantly affected the proliferative status of different progenitor cells. The number of cells in S-phase for the myeloid, erythroid and megakaryocytic lineage demonstrated a marked increase. Megakaryocytic progenitors especially showed a 3-fold increase of cells in S-phase at a dose level of 10 mg/kg. These changes were not associated with an increase in the number of CD34 + cells in the bone marrow. In addition the IL-3 treatment made the bone marrow cells more vulnerable to the effects of additional growth factors. The in vivo exposed bone marrow demonstrated a significant increase in the number of myeloid colonies when the cells were subsequently cultured with G-CSF in vitro. In contrast, this in vitro enhancing effect was not shown in the presence of GM-CSF. Longer treatment of patients with IL-3 demonstrated a different pattern [252,253]. A marked increment in neutrophils, monocytes, eosinophils and basophils was observed in patients treated for 14 days. These changes were associated with a 1.5–2-fold increase in the platelet counts indicating that a long exposure to IL-3 is required for an optimal stimulation of the hematopoietic system.

3.7.2. IL-3 in standard chemotherapy Clinical studies in patients treated with standard chemotherapy for ovarian or small lung cancer showed that the effects of IL-3 were less pronounced in the case in which the growth factor was applied after the chemotherapy course [254,255]. However, an accelerated recovery of the granulocyte and platelet count was still noticed at a dose level of 5–10 mg/kg subcutaneously compared to the previously control cycle. These findings suggest that the application of IL-3 may lead to a better adherence to chemotherapy or finally to dose intensification which is a matter of study in different phase III trials. The dose applied to patients varies between 5–10 mg/kg. Higher doses result in a considerable toxicity including fever, rash, flushing, fluid retention and severe headache. These side effects may be related to the release of cytokines such as IL-6, IL-8, M-CSF and TNF as has been observed in vitro [254– 256]. In addition increased levels of leukotrienes have been observed during the administration of IL-3 which may also be a contributive factor [257]. Finally the side effects of IL-3 may be allied to the modulating effects on other cell types. Recently high affinity IL-3 receptors have been demonstrated on endothelial cells [258]. The IL-3 receptors were up-regulated by exposure to TNF and resulted in augmented cytokine release by the combined treatment of IL-3 plus TNF. In view of these

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data it is conceivable that IL-3 modulates additional endothelial cell functions like transmembrane permeability which may be an important factor for the degree of fluid retention. Several phase I/II studies have been conducted to test whether the sequential or combined administration of IL-3 and GM-CSF or IL-3 and G-CSF will further accelerate the recovery of peripheral blood counts after standard chemotherapy. These studies are based on the observation that IL-3 primes the bone marrow cells for the proliferative and differentiative effects of G-CSF and GM-CSF. In a study with patients with non-Hodgkin lymphoma the most optimal combination appeared to be the combined administration of IL-3 and GM-CSF (7.5 and 3 mg/kg, respectively) [259]. Additional studies will follow for defining the most optimal combination of cytokines application.

3.7.3. IL-3 in autologous bone marrow transplantation The most serious complications during autologous bone marrow transplantation (ABMT) relate to the occurrence of a persisting granulocytopenia and thrombocytopenia. Previous studies with G-CSF and GM-CSF have shown that the application of these growth factors can partially circumvent these problems [260]. G-CSF and GM-CSF accelerate the recovery of the myeloid lineage without affecting the erythroid and megakaryocytic lineage. In view of the broader spectrum of activity of IL-3 in vitro as well as in vivo, much attention has been focused on the speed of platelet recovery. However, no significant effect has been shown on the platelet recovery in the limited number of patients treated so far. In contrast, the recovery of the myeloid lineage was enhanced and comparable to data obtained with GM-CSF after ABMT. An important drawback of IL-3 is the high incidence of side effects at a relative low dose. A recent study recommended a dose of 2 mg/kg for further phase III trials in view of the frequency of side effects at higher doses [261]. However, these results are in contrast with another phase I/II in ABMT where a dose of 7.5 mg/kg IL-3 could be given [262]. The difference may be ascribed to the way of IL-3 application. In the first study IL-3 was applied intravenously during a period of 2 h while in the second study IL-3 was given as a continuously i.v. infusion. The combined treatment of IL-3 and G-CSF has also been applied in ABMT [263]. No advantage was observed with the combined treatment with regard to the recovery of different cell lineages. A disadvantage was the increased toxicity observed with the combined application of these agents and a slower recovery of the platelets compared to the historical control group.

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3.7.4. IL-3 for peripheral stem cell mobilization Studies in patients treated with IL-3 without chemotherapy have shown an elevated number of CD34 + cells and CFU-GM in the peripheral blood during the application of the growth factor [264]. These results indicate that IL-3, similar to G-CSF and GMCSF, has the capacity to mobilize stem cells from bone marrow to peripheral blood. Based on these results several studies have been conducted with IL-3 in combination with GM-CSF after chemotherapy for peripheral stem cell mobilization. No consistent results have emerged. In a study by Brugger et al. an advantage is observed with the sequential administration of IL-3 and GM-CSF compared to the results of GM-CSF alone [265]. However, in additional studies no marked differences are noticed between the stem cell mobilizing effect of GM-CSF versus IL-3 plus GM-CSF [266,267]. The discrepancy may be related to the dose that was used, sequential versus combined treatment, and the applied chemotherapy. 3.7.5. IL-3 in AML and myelodysplasia IL-3 has also the potential to stimulate the proliferation of myeloid leukemic cells in vitro and in vivo [250,268]. This promotive effect of IL-3 gives the opportunity to increase the number of cells in S-phase and subsequently make the cells more vulnerable to the cytotoxic effects of cell-phase specific drugs. In addition the effects of topoisomerase inhibitors like VP-16 may be more pronounced due to an up-regulation of DNA topoisomerase II. Phase I/II studies have demonstrated that doses up to 7.5 mg/kg can be applied to patients with AML during and after the chemotherapy course without the occurrence of severe side effects [269,270]. In addition the application of IL-3 did not result in regrowth of AML blasts during the regeneration phase. These results warrant further investigations focused on whether the application of IL-3 can improve the survival of AML patients in combination with intensive chemotherapy and accelerate the recovery of the different hematopoietic cell lineages after chemotherapy. IL-3 has also been applied to patients with myelodysplasia [268,271], characterized by a low blast count in the bone marrow. These studies have shown that IL-3 stimulates the myeloid lineage, especially eosinophils and neutrophils, without profound effects on the erythroid and megakaryocytic lineage. However, an increase in the platelet count was observed in the minority of patients during longer application of IL-3 which results in platelet transfusion independency. Combination studies have also been performed with IL-3 and Epo. No advantage was observed with the combination of Epo plus IL-3 versus Epo alone suggesting that IL-3 has a limited place in the treatment of this disorder.

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4. Interleukin-4

4.1. History The cytokine presently known as IL-4 was identified in 1982 by its ability to stimulate the proliferation of murine B-cells in the presence of an anti-IgM antibody and therefore was called BCGF (B-cell growth factor) [272]. Then, in 1984, BCGF was found to act on resting B-cells to induce Class II MHC molecule expression and its name was changed into B-cell stimulatory factor-1 (BSF-1) [273,274]. In 1986, when the BSF-1 gene sequence had become available, its high identity with the murine IL-4 gene became apparent and the name BSF-1 was changed into human IL-4 [275 – 277].

4.2. IL-4 gene architecture The gene encoding human IL-4 spans : 10 kB and is located on chromosome 5 at position q23 – 31 [278,279]. Like IL-3, the human IL-4 gene is part of the cluster on chromosome 5 that contains many cytokine genes [135]. The gene contains four exons and three introns [278]. The mature human IL-4 gene product consists of 129 amino acids and has a molecular weight (MW) of 15.4 kDa. IL-4 contains six cysteine residues whose spatial distribution allows formation of three disulfide bridges [280,281]. The three dimensional structure of IL-4 protein has been resolved in solution by multidimensional heteronuclear magnetic resonance spectroscopy [282 – 284] and in crystallized form [285]. A four-helix-bundle structure with an up-up-down-down connectivity has been established. Between the two long loops that connect helices A/B and C/D a short b-sheet occurs [282 – 285]. Two distinct functional sites of IL-4 were identified that are necessary for IL-4 receptor-binding [286]. One of these sites has been used to generate an IL-4 antagonist by replacing a Tyr with aspartic acid at residue 124 [287]. Despite little sequence identity, the overall topology of the IL-4 protein appeared remarkably similar to that of growth hormone and GM-CSF suggesting converged evolution.

