The family of IL-10-related cytokines and their receptors: related, but to what extent?

Cytokine & Growth Factor Reviews 13 (2002) 223–240

Survey

The family of IL-10-related cytokines and their receptors: related, but to what extent? Sergei V. Kotenko∗ Department of Biochemistry and Molecular Biology, New Jersey Medical School, University of Medicine and Dentistry, 185 South Orange Avenue, MSB E-631, Newark, NJ 07103, USA

Abstract Five novel cytokines (IL-19, IL-20, IL-22 (IL-TIF), IL-24 (human MDA-7, mouse FISP, rat C49A/Mob-5), and IL-26 (AK155)) demonstrating limited primary sequence identity and probable structural homology to IL-10 have been identified. These cellular cytokines, as well as several cytokines encoded in viral genomes (viral cytokines), form a family of IL-10-related cytokines or the IL-10 family. These cytokines share not only homology but also receptor subunits and perhaps activities. Receptors for these cytokines belong to the class II cytokine receptor family. The receptors are IL-10R2 (CRF2-4), IL-22R1 (CRF2-9), IL-22BP (CRF2-10), IL-20R1 (CRF2-8) and IL-20R2 (CRF2-11). Biological activities of these cytokines, receptor utilization and signaling, as well as expression patterns for cytokines and their receptors are summarized. Although data indicate that these cytokines are involved in regulation of inflammatory and immune responses, their major functions remain to be discovered. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Interleukin-10-related cytokines; Interleukins; Cytokine receptors; Signal transduction; Inflammatory and immune responses

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. IL-24 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. IL-22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. IL-26 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. IL-19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.5. IL-20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.6. Viral homologs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Class II cytokine receptor family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Functional receptor complexes and signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Mouse receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Receptor expression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Chromosomal localization and gene structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Genes encoding IL-10-related cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Genes encoding receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Tel.: +973-972-3134; fax: +973-972-5594. E-mail address: [email protected] (S.V. Kotenko).

1359-6101/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII: S 1 3 5 9 - 6 1 0 1 ( 0 2 ) 0 0 0 1 2 - 6

224 225 225 226 227 227 228 228 228 228 230 232 232 234 234 235 236 237 238

224

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

1. Introduction Several novel cytokines demonstrating limited primary and likely structural homology to IL-10 have been identified [1–5]. These cellular human cytokines are IL-19 [3], IL-20 [1] (also called Zcyto10), IL-22 (its mouse ortholog was originally designated IL-TIF (IL-10-related T-cell-derived inducible factor [2]), IL-24 (human IL-24 was originally designated melanoma differentiation associated gene 7 (MDA-7) [4], rat IL-24 was designated C49A [6] or Mob-5 [7] and mouse cytokine was designated FISP (IL-4-induced secreted protein) [8]); and AK155 (provisionally designated

IL-26) [5] (Fig. 1 and Table 1). These cellular cytokines, as well as several cytokines encoded in viral genomes (viral cytokines), form a family of IL-10-related cytokines, the IL-10 family. Whereas the biological functions of IL-10 itself have been explored extensively (for review see [9]), functions of other members of the IL-10 family are just starting to be revealed. The immune and inflammatory responses are well tuned processes. Although it is important for the immune system to mount a proper response to any pathological condition it is even more important to inhibit it in a timely manner. An over exaggerated response is destructive for the host immune

Fig. 1. The alignment of the a.a. sequences of human IL-10 [98], IL-19 [3], IL-24 [4], IL-26 [5], IL-20 [1] and IL-22 [21,22] is shown. The sequence of cmvIL-10 is also included in the alignment because of the unique features of this protein, despite the low homology between IL-10 and cmvIL-10 (26% identity), cmvIL-10 binds to and signals through the IL-10 receptor complex and competes for the receptor binding sites with IL-10 [38]. The consensus sequence is shown on the bottom. The color code for identical and similar a.a. is shown on the figure. The a.a. residues are numbered starting from the Met residue (signal peptide a.a. are included). Sequences of IL-19 and IL-24 are presented with short signal peptides (Fig. 7). The ␣ helices A–F, predicted based on the crystal structure of ebvIL-10, Epstein-Barr Virus-encoded IL-10 homolog that is shown on the figure [56], are underlined. Positions of corresponding introns are indicated by arrows. Percent of identity between sequences of IL-10-related cytokines is demonstrated as classification tree. There is a stretch of homologous a.a. near the C-terminus. The four cysteine residues (Cys) necessary to fold the IL-10 monomer correctly [56] are conserved in IL-19, IL-20 and IL-26, although the position of the fourth Cys is shifted in IL-26. IL-22 lacks the fourth Cys at the correct position, but possesses Cys at the C-terminus. IL-19 and IL-20 have an additional pare of Cys. IL-24 lacks the third and fourth Cys. The a.a. in the region of the helix C previously determined to be components of the hydrophobic core of the homodimeric IL-10 molecule [56] are conserved or similar in all cytokines. Thus, at least some of IL-10-related cytokines are likely to adopt a similar folded structure to that of IL-10/ebvIL-10 shown on the figure.

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240 Table 1 Human cytokines of the IL-10 family and their receptors Cytokine

Other names

Human IL-19

ZMDA1

Human IL-20 Murine IL-20

ZCYTO10

Human IL-22 Murine IL-22␣ Murine IL-22␤

IL-TIF IL-TIF, IL-TIF␣ IL-TIF␤

Human IL-24 Murine IL-24 Rat IL-24

MDA-7, suppression of tumorigenicity 16 protein (ST16) FISP C49A, Mob-5

Human IL-26

AK155

Receptor IL-10R1 IL-10R2 IL-20R1 IL-20R2 IL-22R1 IL-22BP

IL-10R, IL-10R␣ CRF2-4, CRFB-4, IL-10R␤ CRF2-8, IL-20R␣, ZCYTOR7 CRF2-11, IL-20R␤, DIRS1, TANGO 241, 4Kaef94 CRF2-9, IL-22R, ZCYTOR11 CRF2-10, CRF2-X, IL-22R, CRF2-s1, IL-22RA2, ZcytoR16

system itself and to other tissues. Several mechanisms are involved in regulating and balancing the immune and inflammatory responses. One of these mechanisms is the expression of cytokines possessing anti-inflammatory, immunosuppressive activities such as IL-10. IL-10 is a pleiotropic cytokine which plays major roles in inflammatory and immune responses [9]. It seems that its main function is to keep under strict control the inflammation by adjusting the intensity of the immune and inflammatory responses to the severity of destruction produced by a pathological condition or a pathogen and, thus, minimizing damage to the host tissues caused by either pathogen or immune system itself. Although the IL-10-related cytokines do not demonstrate “IL-10-like” activities, at least some of them are clearly involved in the regulation of inflammatory responses in various tissues. Up-to-date information about these novel cytokines, their activities and receptors is presented in this review.