4.3. IL-4 gene expression Activated T-cells have been considered as the principal producers of IL-4 [288 – 290]. The frequency of T-cells that do express IL-4 mRNA, was determined by in situ hybridization [291] and later by a bioassay capable of detecting IL-4 production by a single cell [292] and was estimated to be less than 1% of the total population studied. In human cells, production of IL-4 seemed to be restricted to the CD4 + CD45RO + (memory) subset, whereas both naive (CD4 + CD45RA + ) and memory T-cells were found to produce IL-2 [293–

297]. Cloned CD4 + T-cells can be separated in two subsets, producing either IFN-g or IL-4 (Th1 and Th2 subsets, respectively) [146]. To answer the question whether cells that express IL-4 emerge from cells that express IFN-g or vice versa, transgenic mice were constructed in which cells that express or have expressed the IL-4 gene could be selectively eliminated. It was shown that ablation of cells that express, or have expressed, the IL-4 gene leads to suppression of both IL-4 and IFN-g production. These data suggest that cells that produce either IL-4 or IFN-g have a common precursor, which expresses the IL-4 gene [298]. Although T-cells are regarded as the most important producers of IL-4, it was demonstrated that IL-4 production is not restricted to these cells only. Mast cells and basophils, crosslinked to FcoR or FcgR, also produce IL-4 [299–303]. The mechanisms by which the IL-4 gene expression in T-lymphocytes is regulated, are not fully explored. In resting T-cells, the IL-4 gene is constitutively transcribed [152]. Surprisingly, IL-4 mRNA could not be detected in resting T-cells nor could IL-4 protein be measured in supernatant of resting cells indicating that IL-4 transcripts are highly unstable in resting T-cells [152]. Activation with conA, or with conA plus the PKC activator PMA, increased the transcription rate of the IL-4 gene and the stability of IL-4 transcripts. Like IL-3, IL-4 expression is controlled at both transcriptional and post-transcriptional level. Measurements of IL-4 mRNA half-life revealed that the IL-4 transcript is relatively short living [152]. Upon conA treatment, IL-4 mRNA decayed with a half-life of 90 min, whereas the message was stabilized upon conA plus PMA treatment with a half-life exceeding 3 h. Interestingly, IL-4 mRNA expression was downregulated by the addition of exogenous IL-4, indicating that expression of the IL-4 gene is controlled by its own product. IL-4 mRNA expression is also negatively regulated by the PKA-dependent signaling pathway. Both dbc-AMP and PGE2 inhibit conA- and anti-CD3/anti-CD28-induced accumulation of IL-4 mRNA [304]. The inhibitory effect of dbc-AMP and PGE2 were accomplished at transcriptional level in conA-activated T-cells, whereas changes at both transcriptional and post-transcriptional level were involved in anti-CD3/anti-CD28-activated Tlymphocytes. PMA plus A23187-induced IL-4 mRNA but, however, was insensitive to the inhibitory effect of the PKA-dependent signaling pathway, indicating that different signaling pathways contribute to IL-4 gene regulation in T-lymphocytes [304]. Similar to IL-3, an up-regulation of IL-4 mRNA was noticed when activated T-cells were costimulated with IL-7 [305]. In accordance to mRNA studies unstimulated T-cells do not secrete IL-4 protein [293,294,306]. Upon stimulation with conA or anti-CD3 plus anti-CD28, IL-4 protein secretion is noticed after 12 h of stimulation

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[294,306]. Further augmentation of the IL-4 protein secretion can be obtained when the combination of conA plus PMA is used [294]. In contrast, T-cells stimulated with a combination of anti-CD3, anti-CD28 and PMA demonstrated a reduced protein secretion compared to the effects of anti-CD3 plus anti-CD28 [306], indicating that different pathways regulate the secretion of IL-4 protein in human T-cells. Induction of the IL-4 gene is most likely mediated through the synthesis of transcription factors since the protein synthesis inhibitor cycloheximide blocked the conA induced IL-4 mRNA expression in human Tcells. A distance of :300 bp upstream from the cap site of the human IL-4 gene, two protein binding sites (NRE-I and NRE-II) were mapped that were identified as novel T-cell specific negative regulatory elements [307]. In the vicinity of these NREs (at 239 bp from the start site), a positive regulatory element called PRE-1 was found, whose enhancer activity was completely suppressed when the NRE was present. Suppression of the PRE-1 by the NREs was independent on the location of the NREs [308]. Two proteins were identified (POS-1 and POS-2) that bind the PRE-1 sequence [308]. However, activation of the PRE-1 by POS-1 and POS-2 was not only restricted to T-cells. Thus PRE-1 does not represent the sequence that confers cell-specific inducibility of the IL-4 gene. Further upstream, : 75 bp from the cap-site, a DNA segment (P-sequence) was identified that confers responsiveness to antigen stimulation signals on the human IL-4 gene in Jurkat cells [309]. The P-sequence is apparently unique to the IL-4 gene and was conserved between human and mouse genes.

4.4. The IL-4 receptor The divergent activities of IL-4 on hematopoietic and non-hematopoietic cells are mediated through binding of IL-4 to a high-affinity IL-4 receptor (IL-4R). A cDNA encoding the IL-4R has been isolated and characterized [310]. Like the IL-3R, the IL-4R is a member of the recently described superfamily of cytokine receptors [176]. Receptor studies with 125I-labeled IL-4 on resting lymphocytes initially identified a trimolecular complex consisting of a 65/70 kDa doublet and a 120 kDa protein with : 300 high-affinity binding sites [311 –314]. More recently, it has been demonstrated that the polypeptide chain with MW :70 000 (p70) is a breakdown product of p120 [315]. For some years now, it was speculated that IL-4 signaling was mediated by homodimerization of the IL-4R because only a single chain of the IL-4R was found [316]. In contrast, it was recognized that receptors for IL-3, IL-5, GM-CSF share a common b subunit [168,169] and IL-6, leukemia inhibitory factor (LIF), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF) share a common subunit called gp-130

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[317]. It is now common knowledge that the IL-4R forms a complex with a gc subunit called the IL-2Rgc [318,319]. The IL-2Rgc is a common component of several members of the cytokine receptor superfamily, including those for IL-2, IL-4, IL-7, IL-9 and IL-15, and has been named gc [318–321]. The IL-4R chain binds IL-4 with high affinity (Kd : 100 pmol/l) [310– 314]. The presence of gc increased the binding affinity for IL-4 : 2.5–3-fold [319]. Furthermore, both IL-4 and IL-13 induce Tyr phosphorylation of the IL-4R chain, indicating that this is a component of both receptors and accounts for the similarities in signaling pathways shared by IL-4 and IL-13 [322–324]. IL-4 is known to regulate the expression of its own receptor on human T-cells [325–337] and B-cells [328]. Interestingly, it was recently demonstrated that the promoter of the IL-4 receptor gene contains a specific DNA-binding site for the IL-4-inducible factor STAT6 [329]. In addition, STAT6 mutants were shown to be defective in stimulating IL-4-induced transcription from the heterologous reporter gene construct containing the IL-4R STAT6 binding site [329]. In T-cells binding of IL-4 to its receptor causes a transient downregulation of the IL-4R within 1 h. Longer exposure to IL-4 induces an up-regulation of IL-4R mRNA expression in T-cells [147]. The increased expression at mRNA level in human T-cells was due to a 4-fold increase in the IL-4R transcription rate and to stabilization of the IL-4R transcripts from a half-life of 35–40 min in resting T-cells to 140–160 min in IL-4 stimulated Tcells [327]. In B-cells it has been shown that the IL-4-induced up-regulation of IL-4R is intimately associated with the isotype switching to IgE [328]. Interestingly, IL-4 does not affect IL-4R mRNA expression on human monocytes, which underscores the different intracellular signal transduction mechanisms that are induced by IL-4 in different cell types [330,331]. IL-4R are expressed on many hematopoietic and non-hematopoietic cells. At least in some cell types, the gc of the IL-4R complex is essential for some of the signals initiated by IL-4 [319]. This was demonstrated in cells that express the IL-4R but lack gc. Tyr phosphorylation of the insulin receptor substrate-1 (IRS-1), a protein that is phosphorylated in response to IL-4 or insulin [332], did not occur in these cells unless they were transfected with gc [319]. In various other cell lines, on the other hand, it was shown that the gc was dispensable for signaling via the IL-4R [331,333]. The cytosolic domain of the IL-4R is also critical for at least some of the signal transduction. A truncated form of the IL-4R that lacked the cytosolic domain was overexpressed in an IL-2-dependent T-cell line and was shown to be able to bind IL-4 with high affinity, but was unable to transduce a signal [310]. The critical region in the cytoplasmic region of the IL-4R that transduces the signal was located between amino acid residues 433–

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473 [334]. This region showed no homolgy with other cytokine receptors. In mouse Ba/F3 cells it appeared that the region between T462 and S476 of the IL-4R were required for IL-4-mediated cell growth [335]. The sequences C-terminal of S476 were not essential for growth stimulation in this cell line. Mutational analysis of the IL-4R chain in TF-1 cell line showed that a membrane-proximal cytoplasmic region was critical for JAK3 activation, which is compatible with a role of JAK3 upstream of the recruitment of the IRS-1/4PS signaling proteins by IL-4 receptors [336].

4.5. Biochemical pathways of IL-4 action Studies concerning the intracellular signaling pathway that is induced by binding of IL-4 to its receptor were performed in different cell systems. Experiments with the PKC inhibitor staurosporine and measurements of intracellular calcium revealed that IL-4 mediated up-regulation of IL-4R expression in T-cells was not through activation of PKC or increased calcium concentrations in human T-cells [327]. In contrast, in human monocytes the binding of IL-4 to its receptor is associated with a redistribution of PKC activity from the cytosol to the nuclear fraction [337]. The lipoxygenase directed pathway of arachidonic acid metabolism is also involved. The inhibitive effects of IL-4 on LPSand calcium ionophore A23187-induced c-fos mRNA expression in monocytes could be imitated by a lipoxygenase inhibitor. The effect of IL-4 however, was shown to lie behind the conversion of arachidonic acid to the metabolites 5%-HPETE and leukotrien B4 (LTB4) [338]. For human B-cells, it was reported that IL-4 activates through a transient increase in calcium and inositol 1,4,5-triphosphate and through a delayed raise in cAMP levels [339,340]. Earlier, it was demonstrated that in a human B-cell line — Burkitt lymphoma Jijoye —IL-4 increased the low affinity IgE receptor without affecting cAMP levels [341]. In endothelial cells, IL-4 increased adhesiveness for lymphocytes by a cAMP-dependent pathway [342]. More recently two distinct signaling pathways, diverging at the IL-4R complex, were identified in both T-lymphocytes and monocytes. One of these two pathways concerns phosphorylation of IRS-1 and IRS-1-related molecule 4PS [323,343,344]. IRS-1 mediates the activation of a variety of signaling routes by serving as a docking protein for signaling molecules with SH2 domains. Binding of IL-4 to its receptor can direct mitogenesis via the IRS-signaling proteins. The IL-4-induced proliferation of the myeloid progenitor cell line 32D is dependent on the Tyr phosphorylation of 4PS and mutation Y497 of the IL-4R results in the inability of 32D cells to proliferate in response to IL-4 [345– 347].

In the second signaling pathway, JAK3 and, to a lesser extent, JAK1 are Tyr phosphorylated upon activation by IL-4, but also by IL-2, IL-7, and IL-9 [348,349,352]. Phosphorylation of JAK3 leads to activation of the transcription factor STAT6, initially named IL-4 NAF: activated and dimerized STAT6 translocates to the nucleus where it can direct specific gene expression. STAT6 recognizes a target sequence that is found in the promoter regions of many IL-4 responsive genes. [350]. The target site is similar to a DNA sequence, the IFN-g-activated site (GAS), that is recognized by an IFN-g-activated factor (GAF) [350]. Independently, it was shown that IL-4 mediates activation of Io and Fco genes in monocytic U937 cells through induction of binding to a IL-4 responsive element with a consensus sequence similar as described for STAT6 [351].These data indicate that the yet unidentified biochemical pathways by which extracellular binding of IL-4 to its receptor lead to biological responses, might be cell specific. Until now, IL-4 has been shown not to activate the family of MAP kinases [353–355]. In the L-6 myeloblast cell line IL-4 failed to activate p21Ras, ERKs or SAP kinases [344].

4.6. In 6itro effects of IL-4 4.6.1. IL-4 effect on myeloid and erythroid progenitors IL-4 by itself does not stimulate or inhibit the proliferation or differentiation of myeloid progenitors in vitro [356–360]. A different pattern is noticed when IL-4 is combined with additional hematopoietic growth factors. The G-CSF induced granulocytic colony formation is augmented by IL-4, whereas the IL-3 or GM-CSF supported CFU-GM is suppressed [356,359– 361]. These effects of IL-4 in the presence of additional CSFs seem to be a direct effect on the myeloid progenitor cell since experiments with sorted cells showed a similar response pattern [359–361]. Evidence has been obtained that the suppressive effect of IL-4 on the myeloid colony formation in the presence of IL-3 or GM-CSF is restricted to the monocytic colony formation, since IL-4 did not affect the colony formation of the granulocytic or eosinofilic lineage in the presence of IL-3 or GM-CSF. The selective inhibition of the monocytic lineage may be due to an IL-4 mediated reduced release of IL-6 in the culture medium. This is underscored by the finding that the addition of exogenous IL-6 to the culture medium partially restored the monocytic colony formation. The modulating effect of IL-4 also includes the erythroid lineage [362]. Erythroid colony formation supported by Epo is not affected, whereas in the presence of Epo plus IL-3 or GM-CSF, IL-4 inhibited the day 14 erythroid colony formation. These data suggest that IL-4 influences an immature erythroid progenitor cell which is supported by Epo plus IL-3 or GM-CSF. Alternatively, IL-4 interferes

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with the IL-3 receptor expression or the activation pathway originating from binding of IL-3 to its receptor. Finally, it has been shown that IL-4 inhibited pure and mixed megakaryocyte colony formation in a dose dependent manner. The effect seemed to be a direct effect on the CD34 + , HLA-DR + cell population since antibodies against INF or transforming growth factor did not abrogate the inhibitive effect.

4.6.2. IL-4 effect on the myeloid leukemic progenitor cell The effects of IL-4 on the leukemic counterpart differ from the effects on the normal myeloid progenitors. In some cases IL-4 alone supported the acute myeloid leukemic colony forming unit (AML-CFU), whereas in other cases the constitutive colony formation was inhibited by IL-4 [360,363 – 366]. In growth factor supported AML colony formation, IL-4 demonstrated both stimulatory and inhibitory effects [367].This variability in responsiveness is not unique for IL-4 but has also been observed for IL-3, GMCSF, G-CSF [368–370] and could not be ascribed to a lack of IL-4 receptors or a defect in IL-4 receptor regulation on AML cells [371]. Receptor studies with radiolabeled IL-4 have shown that receptor numbers and binding affinities are similar for AML cells and normal monocytes. Several studies have also shown that IL-4 can suppress the IL-1 or IL-3 supported AML-CFU [36,363 – 366,372]. This inhibitive effect could not be ascribed to ongoing differentiation but seemed to be related to a reduced release of either constitutive or IL-1-induced GM-CSF, TNF, IL-1 or IL-6 protein by AML cells due to IL-4 treatment [372]. This would consequently result in a diminished growth/proliferative signal. Although IL-4 overall inhibits cytokine gene expression in AML blasts, the mechanisms by which IL-4 inhibits IL-1 or IL-6 expression in AML cases is variable. In some cases IL-4 merely downregulates the transcription rate of cytokine genes, whereas in other cases the mRNA stability is affected by IL-4 [373]. The cause of the variability in effects of IL-4 on the AML-CFU have not been elucidated but it is conceivable that the maturity of AML-CFU is of importance. This conception is supported by findings in the normal counterpart in which IL-4 enhances the effects of G-CSF on the immature CFU-G [360]. In contrast, IL-4 suppresses the secretion of G-CSF from mature activated monocytes [374]. In vitro studies with cells from patients with chronic myelo-monocytic leukemia (CMML) have also shown that IL-4 can suppress the spontaneous colony formation which could be ascribed to a reduced secretion of different cytokines by the CMML cells [375].