2. Cytokines 2.1. IL-241 The first homolog to IL-10 was cloned by subtraction hybridization in 1995 as a protein whose expression is elevated in terminally-differentiated human melanoma cells [4]. The protein was designated MDA-7. Its homology with IL-10 as well as its cytokine-like features were not originally reported. The cloned MDA-7 cDNA encoded the 1 Cytokines are presented in the order they were reported which does not correspond to numerical order of the nomenclature.

225

protein with unusually long abnormal signal peptide that masked its cytokine identity (see later for details). It was demonstrated that although MDA-7 protein is expressed in normal melanocytes, its expression gradually fades with melanoma progression and is undetectable at the metastatic stage [10,11]. Nevertheless, the expression of MDA-7 is increased in human melanomas after treatment with interferon (IFN)-␤ and the protein kinase C (PKC) activator mezerein [4]. This combined treatment of cultured melanoma cells results in irreversible loss of growth potential, the induction of terminal differentiation, and was reported to cause translocation of MDA-7 from the cytosol to the nucleus of differentiated cells [12]. Nuclear localization of MDA-7 was also observed in breast carcinoma MCF-7 cells infected with adenovirus containing a CMV-IE promoter-driven MDA-7 expression cassette [12]. Moreover, association of MDA-7 with chromatin in cells undergoing mitosis was reported, suggesting the possibility of MDA-7 involvement in chromatin remodeling [12]. However, no preferential nuclear localization was detected in a separate study [10]. Instead, a diffuse cytoplasmic localization of MDA-7 was observed in normal melanocytes and in melanoma cells overexpressing MDA-7 [10]. The function of MDA-7 was linked to selective suppression of tumor growth [10–16]. It was demonstrated that the forced expression of MDA-7 induced selective suppression of the growth and colony formation of diverse human tumor cells. Expression of MDA-7 in normal cells had less profound effects [12,13]. The mechanism of MDA-7 action was linked to the promotion of apoptosis in cancer cells, which appeared to be independent of p53 and retinoblastoma protein (RB), and correlated with upregulation of BAX protein expression [12,13]. Also, G2/M cell cycle arrest inhibiting entry into S phase was observed in cancer cells overexpressing MDA-7 [10,15]. In contrast to these studies, MDA-7 was demonstrated to be a secreted glycosylated protein which appears on SDS-PAGE as several bands in the region of 35–40 kDa [7,17,18]. Moreover, MDA-7 was reported to be expressed at high level in several human colon cancer specimens tested [7], which would appear to be at variance with any generalized anti-tumor effect. Northern blotting revealed MDA-7 expression in tissues associated with the immune system such as spleen, thymus and peripheral blood leukocytes, and also in normal melanocytes [11]. Its identity as a cytokine was confirmed by finding its receptor, first as an entity expressed in ras-transformed cells [7] and then as specific membrane-bound proteins able to induce signaling after binding of MDA-7 [17,18] (see later for details). Based on its cytokine-like properties, MDA-7 was designated IL-24. It is noteworthy that the stimulation of freshly isolated PBMCs with ConA, but not with LPS, induced a rapid secretion of IL-24 as measured by Western blotting [18]. However, unlike IL-10, IL-24 did not inhibit LPS-induced TNF-␣ production by PBMCs [18]. Identification and characterization of rat and mouse IL-24 (MDA-7) orthologs suggested that the function of

226

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

IL-24/MDA-7 is even more complex. The rat and mouse proteins share 83% identity with each other and 65 and 70% identity with human IL-24. The expression of the rat IL-24 ortholog was linked to wound healing ([6]; the protein was designated C49A) and to ras-transformation ([7,18]; the protein was designated Mob-5), and the mouse IL-24 analog ([8]; the protein was designated FISP, IL-4-induced secreted protein) was demonstrated to be specifically produced by activated Th2 cells. Rat MDA-7 (C49A) cDNA was cloned by differential display as a gene expressed at elevated level during wound healing. The level of C49A mRNA was transiently elevated 9–12-fold above unwounded controls [6]. This up-regulation was rapid, reaching maximum level within 12–24 h with subsequent gradual decline to baseline around day 14. The expression of C49A protein was localized primarily to spindle-shaped fibroblast-like cells at the wound edge and base. Wound repair involves regulated proliferation and differentiation of various skin cells including fibroblasts, which by day 2 migrate to the wound and proliferate (for review see [19,20]). Thus, in the rat model of wound repair the expression of C49A is associated with proliferation rather than growth suppression. It was also reported that increased proliferation of normal human skin fibroblasts was associated with an increased level of endogenous IL-24 expression [6]. On the other hand, wound healing, particularly its initial phase, is accompanied by inflammation. C49A could, therefore, also be involved in regulating local inflammatory responses within the wound. Rat IL-24 (Mob-5) was cloned by differential display as a gene induced by oncogenic Ha-ras expression [7]. The expression of Mob-5 in Ha-ras-transformed cells was abolished by treating cells with inhibitors which prevented either ras protein membrane targeting or activation of the MAP kinase pathway, events required for ras-induced cell transformation. The Ras signaling pathway is activated in normal cells by serum stimulation. However, Mob-5 expression was not detected in non-transformed cells following serum addition, demonstrating that the Mob-5 gene is a target specific for oncogenic Ras signaling. However, no detectable morphological changes were observed in cells overexpressing Mob-5 alone. The Mob-5 protein was demonstrated to be secreted from cells and migrated on the SDS-PAGE as a single band of approximately 23 kDa. It was also demonstrated that in addition to Mob-5 itself, its putative receptor was also an oncogenic ras specific target, because Mob-5 binds to the cell surface of ras-transformed cells but not of parental untransformed cells [18]. Thus, this coordinated regulation of a ligand–receptor matching pair by the ras oncogene may create an autocrine activation loop in ras-transformed cells. Constitutive signaling though this receptor could be one of the mechanisms mediating ras-induced transformation. It is also possible that Mob-5/IL-24 may function in a paracrine fashion modulating the host immune response to cancer. A possible function of IL-24 within the immune system is also suggested by properties of the mouse IL-24 ortholog

designated FISP [8]. FISP was identified by a representational difference analysis method, which was employed to isolate genes expressed specifically by Th2 cells. Northern blot analysis demonstrated the expression of FISP mRNA in both total mouse splenocytes and CD-4+ -enriched T-cells, cultured under Th2 differentiation conditions (anti-CD-3, IL-2, IL-4, anti-IL-12). The expression of FISP mRNA gradually increased starting at day 3 and reached the highest level at day 5. Splenocytes or CD-4+ -enriched T-cells incubated under Th1 differentiation conditions (anti-CD-3, IL-2, anti-IL-4, IL-12) failed to produce detectable amount of FISP transcripts. FISP mRNA was also expressed in an established anti-CD-3-treated Th2 cell line and not in a Th1 cell line. Engagement of both the IL-4 receptor and T-cell receptor was required to induce expression of FISP mRNA. Signaling through the IL-4 receptor was Stat6-mediated because FISP transcripts were not induced by anti-CD-3 and IL-4 treatment in Stat6-deficient CD-4+ T-cells. Activation of the T-cell receptor signaling pathway was at least partially mediated by PKC because the PKC activator mezerein in combination with IL-4 treatment was capable of inducing FISP mRNA expression. Interestingly, a Th2 cell line grown in culture for more than 3 months appeared to constitutively express FISP mRNA and secrete FISP protein; anti-CD-3 treatment was no longer required. FISP protein was demonstrated to be secreted protein with a heterogeneous molecular mass of about 27 kDa, most likely resulting from glycosylation. Although it is clear that human IL-24 (MDA-7), mouse FISP and rat C49A/Mob-5 represent species-specific products of the same evolutionary conserved gene, it is possible that the function of these proteins diverged between species. They all are cytokine-like secreted molecules highly homologous to each other but their known up-to-date activities do not overlap. In support of this possibility mouse receptors for IL-24 have unexpectedly low sequence homology in their intracellular domains (see later). Thus, overlapping but distinct signal transduction pathways may be activated by IL-24 in different species. 2.2. IL-22 The cDNA for the mouse IL-22 ortholog, originally designated IL-TIF (IL-10-related T-cell-derived inducible factor), was identified by cDNA subtraction as a gene specifically induced by IL-9 in mouse T-cells [2]. The expression of mouse IL-22 was also induced by IL-9 in BW5147 thymic lymphoma cells, T helper cell clone TS2 and MC9 mast cells, and by IL-9 or Con A in freshly isolated splenocytes. It was also demonstrated that LPS injection in vivo stimulated IL-22 mRNA expression in various organs [21]. Constitutive expression of the mouse IL-22 gene was detected in thymus and brain. Human IL-22 was cloned based on its homology to the mouse ortholog [21] and also as a novel secreted protein [22]. IL-22 mRNA expression can be induced in T-cells by anti-CD-3-stimulation and further

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

up-regulated by the addition of Con A [21,22]. It was reported that activated human and mouse Th1, rather than Th2, CD-4+ cells produce IL-22 [23]. Several IL-22-responsive cell lines have been reported. Rapid Stat activation following treatment with human IL-22 was observed in TK-10 renal carcinoma, SW480 colon adenocarcinoma, A549 lung carcinoma, HepG2 and HepG3 hepatoma, HT29 intestinal epithelial cell line and several melanoma cell lines [21,22,24–26]. Murine IL-22 (MuIL-22) activated Stats in MES13 murine kidney mesangial cells, PC12 rat pheochromocytoma cells, 266-6 pancreatic acinar cell line and isolated primary pancreatic acinar cells [2,27]. Induction of the expression of several genes in response to IL-22 has been reported. Expression of genes for acute phase proteins (APP) such as serum amyloid A, ␣1-antichymotrypsin, and haptoglobin was up-regulated in HepG2 human hepatoma cells [21]. Similar effects were observed in vivo; MuIL-22 injection induced production of serum amyloid A in mouse liver [21]. In addition, induction of mRNA for pancreatitis-associated protein (PAP1) and osteopontin (OPN) in cultured acinar cells and for PAP1 in mouse pancreas in vivo was observed [27]. The effect was tissue-specific because it was not observed in spleen, liver, or kidney, although a slight increase of PAP1 gene expression was detected in small intestine [27]. PAP1 is a secreted protein with uncertain function which is up-regulated in acute pancreatitis, celiac disease, a small bowel disorder, and patients with cystic fibrosis [28–31]. Upregulation of APP and PAP1 mRNA expression is a direct result of IL-22 action because these IL-22-mediated activities were inhibited by neutralizing antibody against IL-10R2, the second chain of the IL-22 receptor complex [21], and were not observed in IL-10R2-deficient mice [27]. It was also reported that administration of MuIL-22 resulted in systemic effects, including decreased red cell count and serum albumin level, an increased platelet count, serum amyloid A and fibrinogen levels, and decreased body weight [23]. Basophilia in the proximal renal tubules was also observed [23]. In concordance with these in vivo data, the expression of IL-22 mRNA was induced by LPS in vivo in various organs including gut, thymus, spleen, lung, liver, kidney, stomach and heart [21]. All these observations indicate involvement of IL-22 in the inflammatory and perhaps immune responses in various organs [21,27]. However, IL-22, in contrast to IL-10, did not inhibit LPS-induced production of TNF, IL-1 and IL-6 from freshly isolated human monocytes. Furthermore, IL-22 did not inhibit the action of IL-10 in these assays [22]. Also IL-22 had no effect on IFN-␥ production from in vitro polarized Th1 cells, although a modest inhibitory effect on IL-4 production from Th2 cells was observed [22]. 2.3. IL-26 Another IL-10 homolog, originally designated AK155, was cloned as a protein expressed by herpesvirus saimiri (HVS)-transformed T-cells [5]. The protein was recently designated IL-26. HVS is a T-cell tumor virus of New