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4.6.3. IL-4 effect on monocyte functions Monocytes are prone to the effects of IL-4. This is reflected by changes in the surface antigen expression in response to IL-4 stimulation. In addition monocytes are triggered to differentiate to macrophages, a process accompanied by an augmented adhesion and an increased expression of RFD9 antigen [376–380]. Another function which is affected by IL-4 is the expression of cytokines. LPS or IL-1 stimulated monocytes express different cytokines at mRNA level after 2–4 h of exposure, such as IL-1b, IL-6, TNF-a and IL-8 [381–390]. This stimulatory effect on the gene expression by LPS or IL-1 can be counteracted by exposing the monocytes to IL-4 [374,389,391–400]. In particular a short period of pre-exposure to IL-4 totally abolishes the stimulatory effect of LPS or IL-1. mRNA studies have suggested that the suppressive effect of IL-4 is related to a reduced transcription rate in response to LPS stimulation and to a decrease in the half-life of cytokine mRNA [390]. The suppressive effect of IL-4 on the transcription rate may be caused by a reduced production of transcription factors such as activator protein-1 (AP-1) and nuclear factor-kB (NF-kB) which tightly control the transcription of different cytokine genes. Indeed, IL-4 was shown to inhibit LPS-induced expression of cfos and c-jun mRNA and the expression of AP-1 in human monocytes [401,401a]. The effects of IL-4 on LPS-induced NF-kB are contradictory. Donnelly et al. demonstrated an inhibitory effect of IL-4 on IL1-induced NF-kB [402], whereas Dokter et al. could not detect any effects of IL-4 on LPS-induced NFkB activation [403]. This might suggest a selective effect of IL-4 on the IL-1-induced pathway that leads to NF-kB activation without affecting the LPS-induced pathway. Additional mechanisms are also involved in the suppressive effect of IL-4 on cytokine expression in monocytes and PBMC, respectively. Firstly, a reduced production of PGE2 have been demonstrated in the presence of LPS plus IL-4 versus LPS alone [374,392]. PGE2 is a known activator of the PKA dependent pathway and has divergent effects on monocyte functions [404–407]. Secondly, IL-4 downregulates the expression of CD14 antigen on human monocytes [408,409]. The CD14 antigen is identified as a receptor for LPS binding protein and is required for the LPS mediated signal transduction [410]. It is conceivable that a reduced expression of CD14 results in a diminished activation by LPS. Thirdly, IL-4 up-regulates the expression of IL-1 RA at mRNA and protein level [411]. This may be of importance for interrupting the autocrine stimulation of monocytes by IL-1 after LPS activation.

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4.7. Clinical application of IL-4 A limited number of clinical studies have been performed in cancer patients with IL-4. In a study described by Atkins et al., ten patients with refractory malignancies received IL-4 by bolus intravenous injection every 8 h on day 1 – 5 at a dose of 10 and 15 mg/kg [412]. No significant effect was observed on the neutrophil and lymphocyte count, while a marked decrease in the percentage of circulating monocytes (CD14 + cells) were shown. Measurements of cytokines during IL-4 treatment did not demonstrate elevated plasma levels of TNF or IL-1. In contrast, plasma levels of IL-1Ra and CD23 demonstrated a marked increase. These results were confirmed by Wong et al., demonstrating IL-1 RA mRNA expression in monocytes from cancer patients treated with IL-4 [413]. The increased expression in IL-1 RA mRNA was observed within 2 h of IL-4 application and could be ascribed to an increase in the transcription rate of the IL-1Ra gene. The maximal tolerated dose applied to patients was 10 mg/kg. Higher dose caused severe side effects including nasal congestion, diarrhea and fluid retention.

5. Interleukin-6

5.1. History IL-6 was identified by Kishimoto and coworkers in 1981 [414] as a factor in the culture supernatants of mitogen or antigen-stimulated PBMC. At that time several other factors were identified which were named B-cell stimulatory factor-2 (BSF2), INF-b2, 26 kDa protein, hybridoma/plasmacytoma growth factor (HPGF or IL-HP1), hepatocyte-stimulating factor (HSF), or monocyte – granulocyte inducer type 2 (MGI2) [415–420]. Since the cloning of these factors it became clear that these factors were similar and they were named IL-6.

5.2. IL-6 gene architecture The human IL-6 gene has been mapped on chromosome 7 [421] and was further localized to 7p21 [422]. The IL-6 gene contains five exons and four introns and its length is :5 kb [423]. IL-6 consists of 212 amino acids and has a MW of 21 – 28 kDa. IL-6 contains four cysteine residues that can be replaced by Ser residues without any loss of biological activities of the cytokine [424]. Searches for similarities with other cytokines revealed a significant homology with human G-CSF. The promoter regions of both genes demonstrate binding sites for similar transcription factors and both genes have the same number of exons and introns and the size of each exon is similar. Furthermore, the position of the

four cysteine residues match. The latter suggests a similarity in the tertiary structure of the molecules and a possible functional similarity [425]. Both genes might be evolutionarily derived from a common ancestor gene.

5.3. IL-6 gene expression IL-6, in contrast to IL-3 and IL-4, is not a typical T-cell-derived cytokine but is expressed by many different cell types like T- and B-cells, monocytes, fibroblasts, keratinocytes, endothelial cells, astrocytes, bone marrow stromal cells and mesangial cells. IL-6 production is induced by a variety of stimuli. LPS, a bacterial cell wall component of gram-negative bacteria, induces IL-6 expression in monocytes, fibroblasts and endothelial cells [426–428]. N-acetylglucosaminyl-1,6-anhydro-Nacetylmuramyl-L-alanyl-D-isoglutamyl-m-diaminopimelyl-D-alanine (G(Anh)MTetra), a bacterial breakdown product of peptidoglycan induces IL-6 expression in monocytes [37]. Fibroblasts and monocytes also produce IL-6 in response to PKC activation by phorbol ester or by treatment with agents that increase intracellular cAMP [429,430]. Growth factors like IL-1, TNF, IL-2, IFN-b, and platelet-derived growth factor (PDGF) also induce IL-6 production [417,418,431]. IL3, however, is incapable of inducing IL-6 mRNA in monocytes by itself, but it primes monocytes to enhance the IL-6 mRNA expression when costimulated with LPS [241]. In human T-cells, IL-6 expression is induced by T-cell mitogens or antigenic stimulation [427,432– 436]. T-cells stimulated with PMA plus anti-CD28 demonstrated a strong secretion of bio-active IL-6. The secretion of IL-6 could be further increased by costimulation of PMA with anti-CD28 plus anti-CD2 [436]. Experiments in T-cell subsets showed that both the CD4 + CD45RA + and CD4 + CD45RO + subsets of human T-cells produced IL-6 [436]. T-cells stimulated with pokeweed mitogen (PWM) strongly express IL-6 mRNA [437]. Interestingly, the production of IL-6 by T-cells requires the presence of very small numbers of monocytes, whereas monocytes do not require the presence of lymphocytes [427]. The peak in IL-6 mRNA expression in monocytes is found 2–5 h after stimulation in vitro. In contrast, IL-6 mRNA expression in T-cells is found after 24–48 h of stimulation, indicating that IL-6 produced by monocytes and T-cells may have different roles and effects at different phases of the immune response [438]. Studies toward the mechanisms by which IL-6 expression is controlled are mainly performed in monocytes and monocytic cell lines. No studies so far report the molecular mechanisms by which IL-6 expression is controlled in T-cells. In monocytes, IL-6 mRNA expression is relatively rapidly induced. As early as 1 h after stimulation with LPS, IL-6 mRNA levels are

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strongly increased. Maximal levels of IL-6 mRNA are found 2–5 h after stimulation [37,241,389,428]. IL-6 expression is controlled at both the transcriptional and the posttranscriptional level. Transcriptional control was demonstrated by the increase of the IL-6 transcription rate after stimulation with LPS, G(Anh)MTetra, or LTB4 [37,439,440]. Posttranscriptional control of IL-6 expression was shown by the increase in LPS-induced IL-6 mRNA stability by IFN-g and by a decrease in LPS-induced IL-6 mRNA stability by IL-4. Furthermore, LTB4 stabilized IL-6 transcripts [440]. Induction of IL-6 mRNA expression can be mediated by a PKC-dependent pathway and IL-6 mRNA expression depends on the synthesis of new protein [37]. Another signaling pathway which is involved in IL-6 gene regulation is the mobilization of intracellular Ca2 + by A23187 [441]. The effect of A23187 is independent of its ability to stimulate the prostaglandin (via PGE2) pathway or to stimulate leukotriene production [441]. Involvement of the MAP kinase pathways in IL-6 gene regulation is a more recent discovery. The p38/RK MAP kinase signaling route has been demonstrated to be involved in TNF-a-mediated IL-6 expression [102]. Both ERK1/ERK2 and p38 have also been implicated in LPS- and IL-1-mediated IL-6 protein secretion from human monocytes [100a]. The promoter region of the IL-6 gene contains binding sites for four inducible transcription factors. At 270 bp from the start site, an AP-1 binding site is found [442]. At 150 and 140 bp from the transcription start site binding sites are found for a cyclic responsive element binding protein (CREB) and for NF-IL6, respectively [443,444]. Finally, at 75 bp from the start site a binding site is found for NF-kB [445,446]. NF-kB was shown to be especially important in the transcriptional control of IL-6 expression [450]. Studies in monocytic cell lines showed that LPS-, PHA- and TNF-a-induced IL-6 transcription is mediated through binding on the NF-kB sequence [447,448]. LTB4-induced IL-6 expression is mediated through NF-kB and to a lesser extent through NF-IL6 [449]. However, experiments in which cycloheximide, a protein synthesis inhibitor, was used, showed that IL-6 mRNA expression was dependent on the synthesis of new protein [37]. NF-kB is a homodimer of p50 subunits, or a heterodimer of p50 and p65 subunits, present as an inactive component in the cytosol, due to complex formation with the inhibitor protein IkB [451,452]. Phosphorylation of IkB and the subsequent dissociation of active NF-kB can occur in the absence of newly synthesized protein. Therefore, although NF-kB is a very important factor for the control of IL-6 expression, it cannot initiate IL-6 expression in vivo without at least one additional factor which needs to be synthesized after stimulation. No studies so far report results with transfection experiments with IL-6 promoter con-

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structs in human T-cells or T-cell lines. Therefore it is unknown whether IL-6 expression in T-cells is regulated in a similar fashion.

5.4. The IL-6 receptor IL-6 has effects on many different cell types. In accordance, its specific receptor was found to be expressed on a variety of cells, such as resting T-cells, B-lymphoblastoid cell lines, myeloma cell lines, hepatoma cell lines and monocytic cell lines. In contrast to activated B-cells, normal and resting B-cells do not express IL-6R [453]. The number of IL-6R on cells is very low compared to the numbers of other growth factor receptors [454]. A cDNA for the IL-6R has been isolated and characterized [178] and the amino acid sequence revealed that the IL-6R is a member of the superfamily of cytokine receptors. Crosslinking experiments with 125I-IL-6 showed that a single 80 kDa protein is involved in low-affinity binding of IL-6. Interestingly, the cytoplasmic domain of the IL-6R is not required for IL-6-mediated signal transduction [455] and therefore it was assumed that transduction of the IL-6 signal could be mediated through another molecule associated with the IL-6R. It was shown that binding of IL-6 to its receptor triggers the association of this complex with a non-ligand-binding membrane glycoprotein, gp130, resulting in a high-affinity IL-6R complex. However, gp130 does not bind IL-6 or IL-6R on their own, but only associates with pre-formed IL-6/IL-6R complex [456,456a]. A soluble IL-6R lacking the transmembrane and intracytoplasmic domains can associate with gp130 in the presence of IL-6 and mediate its function [455]. The gp130 subunit is also a member of the superfamily of cytokine receptors [188] and is shared by IL-6, LIF, OSM and CNTF [457]. In TF-1, a human erythroleukemic cell line, it was shown that antibodies against gp130 blocked effects of IL-11, indicating that gp130 also is involved in IL-11-mediated signal transduction [458]. Although shared by different receptors, the mechanisms by which gp130 transduces a signal differ for IL-6R and LIFR. IL-6 binding to its receptor induces homodimerization of gp130 by disulfide linking [459]. In fact, recent studies have suggested that the high-affinity IL-6R complex is a hexamer, consisting of two distinct IL-6, IL-6R and gp130 molecules [456]. The signal is thus transduced by the cytoplasmic regions of two linked gp130 molecules. In contrast, LIFR and CNTFR associate only with a single gp130 and form a heterodimer with this molecule [460]. Therefore, these signals are transduced by the cytoplasmic regions of gp130 and LIFR or CNTFR. The IL-6-induced gp130 homodimer appears to be similar in function to the heterodimer formed between the LIFR and gp130 and CNTFR and gp130 [459].

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The IL-6R can also be secreted in the soluble form (sIL-6R), bind to IL-6 and act as an agonist, since it can then render cells expressing gp130 but not IL-6R sensitive to IL-6 [461,461a,461b].

5.5. Biochemical pathways of IL-6 action Activation of the IL-6R by binding of IL-6 induces Tyr phosphorylation of gp130 but it is unknown whether or not this causes association with other signal transducing molecules [455,457]. Tyr kinase activity and subsequent cellular responses of IL-6 were abolished when Ser residues 656 and 658 in the cytoplasmic region of gp130 were replaced by proline residues [459]. However, data on the kinases that are involved in mediating the IL-6 signal is scarce. NF-IL6 binds in the promoter region of the IL-6 gene [443,444] and plays an important role in the induction of expression of acute phase proteins [462]. Therefore, it is assumed that NFIL6 plays an important role in the signaling pathway induced by IL-6. IL-6 induced phosphorylation of NFIL6 which was shown to be dependent on ras-activity and on MAP-kinase activity [463,463a]. Furthermore, the involvement of MAP kinase and MAPKAP kinase 2 was demonstrated in IL-6 mediated Ser phosphorylation of the small heat shock protein 27 [464]. Binding of IL-6 to its receptor was also found to result in rapid Tyr phosphorylation of the receptor and activation of the JAK/STAT pathway [465,466]. Of the JAK family kinases, JAK1, JAK2 and Tyk2 associate constitutively with the gp130 receptor [467,468,468a]. The activated JAK Tyr kinase, in turn, phosphorylated and activate the STAT family of proteins, especially STAT3 and STAT1. The IL-6 mediated JAK/STAT pathway was shown to activate several genes including junB, acute phase reactants, and INF regulatory factor1 (IRF-1). Nevertheless, the exact physiological role of the IL-6-mediated JAK/STAT signaling remains largely unknown. Attempts to elucidate the relevance of IL-6induced STAT3 were undertaken by transfecting the M1 leukemic cell line with dominant negative mutants of STAT3. These mutant forms of STAT3 inhibited both IL-6-induced growth arrest at G0/G1 and macrophage differentiation of the M1 transformants [469]. Recently, it was reported that IL-6 causes the rapid and transient Tyr phosphorylation of five cytosolic phosphoproteins [470]. It was shown that Tyr phosphorylation of these proteins was mediated through activation of p56Lyn, a Tyr kinase of the SRC family.