227

World monkeys. HVS is persistently present in its natural host, the squirrel monkey, without causing disease, whereas, experimental infection of other monkey species results in fatal acute T-cell lymphoma [32]. Due to its ability to transform human T-cells, the virus is used to obtain human T-cell lines. HVS-transformed T-cells can be maintained in culture and retain several characteristics of non-transformed parental cells. AK155 was one of the cDNA clones identified in a search for genes which are preferentially expressed by HVS-transformed T-cells and not by parental T-cells [5]. Further analysis revealed that the AK155/IL-26 transcript was detectable by Northern blotting in several HVS-transformed human T-cells as well as in transformed T-cells from New World monkeys. More sensitive RT-PCR assays demonstrated that the IL-26 mRNA was also expressed at low level in several other (non HVS-transformed) T-cell lines including human T-cell leukemia virus (HTLV)-transformed cell lines and also in freshly isolated PBMCs from healthy donors. The IL-26 expression was rather restricted to T-cells; several B cell and other hematological cell lines, carcinoma cell lines and primary skin biopsy cells and fibroblasts were negative for IL-26 expression, with the exception of human herpes virus 8 (HHV-8)-transformed B cell lines where a low level of IL-26 transcript was detected by RT-PCR. Thus, it appears that primary T-cells are likely to express low amount of IL-26 mRNA whereas the message is overexpressed in HVS-transformed T-cells. The IL-26 protein is likely to form a homodimer similarly to IL-10. IL-26 tagged with either His or FLAG epitope migrated as a 19 kDa band on SDS-PAGE, whereas the 19 kDa band shifted to the 36 kDa position on native nondenaturing gels. HVS-transformed T-cells constitutively secrete endogenous IL-26 which migrated on the SDS-PAGE in the region of 18 kDa as demonstrated by Western blotting with antiserum raised against IL-26. Thus, the IL-26 protein is apparently not glycosylated to a significant extent. The function of IL-26 remains to be elucidated. It is intriguing to speculate that IL-26 could play the role of an autocrine growth factor causing uncontrolled proliferation of HVS-infected T-cells and subsequently leading to malignant transformation of T-cells. It may also be involved in regulating the immune response to HVS infection. 2.4. IL-19 IL-19 was identified by scanning sequence databases for potential IL-10 homologs [3]. Transcription of the IL-19 gene can be induced in monocytes by LPS treatment as detected by Northern blotting [3]. The appearance of IL-19 mRNA in LPS-stimulated monocytes was slightly delayed compared to expression of IL-10 mRNA: significant level of IL-10 mRNA expression was induced within 2 h after LPS treatment, whereas IL-19 mRNA was not detectable until 4 h post-stimulation. Although treatment of monocytes with LPS alone induced a relatively low level of IL-19 gene

228

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

expression, priming monocytes with IL-4 or IL-13, but not IFN-␥, significantly increased the levels of IL-19 mRNA induced by subsequent stimulation with LPS. Pretreatment with IL-13 had a lesser effect on potentiating LPS-induced IL-19 expression. In contrast, all three cytokines (IL-4, IL-13 and IFN-␥) demonstrated similar ability to enhance IL-10 gene expression in LPS-stimulated monocytes. Treatment of monocytes with either IFN-␤, IFN-␥, IL-4, IL-10, or IL-13 did not induce de novo expression of IL-19. However, GM-CSF was capable of directly inducing IL-19 gene expression in monocytes [3]. The FLAG epitope-tagged IL-19 protein was secreted from COS cells and migrated on SDS-PAGE as multiple bands in the region of 30–40 kDa as demonstrated by Western blotting with anti-FLAG antibody. Multiple forms of IL-19 are the result of glycosylation of the protein. There are two potential sites for N-linked glycosylation, and the treatment of the protein with peptide: N-glycosidase F resulted in the disappearance of the bands in the region of 35–40 kDa and the formation of a strong single band in the region of 21 kDa for FLAG-tagged-IL-19. The function of IL-19 awaits to be determined. The mRNA for IL-19 is not detectable in monocytes until 4 h after LPS treatment and closely follows the expression of IL-10 mRNA which is detectable 2 h post-stimulation, which in turn, follows the expression of proinflammatory cytokines such as IL-1 and TNF-␣, which are expressed within 1 h post-stimulation. This pattern of IL-19 gene expression may suggest a role for this cytokine as a feedback inhibitor of proinflammatory cytokine production, similarly to IL-10. However, the fact that IL-19 is expressed 2 h later then IL-10, may also suggest that the function of IL-19 may be to limit the anti-inflammatory action of IL-10. In any case, the induction of IL-19 by LPS indicates that this cytokine is likely to participate in the complex regulation of the inflammatory response. It is noteworthy that ESTs representing IL-19 cDNA were cloned from pregnant uterus. It is known that during pregnancy immunity of the mother is shifted toward Th2 type of immune response [33,34] and IL-19 may contribute to this shift. 2.5. IL-20 IL-20 was identified in a database search for helical cytokines [1]. The action of IL-20 was linked to skin development. Transgenic mice with either ubiquitous IL-20 expression, or expression targeted to liver, lymphocytes, or epithelium, died within days after birth, were smaller in size, and had shiny, wrinkled skin. Further analysis revealed various skin abnormalities similar to those observed in psoriasis. Aberrant epidermis was thicker than in the age-matched control, and showed thickened stratum spinosum, but more compact stratum corneum layers. Several differentiation and proliferation markers normally confined to the basal layer of the epidermis were detected also in the suprabasal layer. These changes indicate altered epidermal differen-

tiation with hypoproliferation of keratinocytes. However, the skin of transgenic mice did not contain the immune infiltrates commonly present in psoriatic skin. Other abnormalities included apoptotic thymic lymphocytes in many of the transgenic mice, swollen extremities and visible lack of adipose tissue. The human HaCaT keratinocyte cell line responded to IL-20 with Stat3 activation and reporter gene expression. IL-1␤, epidermal growth factor (EGF) and TNF-␣ involved in proliferative and inflammatory signals in the skin, enhanced the action of IL-20. In addition, the expression of several genes involved in inflammation were increased in HaCaT-cells in response to IL-20. IL-20 and IL-1␣ had synergistic effect on the induction of some of these and other genes. Thus, IL-20 may modulate the inflammatory response in the skin. 2.6. Viral homologs Several viruses from the herpesvirus or poxvirus genera encode viral cytokines which can be assigned to the family of IL-10-related cytokines [35]. These viruses are likely to have captured the genes encoding these cytokines from host genomes, and benefit from expressing these cytokines. Most of these viral cytokines posses IL-10-like biological activities and signal through the host IL-10 receptor complex. HHV encoding viral IL-10 (vIL-10) are Epstein-Barr virus (EBV; ebvIL-10 or vIL-10; [36,37]) and cytomegalovirus (cmvIL-10, Fig. 1; [38,39]). Two poxviruses which are able to infect humans and also other species encode IL-10 homologs: orf virus (ovIL-10; [40]) and Yaba-like disease virus (YLDV, [41]). The YLDV-encoded cytokine is the only viral cytokine which demonstrates more homology to IL-24 than to IL-10 itself [41]). Numerous animal viruses, also from herpesvirus or poxvirus genera, encode their own IL-10 homologs. Virus-encoded cytokines may act in either autocrine fashion, increasing proliferation and viability of virus-infected cells by protecting them from apoptosis, or in paracrine fashion, modulating the immune response against viral infection thus helping viruses to escape immune surveillance and survive in the host. It is of interest that viruses encoding IL-10-related cytokines are either capable of establishing life-long latency in the host (EBV, CMV and several other animal herpes viruses) or long-lasting persistent infection. Nevertheless, the exact in vivo roles of viral IL-10-related cytokines in the viral life cycle, in immune evasion and/or in helping virus-infected cells to survive immune surveillance remain to be defined. 3. Receptors 3.1. Class II cytokine receptor family Cytokines exert their actions by binding to specific cell-surface receptors that leads to the activation of cytokine-