5.6. In 6itro effects of IL-6 5.6.1. IL-6 effect on erythroid, myeloid and megakaryocytic progenitors In vitro studies with IL-6 have shown that IL-6 has a

limited capacity to stimulate the proliferation of myeloid and erythroid progenitors. Sorted CD34 + cells cultured in the presence of IL-3, GM-CSF or Epo did not demonstrate higher CFU-GM or BFU-E numbers compared to studies with IL-6 [471,472]. Different results were obtained with cell suspension culture assays. CD34 + cells cultured in suspension with IL-6 for 7 days and subsequently costimulated with G-CSF or GM-CSF demonstrated a higher proliferative response compared to cells pre-cultured with medium alone. The most pronounced effect of IL-6 was obtained with serum-free culture conditions. These data suggest that IL-6 might be considered as a survival factor for myeloid progenitors by preventing apoptosis. Comparable results have been observed in pre-B-cells and murine myeloid leukemic cells whereby IL-6 prevented apoptosis [473]. With regard to the monocytic lineage it has been demonstrated that IL-6 alone did not affect the proliferation of macrophage precursor cells. However, a marked increase in macrophage colony formation (CFU-M) is noticed when human bone marrow cells were cultured with M-CSF plus IL-6 compared to the results with M-CSF alone [471–473]. The promotive effect of IL-6 seemed to be a direct effect since similar results were obtained by using mononuclear cells or CD34 + sorted cells. Moreover the effect of IL-6 on CFU-M precursor was restricted to M-CSF. No change in CFU-M colony numbers were observed by culturing the cells with IL-3 or GM-CSF in the absence or presence of IL-6. In summary these data suggest that IL-6 can be considered as a permissive factor for the development of the macrophage lineage. Finally distinct effects of IL-6 have been observed on megakaryocytic progenitor cells, especially in the presence of an additional growth factor [474,475]. IL-6 alone did not affect the megakaryocytic progenitor, neither in the short-term nor in the long-term bone marrow culture assay. However, IL-6 combined with IL-3 or stem cell factor/c-kit ligand (SCF) did further enhance the CFU-MEG numbers. The promotive effect of IL-6 included a growth promotive as well as a maturation effect.

5.6.2. IL-6 effect on AML The in vitro effects of IL-6 on AML progenitors have been evaluated in a limited number of studies [476]. In a minority of cases IL-6 enhanced AML colony numbers alone. However, mostly the promotive effect of IL-6 was observed in combination with IL-3 or IL-4 whereby the number of colonies increased by a factor of 1–2. The proliferative response on IL-6 was not linked to a subtype of the FAB classification, especially no correlation existed with FAB type M4 or M5. Moreover, the stimulative signal was not associated with

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differentiation which is in contrast to observations with murine myeloid leukemic cell lines.

5.7. Clinical application of IL-6 Phase I/II studies in cancer patients have shown that IL-6 affects significantly the megakaryocytic lineage [477,478]. A dose dependent increase in the platelet count is shown between 0.5 and 20 mg/kg, with a 1.5 – 2-fold increase at a dose of 10 mg/kg. In addition changes in neutrophil and lymphocyte counts are observed. On day 3 of IL-6 application (10 mg/kg) a marked increase in neutrophils is noticed, while an increase in circulating lymphocytes is observed at lower dose (2.5–5 mg/kg). Expansion of monocytes is also reported [479]. Immunophenotyping of the lymphocytes demonstrated an absolute increase in CD3 + , CD4 + and CD8 + T-lymphocytes after 7 days of application. Moreover, increased levels of IL-4 and IL-10 mRNA would suggest activation of Th2-like T-cells [479]. In addition a marked decrease in hemoglobulin level occurred during the application of IL-6. The decline in hemoglobulin cannot be ascribed to hemolysis or to a decrease in the number of erythroid bone marrow progenitors since no change in CFU-Es and BFU-Es was noticed tested in in vitro culture assays. Normalization of the hemoglobulin level occurred within 4–7 days after cessation of IL-6 application. The anemia coincided with an acute phase response in all patients reflected by an increase in C-reacting protein, fibrinogen and serum amyloid A level. The maximum tolerated dose of IL-6 appeared to be 10 mg/kg. A higher applied dose can cause fever, fatigue, hepatoxicity and cardiac arrhytmia. Murine monoclonal antibodies (MoAbs) directed against human IL-6 or hIL-6R may prove useful in diseases in which abnormal expression of IL-6 may be involved in the pathogenesis of the disease, a few of which are multiple myelome, chronic autoimmune diseases, rheumatoid arthritis and acquired immunodeficience syndrome (AIDS). Clinical trials have shown that such MoAbs were successful in decreasing the IL-6-related symptoms in patients of certain diseases, although obstacles such as antimouse Ig antibody response are still to overcome [480,480a].

6. Interleukin-9

6.1. History IL-9 was described in 1988 as p40 and was isolated based on its ability to support the growth of certain Th cell clones [268]. After the human homologue was cloned [481,481a] it was proposed to designate p40 as IL-9.

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6.2. IL-9 gene architecture The gene encoding IL-9 was mapped to chromosome 5 [482] and has been regionally mapped by in situ hybridization to 5q31–32 [483]. Interestingly, human IL-3, IL-4, IL-5, GM-CSF and IL-13 gene clusters have also been localized on the same locus [135]. The IL-9 gene contains five exons and four introns [483,484]. The mature human IL-9 protein consists of 144 amino acids, has a calculated MW of 16 kDa and contains ten cysteine residues [483,485]. The IL-9 sequence contains four potential sites for aspargine-linked glycosylation [485].

6.3. IL-9 gene expression CD4 + T-cells activated with conA, PMA, or antiCD3 express IL-9 mRNA and secrete IL-9 protein [484]. Because kinetic studies on the expression of the IL-9 gene showed that IL-9 induction peaks as late as 28 h after stimulation, it was thought that IL-9 expression was mediated by secondary signals. This was supported by the finding that IL-9 mRNA expression was blocked by the protein synthesis inhibitor cycloheximide [484]. Indeed, it was found that a secondary signal was involved since anti-IL-2R antibody blocked the IL-9 expression in activated T-cells [486]. Furthermore, IL-2 strongly induced IL-9 mRNA expression [486]. Later it was demonstrated that the inhibition caused by anti-IL-2R antibody on IL-9 production could be reversed by the addition of a combination of IL-4 and IL-10 [487]. Moreover, IL-9 production by T-cells activated by PMA plus anti-CD3 was blocked by the addition of anti-IL-4 and anti-IL-10 antibodies, indicating that multiple secondary signals are involved in the expression of IL-9 in T-lymphocytes [487]. Recent studies in the human T-cell leukemia virus type I-transformed T-cell line, C5MJ2, revealed that after PHA/12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation steady-state IL-9 mRNA peaked 11 h after treatment [488]. In unstimulated cells IL-9 mRNA was almost negligent. Exactly 24 h after stimulation, IL-9 mRNA levels were still three times higher than in control cells. Experiments towards the transcription rate of the IL-9 gene after PHA/TPA treatment showed that after 5 h a 10-fold induction peak could be observed in this cell line, which gradually decreased after this time point. It is concluded that the induction of IL-9 mRNA during the first 5 h is mainly based on the transcriptional activation of the gene, whereas predominantly post-transcriptional events were evidenced 11 h after stimulation. Consequently, a shift in regulatory mechanisms of IL-9 mRNA accumulation takes place, from the transcriptional to the post-transcriptional level. Since IL-9 mRNA contains AU-rich elements, increasing mRNA stability most likely determines the observed post-transcriptional events [483].

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The promoter region of IL-9 contains several consensus sequences for eucaryotic transcriptional control elements including AP-1, NF-kB, octamer, glucocorticoid response element, INF-inducible element and Tax response element [483]. The precise role in positive and negative regulation of IL-9 transcription of the factors that bind to these sequences has been partly established. It was shown that an 0.9 kb promoter region of the IL-9 gene was able to drive the transcription of a reporter gene. Transcription was constitutive in human T-lymphotropic virus-I-transformed T-cell lines and could be further enhanced by stimulation with TPA [483]. Transfections of a series of IL-9 promoter deletion constructs into the C5MJ2 cells revealed that deletion of the DNA sequence between −878 and − 379 resulted in up-regulated promoter activity [489]. This would imply the existence of negative control elements in this region. Between − 379 and −143 several positive and negative regulatory sequences have been identified. Mutagenesis studies indicated that only an AP-1-like site at −146 to − 140 was important in controlling IL-9 gene transcription [489]. Both basal and PHA/TPA-inducible promoter activity decreased 2 – 3-fold when this site was mutated. The DNA-binding proteins are most likely c-Jun and c-Fos, the most common subunits of the AP-1 transcription factor. The sequence between − 125 and − 46 appeared essential for constitutive and inducible expression of the IL-9 gene in C5MJ2 cells [489]. Mutation within the NF-kBlike binding motif located at −59 to − 50, and the CRE-binding motif immediately upstream, resulted in almost completely abolished promoter activity. The transcription factor NF-kB was shown to bind to the NF-kB-like sequence: the protein complex binding to the CRE-like-motif contains c-Jun and a unidentified 35 kDa protein.

for IL-9-mediated Tyr phosphorylation of the receptor and for STAT activation, but not for IRS-2/4PS activation or for JAK1 phosphorylation, which is dependent on a domain closer to the plasma membrane [493]. The abovementioned data were obtained when the human IL-9 receptor was transfected into mouse lymphoid cell lines. As mentioned in chapter 4, the IL-2Rgc is a common component for the IL-9 receptor as well as for the receptors of IL-2, IL-4, IL-7 and IL-15 [318–320]. Moreover, it has now become clear that mutation of the gc is responsible for the X chromosome-linked severe combined immune deficience syndrome (XSCID) [494,495].

6.5. Biochemical pathways of IL-9 Although the IL-9R contains a potential PKC phosphorylation site, IL-9 did not stimulate phosphorylation of MAP kinase or Raf-1, nor did it enhance MAP kinase activity [496]. However, four proteins were phosphorylated at Tyr residues by IL-9 in MO7e cells which could be inhibited by the addition of genistein, a Tyr kinase inhibitor [496]. Recently, it was demonstrated that IL-9 induces Tyr phosphorylation of insulin-related substrate-1 (IRS-1), 4PS/insulin receptor substrate-1-like protein, as well as JAK1, JAK3 and Tyk2 [497,498]. In fact, activated JAK1 and JAK3 are capable of not only associating with IRS-1 but also of Tyr phoshorylating this protein [498]. IRS-1 acts as an interface between signaling proteins with SRC-homology-2 domains (Sh-2 proteins) and the receptors for, among others, IL-9 and IL-4. Subsequently, the transcription factors STAT1, STAT3 and STAT5 are phoshporylated in response to IL-9 [493,499].

6.6. In 6itro effects of IL-9 6.4. The IL-9 receptor IL-9 receptors are expressed on a human megakaryoblastic leukemia line, T-cell lines, normal Blymphocytes and human erythroid and myeloid precursors [485,487– 491]. A cDNA encoding the human IL-9R has been cloned from the human megakaryocytic cell line UT-7 [180]. The human IL-9 receptor gene consists of ten exons spread over :13.7 kb of DNA [492]. The deduced protein sequence consisted of 522 amino acids and showed consensus sequences for the hematopoietic receptor superfamily. The cytoplasmic part of the IL-9R contains one potential PKC phosphorylation site [180]. Binding characteristics, parts of the receptor that are important for signal transduction, and possible subunits that are needed for IL-9 signal transduction need further investigation. One report describes a single Tyr at position 116 in the cytoplasmic domain which was shown to be necessary

The targets of IL-9 include T-cells, B-cells, mast cells, erythroid and myeloid precursors, and fetal thymocytes [500,500a–503]. It supports the development of BFU-E in cultures supplemented with Epo [488,504,505]. The enhancing effect by IL-9 is Epo dependent and is a direct effect on erythroid progenitors [295]. More recently, IL-9 was proven to induce the proliferation of multipotent hematopoietic CD34 + CD33 − DR-cells in combination with c-kit ligand [506]. IL-9 also appeared to be a major proliferative factor for AML blasts and leukemic cell lines, by stimulating leukemic cells to enter the S-phase [507]. Moreover, IL-9 acts synergistically with SCF to recruit quiescent leukemic cells out of the G0-phase [507]. IL-9 was shown to play a regulatory role in the IL-4 dependent immunoglobulin production since it potentiated the IL-4-induced IgE production by human Blymphocytes [490]. Interaction of IL-9 with its receptor

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also regulates proliferation of T-lymphocytes [508]. Both 3H-thymidine incorporation and BrdU experiments demonstrated that IL-9 drove PHA-activated T-cells through more than one cell cycle [508]. The preferential expression of IL-9 in cell lines derived from patients with Hodgkin disease and anaplastic large cell lymphoma [509,509a,509b] suggests involvement of IL-9 in tumorigenesis via an autocrine growth loop. In the human factor-dependent cell line MO7e, molecular mechanism underlying the cell proliferation action of IL-9 were studied [510]. IL-9 stimulation resulted in rapid and transient elevation of primary response genes including c-myc and junB. The different responses of the c-myc and junB messages to different protein kinase inhibitors suggested that more than one pathway may be involved in IL-9-mediated signaltransduction leading to the expression of c-myc and junB.

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7. Interleukin-10

tion is observed when cells are stimulated with LPS. However, IL-10 mRNA expression is delayed relative to that of TNF-a, IL-1b and IL-6 [523]. Expression of IL-10 mRNA was inhibited by IL-4, IL-10 and IFN-g [523,524]. The autoregulatory role of IL-10 in controlling its own expression in monocytes was confirmed using an anti-IL-10 monoclonal. Incubation of monocytes with LPS plus anti-IL-10 antibody resulted in higher IL-10 mRNA levels compared to the effects of LPS alone [524]. It is unknown whether expression of IL-10 in T-cells or in monocytes is regulated by similar mechanisms. The 3%-untranslated region of the IL-10 mRNA contains several AU-rich sequences, suggesting at least some control of IL-10 mRNA expression at the level of mRNA stability [512]. Little is known with respect to the IL-10 promoter: the essential promoter was found to require a TATA box at − 77, and up to 150 additional 5% nucleotides. Positive regulatory sequences are located between −1100 and − 900, whereas negative regulatory elements were identified between −800 and − 300 [521].

7.1. History

7.4. IL-10 receptor

One year after the identification of IL-9, a factor was identified that inhibited cytokine synthesis in Th1 cells [511]. The factor, initially called cytokine synthesis inhibitory factor (CSIF), was named IL-10 in 1990 [512].

IL-10 binds as a dimer to a single class of receptor with a Kd : 50–200 pmol/l [525]. The amount of IL10R on ten cell lines that were tested was tiny [525,526]. The human IL-10R cDNA has been cloned from a Burkitt lymphoma cell line BJAB [527]. The hIL-10R gene is located on chromosome 11. Expression of hIL10R mRNA seems to be restricted mainly to human hematopoietic cells and cell lines. In a number of T-cell clones, expression of hIL-10R is down-regulated after activation of the cells with anti-CD3 and phorbolester [527]. The receptor for IL-10 is structurally related to the IFN-g receptor: since IL-10 inhibits macrophage activation by IFN-g, this relationship could suggest possible shared receptor or signal transduction pathways [527].

7.2. IL-10 gene architecture IL-10 has been mapped on chromosome 1 [513]. The deduced IL-10 protein consists of 160 amino acids, the one potential N-glycosylation site is not used and its MW is : 18 kDa [514]. IL-10 contains four cysteine residues that form two disulfide bonds [514]. Recently, the secondary protein structure of IL-10 was solved [515]. Sequence homology searches revealed that the gene encoding IL-10 was highly homologous to an open reading frame BCRF1, in the Epstein-Barr virus genome [512,514,516,517]. The protein product of BCRF1 indeed mimics IL-10 activity and is therefore named viral IL-10 (vIL-10) [517]. It is believed that vIL-10 plays an important role in the host – virus interaction [512,514,516– 519].