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

229

Fig. 2. The ␥R1 and ␥R2; and ␣R1 and ␣R2 are two subunits of the IFN-␥ (type II IFN) [99,100], the IFN-␣ (type I IFN) receptor complexes, respectively [82–84,101]. IFN-␣R2 has two membrane-bound splice variants, IFN-␣R2c with longer intracellular domain and IFN-␣R2b with shorter intracellular domain. Only IFN-␣R2c is thought to be competent for Jak and Stat recruitment and signaling. TF is a receptor for coagulation factor VIIa (FVIIa) [102–105]. 10R2 can be combined with either 10R1 or 22R1 to assemble the IL-10 or IL-22 receptor complex, respectively [25,27,52,53,106]. The 22R1 can also function with 20R2 generating the receptor complex for IL-20 and IL-24 [17,18]. In turn, 20R2 can also join IL-20R1 to form the receptor complex for IL-19, IL-20 and IL-24 [1,17,18]. The 22BP is the IL-22 binding protein, the only soluble receptor from this family [24,26,63,64]. There is a new receptor CRF2-12 coming to the field with no published information available. Jak members associated with the intracellular domains of the receptors and Stat members recruited directly or indirectly (in parentheses) through these receptors are shown. The dashes indicate these receptors do not recruit Stats or associated with Jaks. The “Tyk2?” and “Jak1?” means we predict that Tyk2 and Jak1, respectively, are recruited to the receptor chain based on the structure of the intracellular domains.

specific signal transduction pathways. All IL-10-related cytokines including IL-10 itself, signal through receptors belonging to the class II cytokine receptor family [42,43] (Figs. 2 and 3). In addition, receptors from this family are utilized by types I and II IFNs and by coagulation factor VIIa (FVIIa). Class II cytokine receptors are characterized by the patterns of conserved amino acid (a.a.) residues within the receptor extracellular domains (Fig. 3) [42,43], although overall homology in their extracellular domains is low and there is no apparent homology within the transmembrane and intracellular domains of the receptors. The extracellular domains of the receptors are composed of tandem fibronectin type III (FNIII) domains with a characteristic pattern of proline and cysteine residues, as well as other conserved features. Most known family members have two tandem FNIII domains with the exception of IFN-␣R1, a subunit of the type I IFN receptor complex, which has four FNIII tandem domains (Figs. 2 and 3). There are 12 members of this family: two receptor chains for each types I and II IFNs; two receptor chains for IL-10; the tissue factor (TF) that binds FVIIa; four receptors that are utilized by IL-10-related cytokines for signaling; and one currently orphan receptor

(Fig. 2). This review is mainly focused on receptor complexes for IL-10-related cytokines. Receptor complexes for types I and II IFNs and IL-10, the complex between TF and FVIIa, and their ligand-induced signal transduction events have been subjects of recent reviews [44–51]. All novel receptor chains for IL-10-related cytokines were discovered in silico [1,24,26,50]. Our designation of these initially orphan receptors followed the nomenclature used by Lutfalla et al. when the first orphan receptor from the class II cytokine receptor family was cloned [52]. This receptor was originally designated cytokine receptor family class II member 4 (CRF2-4) and later was demonstrated to be a shared receptor subunit of the IL-10 and IL-22 receptor complexes [53,25,22]. Thus, based on this nomenclature the orphan receptors were designated CRF2-8, CRF2-9, CRF2-10, CRF2-11 and CRF2-12 (Fig. 2 and Table 1) [50,24]. Although the receptors were later named according to their functions, their nomenclature as CRF2-N may turn out to be more convenient because some of these receptors are shared between different receptor complexes and therefore do not have a single function. Moreover, the extent of receptor sharing has not been entirely defined.

230

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

Fig. 3. Full length extracellular domains with signal peptides are shown for IFN-␣R2, TF, IFN-␥R1, IFN-␥R2, IL-10R1, IL-10R2, IL-22R1 and IL-20R1, IL-20R2 and IL-22BP. The extracellular domain of the IFN-␣R1 chain is divided into two segments: signal peptide and N-terminal D200 domain comprise IFN-␣R1n and the C-terminal D200 is designated here IFN-␣R1c. The consensus sequence is shown on the bottom. The color code for identical and similar a.a. is as in Fig. 1.

3.2. Functional receptor complexes and signaling The receptor complexes for IL-10-related cytokines will likely follow the paradigm of signaling for cytokines utilizing class II cytokine receptors [48–50,53]. The paradigm has been established based on common structure-functional features of receptor complexes for IFN-␥ and IL-10 (Fig. 4A). These ligands signal through receptor complexes composed of two distinct receptor chains leading primarily to the activation of the Jak–Stat signal transduction pathway. Ligand binding induces oligomerization of receptor subunits. The receptor chains within a given receptor complex can be divided into two classes denoted R1 and R2. An R1 type subunit (e.g. IFN-␥R1 and IL-10R1) binds ligand with high affinity, has a long intracellular domain which is associated with Jak1 tyrosine kinase, is phosphorylated on Tyr residues after receptor engagement and therefore drives recruitment of various signal transducing, SH2 domain-containing proteins, particularly Stats, to the

receptor complex. Thus, the R1 chain defines the specificity of signaling. The Stats are then activated by Jak-mediated tyrosine-phosphorylation, form homo- or hetero-dimers, dissociate from receptors and translocate to the nucleus. In the nucleus, the Stat dimers, in combination with other factors, modulate the finely-tuned and well-orchestrated transcription of cytokine-regulatable genes. IFN-␥ and IL-10 are homo-dimers [54–56] and their binding to the R1 subunit leads to its homo-dimerization [57,58]. However, this event alone, without engagement of the R2 type subunit (e.g. IFN-␥R2 and IL-10R2), is not sufficient to initiate signaling. The R2 type subunit does not bind ligand on its own, possesses a short intracellular domain which is associated with Jak2 (IFN-␥R2) or Tyk2 (IL-10R2) tyrosine kinases and does not recruit Stats. It seems that the only function of the R2 subunit is to initiate signal transduction events by bringing an additional tyrosine kinase to the receptor complex and, thus, allowing Jak cross-activation [53,59–62].

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

231

Fig. 4. IL-10 is an intercalating homo-dimer. Structures of IL-10-related cytokines (IL-X) have not been defined. Although most of them are likely to form homodimeric structures, some ligand may exist as monomers. Nevertheless, all ligands require two distinct receptor chains (R1 and R2 type) to induce signal transduction. In the case of dimers, the receptor complex is likely to be structurally homologous to the IFN-␥ and IL-10 receptor complexes, which are composed of two molecules of each receptor chain (A). Monomers may signal through heterodimeric receptor complexes consisting of various R1 and R2 type receptors (B). Each R1 type chain (IL-10R1, IL-20R1, IL-22R1) is associated with Jak tyrosine kinase, likely Jak1, and is responsible after phosphorylation of its intracellular domain for the recruitment of a variety of signaling molecules. Each R2 type chain (IL-10R2 and IL-20R2) has relatively short intracellular domain which is associated with another Jak tyrosine kinase, likely Tyk2. Upon formation of the ligand-induced hetero-dimerization or heterooligomerization of various R1 and R2 chains receptor-associated Jaks crossactivate each other, phosphorylate the R1 intracellular domain and, thus, initiate the cascade of signal transduction events. It seems that the only function of the R2 type chain is to bring another Jak member to the receptor complex to allow Jak crossphosphorylation. Stat3 is a predominant Stat molecule activated by all IL-10-related cytokines. Stat1 and Stat5 activation have also been detected for several cytokines. Soluble receptor IL-22BP binds IL-22, prevents its binding to the membrane-bound IL-22 receptor complex and, thus, neutralizes its activity.

The receptor complexes for IL-19, IL-20, IL-22 and IL-24 were recently defined by functional reconstitution (Fig. 2) [1,17,25,18,22]. At present, the IL-26 receptor complex remains to be determined. All these cytokines require two distinct receptor subunits for signaling. The functional IL-22 receptor complex consists of IL-22R1 (CRF2-9) and IL-10R2 (CRF2-4) [22,53,25]. Thus, IL-10R2 is a common subunit for the IL-10 and IL-22 receptor complexes. Both IL-20 and IL-24 can exert their actions through two types of receptor complexes; IL-20R2 (CRF2-11) can pair with either IL-20R1 (CRF2-8) or IL-22R1 (CRF2-9) [1,17,18]. IL-19 requires IL-20R1 (CRF2-8) and IL-20R2 (CRF2-11) for signaling. Based on the length of their intracellular domains and participation in the Stat recruitment process, the receptor pairs within a given complex can be well described by the R1/R2 type division. However, ligand binding does not follow the previously established paradigm when one subunit binds ligand strongly and one subunit does not. IL-22 demonstrates comparable binding to both subunits of its receptor complex, IL-22R1 (CRF2-9) and IL-10R2 (CRF2-4) [25,22]. IL-20 requires both receptor

subunits, IL-20R1 (CRF2-8) and IL-20R2 (CRF2-11) for high affinity binding and does not detectably bind to either subunit expressed alone [1]. Binding of IL-20 to IL-22R1 (CRF2-9) as well as to the complex of IL-22R1 (CRF2-9) and IL-20R2 (CRF2-11) has not been defined. IL-24 exhibits significant binding to the R2 type subunit, IL-20R2 (CRF2-11), whereas coexpression of either R1 type subunits, IL-20R1 (CRF2-8) or IL-22R1 (CRF2-9) dramatically increases binding affinity [18]. Neither IL-20R1 nor IL-22R1 alone were capable of binding IL-24 [18]. The binding pattern of IL-19 remains to be determined. It is of interest that human IL-24, unlike rat IL-24/Mob-5, was not capable of binding to ras-transformed rat cells suggesting a certain degree of species-specificity of IL-24 [7]. The species-specificity of other IL-10-related cytokines is currently unknown. A soluble receptor from this family has been identified [24,26,63,64]. The COS-cell-expressed secreted protein appeared on the SDS-PAGE as a broad band in the region of about 35–45 kDa, suggesting probable glycosylation of the protein. Experiments demonstrated that the protein

232

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

binds IL-22 and prevents binding of IL-22 to the functional cell surface IL-22 receptor complex. It seems that this soluble receptor has higher affinity for IL-22 binding than the membrane-bound IL-22 receptor complex [24]. This soluble receptor, designated IL-22 binding protein (IL-22BP or CRF2-10), is capable of neutralizing IL-22 activity in several assays [24,26,63]. It also appears that the IL-22:IL-22BP complex is stable and little or no dissociation of the complex occurs [24]. IL-22BP does not potentiate IL-22 cellular activities at a low concentration [26]. Interaction of IL-22BP with IL-22 is very specific; IL-22BP-Fc fusion protein was not able to bind IL-19, IL-20 and IL-24 [17] and also IL-22BP failed to neutralize IL-10 activities [24,26]. Thus, IL-22BP is a naturally occurring, highly specific IL-22 antagonist. As with IL-10, the related proteins IL-19, IL-20, IL-22 and IL-24 signal through the Jak–Stat pathway (Fig. 4). Stat3 is the predominant Stat protein activated by all four cytokines as well as by IL-10 itself [1,2,17,18,21,22,24–27,53,65–67]. In addition, Stat1 is activated by IL-22 and IL-24 [18,21,22,24,25], and IL-22 can also activate Stat5 [2,22]. Stat3 is recruited to the tyrosine-phosphorylated IL-10R1 intracellular domain through two Stat3 docking sites [67], which conform with the classical Stat3 recruitment motif (YXXQ) [68]. Analysis of receptor intracellular domains reveals that IL-20R1 (CRF2-8) and IL-22R1 (CRF2-9) also possess two and four classical Stat3 recruitment sites, respectively, and probably also a Jak1 association site [50]. The IL-10R2 (CRF2-4) intracellular domain is associated with Tyk2 [61,53]. Both the IL-10R2 (CRF2-4) and IL-20R2 (CRF2-11) intracellular domains demonstrated some sequence similarity with the Tyk2 association site on the IFN-␣R1 intracellular domain [69], suggesting that IL-20R2 interacts with Tyk2. However, the pattern of Jak activation by IL-10-related cytokines remains to be determined experimentally. Whereas IL-10 and IFN-␥ form intercalating non-covalent homo-dimers [54–56], the structure of IL-10-related cytokines has not been defined, although IL-26 seems likely to form homo-dimers [5]. Crosslinking studies with radioactively labeled IL-19, IL-22 and IL-24 indicated that like IL-10, these proteins may form dimers or tetramers ([24,25], unpublished data). If so, the functional receptor complexes may involve a ligand dimer, two copies of the R1 and two copies of the R2 subunits specific for each receptor complex (Fig. 4A). In contrast, it was predicted and supported by preliminary data that IL-20 does not form an intercalating homo-dimer [1]. In such a scenario ligand-induced homo-dimerization of two R1 chains is unlikely. Thus, the IL-20 receptor complex could consists of one molecule of R1 type receptor subunit, either IL-20R1 or IL-22R1, and one IL-20R2 molecule (Fig. 4B). Thus, further functional and structural characterization of receptor complexes for IL-10-related cytokines may extend and modify the existing paradigm for cytokine class II receptor complexes and signaling.