7.3. IL-10 gene expression Like IL-6, IL-10 is not a typical T-cell-derived cytokine but it is expressed in T-lymphocytes, monocytes and eosinophils [520]. The levels of constitutive IL-10 expression in normal cells is extremely low [521]. In T-cells IL-10 mRNA and IL-10 protein were detected in both Th1 and Th2 CD4 + T-cell clones [522]. In monocytes, IL-10 mRNA expression and protein secre-

7.5. Biochemical pathways of IL-10 Treatment of monocytes or basophils with IL-10 activated DNA binding proteins that recognize the IFN-g response region of the Fcg promoter [528]. The essential step in this process was the Tyr phosphorylation of a 91 kDa protein, p91, that is important in mediating effects of IFN-g [528]. Later it appeared that this factor was a member of the STAT family, namely STAT1. Moreover, in both monocytes and T-cells not only STAT1 but also STAT3 was activated by IL-10 [529,531]. IL-10 treatment of these cells resulted in ligand-induced Tyr phosphorylation of Tyk2, and JAK1, but not JAK2 and JAK3, kinases upstream from the STATs [529,530]. In murine Ba/F3 cells that

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stably express the murine IL-10R, STAT5 is also activated by IL-10 [532]. Two Tyr residues (Tyr 427 and 477) in the intracellular domain of the murine IL-10R were found to be redundantly required for receptor function and for activation of STAT3, but not STAT1 or STAT5 [532]. This would suggest that STAT3 is directly recruited to the ligand-activated IL10R by binding to specific, but redundant, receptor intracellular domain sequences containing phosphotyrosine. The concept that utilization of distinct STAT proteins by different cytokine receptors is dependent on the expression of particular ligand-activated Tyr containing STAT docking sites in receptor intracellular domains, is thus strengthened. It is furthermore described that deactivation by IL10 of LPS-stimulated monocytes occurs via inhibition of p56Lyn Tyr kinase activation and all other subsequent events in this pathway, including activation of the Ras/MAPK pathway [533]. This would suggest that early events in the LPS response are targets for IL-10-mediated deactivation of monocytes.

7.6. In 6itro effects of IL-10 Many effects of IL-10 have been described. The first was its CSIF activity. IL-10 inhibited the expression of IFN-g and GM-CSF mRNA and protein by PBMC activated with PHA or anti-CD3 [514]. Later it was demonstrated that other cytokines, IL-1b and IL-12, were involved in this inhibiting effect. Production of IL-12 which is a powerful stimulator of IFN-g production, and also the production of IL-1b by PBMC, were inhibited by IL-10 [534]. Moreover, IL10 was shown to down-regulate both spontaneous and IL-8-induced IL-8 production by CD4 + T-cells [535]. Other effects on T-cells were the ability to strongly reduce antigen-specific proliferation of T-cells and CD4 + T-cell clones when antigen is presented by monocytes [536]. IL-10 also directly inhibits growth and IL-2 production in T-cells stimulated by immobilized OKT3 antibody in the absence of monocytes [537]. In neutrophils, IL-10 selectively inhibited LPSinduced PGE2 production, further demonstrating the anti-inflammatory function of IL-10 [538]. Effects on B-lymphocytes have also been described. IL-10 stimulates proliferation of B-cells that were stimulated via their antigen receptor or through their CD40 antigen [539]. Furthermore, IL-10 blocks IL-4-induced IgE and IgG4 synthesis by B-cells in PBMC. Once again, the inhibitive effect of IL-10 was mediated through monocytes [540]. In contrast to the effect in monocytes, IL-10 enhanced the LPS-induced expression of IL-6 mRNA in endothelial cells [541]. As already described, many effects of IL-10 are mediated through monocytes, via the inhibition of gene transcription of

IL-1b, IL-6, IL-8 and TNF-a [397–402,542]. In this regard it is interesting that many of its effects are IL-4-like effects. Additionally, both IL-10 and IL-4 significantly inhibited the production of other proinflammatory mediators, such as reactive oxygen intermediates, reactive nitrogen intermediates and prostaglandines in monocytes/macrophages [399,543– 545]. However, very often IL-4 and IL-10 work synergistically indicating that different mechanisms and or secondary signaling pathways are used by IL-4 and IL-10. This is underscored by the finding that IL-10 had no effect on CD14 antigen expression, whereas IL-4 is known to strongly downregulate CD14 [546]. Both cytokines however, have strong and at some points differential anti-inflammatory activities and may be used as suppresser factors in immune reactions. Indeed, in two recent reports, IL-10 was successfully used to protect mice from lethal endotoxemia [547,548]. Recently, IL-10 was demonstrated to inhibit the autonomous growth of myeloid colonies (colony-forming unit-granulocyte-macrophage (CFU-GM)) in methylcellulose cultures containing PBMC [549]. The autonomous CFU-GM growth, resulting from an interaction of monocytes and T-cells, was caused by endogenous GM-CSF release. Exogenously added IL10 profoundly suppressed GM-CSF release and thus colony formation, implicating IL-10 as an useful cytokine in the treatment of myeloid malignancies in which autocrine and/or paracrine mechanisms involving GM-CSF are known to play a pathogenetic role. An important mechanism for IL-10 suppression of cytokine gene transcription in human monocytes is the inhibition of LPS- or TNF-a-induced NF-kB activation. NF-kB is an important transcription factor involved in the expression of inflammatory cytokines. The activity of the transcription factors AP-1, NFIL6, AP-2, CREB, Oct-1 and Sp-1 was not affected by IL-10 [550]. More upstream, IL-10 completely inhibited LPS-induced P56Lyn Tyr kinase activation in human monocytes and all other subsequent events in this pathway including Vav and p21Ras activation. GTP-bound Ras can activate Raf-1, which can bind to MEKI, an activator of MAP kinases. Consequently, it was demonstrated that IL-10 also inhibited the LPS-induced MAP kinase activity [551]. Thus, the Ras pathway appears to be a target for monocyte deactivation by IL-10.

Reviewer This paper was reviewed by Alessandro Rambaldi, MD, Divisone di Ematologia, Ospedali Riuniti di Bergamo, 24100 Bergamo, Italy.

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Appendix A. Nomenclature 3%-UTR 4PS ABMT AML AML-CFU AP-1 ARE bc C/EBP cAMP CMML CNTF conA CRE CREB CSF CSIF CSP DAG dbc-AMP EMSA Epo ERK gc G-CSF GAF GAS GM-CSF IkB ICE IFN-g IL-1 IL-1R-AcP IL-1Ra IL-1RI IL-1RII IL-3Rac IP3 IRF JAK JNK LIF LIL-STAT LILRE LPS LTB4 M-CSF MAPK MoAbs NF-kB

3%-untranslated region IL-4-induced phosphotyrosine substrate autologous bone marrow transplantation acute myeloid leukemia AML colony forming unit activator protein-1 AU-rich element common b chain CCAAT/enhancer binding protein cyclic AMP chronic myelo-monocytic leukemia ciliary neurotrophic factor concanavalin A cAMP responsive element cAMP responsive element binding protein colony stimulating factor cytokine synthesis inhibitory factor cap site proximal promoter diacylglycerol dibutyryl cAMP electrophoretic mobility shift assay erythropoietin extracellular regulated kinase common g chain granulocyte colony stimulating factor interferon-g-activated factor interferon-g-activated site granulocyte-macrophage colony stimulating factor inhibitor k B IL-1 converting enzyme interferon-g interleukin-1 IL-1R accessory protein IL-1 receptor antagonist IL-1R type I IL-1R type II IL-3 receptor a chain inositol 1,4,5-triphosphate interferon regulatory factor Janus kinase c-Jun-terminal kinase leukemia inhibitory factor LPS-and IL-1-inducible STAT LPS and IL-1 responsive element lipopolysaccharide leukotrien B4 macrophage colony stimulating factor mitogen-activated protein kinase monoclonal antibodies nuclear factor k B

NF-IL6 NIK NIP NK cells OSM PBMC PDGF PGE2 PHA PKA PKC PMA PTK SAPK SCF Ser Sh-2 SOS STAT Th1 Th2 Thr TNF-a TPA TRAF-6 Tyr XSCID

197

nuclear factor IL-6 NF-kB-inducing kinase nuclear inhibitory protein natural killer cells oncostatin M peripheral blood mononuclear cells platelet-derived growth factor prostaglandin E2 phytohemagglutinin protein kinase A protein kinase C phorbol myristate acetate protein tyrosine kinase stress-activated protein kinase stem cell factor/c-kit ligand serine SRC-homology-2 son of sevenless signal transducer and activator of transcription T helper 1 cells T helper 2 cells threonine tumor necrosis factor a 12-O-tetradecanoylphorbol-13-acetate TNF-receptor associated factor-6 tyrosine X-chromosome-linked severe combined immune deficiency syndrome

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Biography Edo Vellenga studied at the Medical School, University Groningen, The Netherlands, from where he received his PhD in 1983. He has been awarded several fellowships, including Fellow of the Netherlands Cancer Foundation, the Fulbright Scholarship, and Fellow of the Royal Netherlands Academy of Arts and Sciences. Since 1990 he has been Associate Professor at the Department of Hematology, University Hospital Groningen.