3.3. Mouse receptors Genes encoding mouse CRF2-8, CRF2-9, CRF2-10 and CRF2-11 orthologs were identified and their corresponding cDNAs predicted (Fig. 5) [70]. Sequences of CRF2-10 and CRF2-11 are highly conserved between human and mouse proteins as well as sequences of the extracellular domains of CRF2-8 and CRF2-9. In contrast, the intracellular domains of CRF2-9 and particularly CRF2-8 demonstrate only limited homology. These domains are solely responsible for the recruitment of various molecules which will be activated by engagement of these receptors with particular cytokines. Thus, they define the specificity of signal transduction pathway. The membrane-proximal parts of the intracellular domains are preserved more than the rest of the intracellular domains, suggesting that Jak association sites are likely to be intact and functional. Sequence motifs containing phosphorylated Tyr residues can serve as docking sites for the recruitment of SH2-domain containing proteins. There are multiple Tyr residues that are present only in mouse or human receptors, raising the possibility that distinct subsets of signaling molecules can be activated through mouse or human receptors. However, Stat3 should be activated through CRF2-8 and CRF2-9 of both human and mouse origin. All four Stat3 recruitment sites were preserved in mouse CRF2-9 and, although both Stat3 docking sites of human CRF2-8 are mutated in mouse CRF2-8, there is a single alternative site introduced into mouse CRF2-8. Thus, it is possible that mouse and human IL-10-related cytokines may possess overlapping but distinct biological activities. It is interesting to note, that there are data suggesting that this could be the case for human versus mouse IL-24 (described here previously). 3.4. Receptor expression Since each cytokine signals through two distinct receptor subunits, the simultaneous presence in a cell of both receptor subunits is required for cytokine activity. For most of the newly discovered receptors, studies of their expression are fragmentary. IL-10R2 (CRF2-4), which is used by IL-10 and IL-22, is ubiquitously expressed. Its mRNA was detected by Northern blotting in all tissues tested albeit with very low level of expression in the brain [27,71]. Thus, the expression of IL-10R1 and IL-22R1 in cells will enable or limit the action of IL-10 and IL-22. IL-22R1 (CRF2-9) is a subunit of receptor complexes for IL-20, IL-22 and IL-24. By Northern blotting, the expression of the IL-22R1 mRNA was detected in several normal tissues including kidney, liver, intestine and pancreas, where the level of expression was the highest [25,27]; low expression was observed in adrenal gland, uterus and lung [27]. The expression pattern correlates well with the in vivo biological activities of IL-22 reported so far: induction of APP in liver, PAP1 in pancreas and basophilia in the proximal renal tubules (see before for details). Several solid tumor cell

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

233

Fig. 5. Alignment of mouse and human IL-20R1 (CRF2-8), IL-20R2 (CRF2-11), IL-22R1 (CRF2-9) and IL-22BP (CRF2-10). The alignment of the a.a. sequences of human and mouse receptors is shown. The consensus sequence is shown on the bottom. Identical a.a. corresponding to the consensus sequence are shown in black outline with white lettering. Similar a.a. are shown in gray outline with white lettering. The a.a. residues are numbered starting from first Met residue (signal peptide a.a. are included).

lines constitutively express the IL-22R1 mRNA, including colorectal adenocarcinoma SW480, lung carcinoma A549, melanoma G361, hepatoma HepG2 and renal carcinoma Caki-1 and TK-10 cell lines, HT29 intestinal epithelial cell line and HaCaT keratinocyte cell line [18,21,22,25,26]. It is interesting to note that cell lines expressing the IL-22R1 mRNA are non-hematopoietic tumor cell lines. Inasmuch as IL-22 is implicated in inflammation, the expression of IL-22BP (CRF2-10) in certain tissues can, per-

haps, modulate local inflamation. In this light, it is of interest that IL-22BP expression was detected by in situ hybridization in the mononuclear cells of inflammatory infiltration sites, plasma cells, and a subset of epithelial cells [63]. Cells expressing IL-22BP as detected by in situ hybridization were observed in several tissues including placenta, skin, inflamed appendix, lung, gastrointestinal tract, lymph node, thymus, and spleen [63]. Also, strong signals were detected in epithelial cells and some interstitial cells (most likely

234

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

mononuclear cells) in ovarian carcinoma, although, there was no signal observed in the normal ovarian tissue [63]. The regulation of IL-22BP expression is not known: induction of IL-22BP expression in response to LPS or anti-CD-3 Abs in peripheral mononuclear cells was not detected [26]. Also, IL-22 stimulation did not induce IL-22BP production [26]. The IL-22BP expression profile generated by Northern blot and PCR analysis indicated that IL-22BP is highly expressed in placenta, mammary gland, breast, spleen, skin, and lung, with lower expression in a variety of other tissues such as heart, pancreas, testis, thymus and prostate [24,26,63,64]. IL-22BP expression was detected in the digestive system (stomach, small intestine, esophagus, gastro-esophageal, pancreas, duodenum, ileum, colon, and small bowel), the female reproductive system (mammary gland, endometrium, and breast), and other systems (lymph nodes, lung, skin, parotid, bladder, bronchus, heart ventricles, and kidney) [63]. It is noteworthy that IL-22BP is expressed in certain tissue-specific tumors such as ovarian, uterine and rectal cancers, but not in the corresponding normal tissues [63]. IL-20R1 (CRF2-8), which appears to be utilized by IL-19, IL-20 and IL-24, demonstrates a wide expression pattern [1]. A high level of IL-20R1 mRNA expression was detected in skin, testis, heart, placenta, salivary gland and prostate by RT-PCR. Moderate expression was observed in brain, lung, stomach, pancreas, ovary, uterus and thyroid and adrenal glands. Hardly detectable level was seen in kidney, liver, colon, muscle and small intestine. IL-20R2 (CRF2-11), a shared receptor subunit for the IL-19, IL-20 and IL-24 receptor complexes, has rather limited pattern of expression as demonstrated by RT-PCR [1]. Its message was detected at high level in skin and testis, at moderate level in ovary, at very low level in heart, lung, muscle, placenta, and adrenal gland, and barely detectable level in small intestine, salivary gland and peripheral blood leukocytes. The expression of IL-20R2 should be a limiting factor dictating the physiological sites of action of IL-19, IL-20 and IL-24. The differential physiology of IL-19, IL-20 and IL-24 in particular, presents an exciting area of future research. It is important to note that the expression of the IL-20 receptor subunits (IL-20R1 and IL-20R2) was found to be up-regulated in psoriatic skin whereas normal skin had low level of receptor expression. The expression of receptors was also detected in keratinocytes, endothelial cells and immune cells in psoriatic lesions [1]. 4. Chromosomal localization and gene structure 4.1. Genes encoding IL-10-related cytokines The genes encoding IL-10-related cytokines are clustered at two chromosomal loci (Fig. 6) [70]. A 200-kb region on chromosome 1q32+2 contains genes for IL-10, IL-19, IL-20 and IL-24. The IL-19, IL-20 and IL-24 genes are positioned

in a head-to-tail direction, whereas the IL-10 gene is transcribed in the opposite direction toward the telomere. The genes encoding IL-22 and IL-26 are mapped to chromosome 12q14+3, 30 kb apart of each other and within 100 kb of the IFNG gene. All three genes are oriented toward the telomere. It is interesting to note that both IFN-γ and IL-26 are overexpressed by HVS-transformed T-cells [72,5]. Because both genes are closely positioned in head-to-tail orientation it is possible that the genes share common regulatory elements. There are several loci within this region of chromosome 12 which were linked by genetic studies to asthma and atopy (for review see reference [73]). The strongest evidence for linkage is for a region near the IFNG gene [74–77]. However, the gene for IFN-␥ appears to be highly conserved, suggesting that mutations of the IFNG gene are unlikely to be a significant cause of inherited asthma [78]. The IL-22 and IL-26 genes are positioned next to the IFNG gene on chromosome 12 and, thus, are possible candidates for linkage to asthma. Also the multiple aberration region (a chromosomal breakpoint region) in several benign tumors, such as leiomyomas of the uterus, lipomas and pleomorphic adenomas of the salivary gland was mapped to this region of chromosome 12 [5,79,80]. All genes encoding IL-10-related cytokines have similar structural features. The coding region of each of the genes is divided into five exons (exons 1–5 on Fig. 7A). Positions of the intron/exon junctions are conserved within the genes, although intron sizes vary substantially. However, genes encoding IL-19, IL-22 and IL-24 have additional exons positioned upstream of their first coding exons (exons 1a and 1b on Fig. 7A and B) [81,3,11]. It appears that these exons encoding the 5 -UTRs of the IL-19 and IL-24 mRNAs can be alternatively spliced. This is well established for the IL-19 gene, for which two alternatively spliced transcripts have been reported [3]. It appears that there are at least two alternative exons 1a (exon 1a1 and exon 1a2) within the IL-19 gene (Fig. 7A and B). One of them is mapped within 37.6 kb of exon 1, positioning the IL-19 gene promoter to a region upstream of exon 1a1. Exon 1a2 maps within 2.3 kb of exon 1. It seems likely that the IL-19 gene can be transcribed from two separate promoters which may have differential regulation. The IL-24 gene has two exons (exon 1a and exon 1b) upstream of exon 1 (Fig. 7B). So far there is only one EST (GeneBank Accession Number T27306), indicating that exon 1a can be spliced out in one of the IL-24 transcripts (Fig. 7A). Interestingly, both exons, exon 1a2 in the IL-19 gene and exon 1a in the IL-24 gene, generate additional upstream ATG codons (Metupstream ) in frame with the first ATG codons (Met) (Fig. 7B). The translation from Metupstream generates a long abnormal signal peptide for the IL-19 and IL-24 proteins (Fig. 7B and D). Alternatively, when exon 1a is spliced out in the IL-24 transcript or exon 1a2 is substituted by exon 1a1 in the IL-19 transcript, the translation of both genes proceeds from the ATG codon encoded by the exon 1 (Fig. 7A). This generates proteins with canonical signal peptides. Interestingly, expression of either

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

235

Fig. 6. The NCBI database [70] was used to determine the chromosomal localization of the genes encoding IL-10-related cytokines and receptors from the class II cytokine receptor family and to generate the ideograms of chromosomes.

IL-19 or IL-24 driven from plasmids encoding the extended abnormal signal peptide severely limited the amount of proteins secreted ([3], and unpublished data), whereas the expression of the proteins with shorter signal peptide led to the secretion of proteins at higher level. 4.2. Genes encoding receptors The genes encoding receptors from the class II cytokine receptor family are scattered between chromosomes 1, 3, 6, 11 and 21 [70]. Some genes are clustered: four genes (the IFNAR1, IFNAR2, IL-10R2 and IFNGR2 genes) are on chromosome 21 and three genes (the IFNGR1, IL-20R1 and IL-22BP genes) on chromosome 6. The genes for TF and IL-22R1 are mapped to different regions of chromosome 1 and the IL-10R1 chain is encoded on chromosome 11. The genes for the receptors also retain conserved structures. The coding regions of the receptor genes are composed of seven exons (exons 1–7, Fig. 7C). Exon 1 encodes the 5 -UTR and the signal peptide, the extracellular domain is encoded by exons 2, 3, 4, 5, and part of the exon 6. Exon 6

also encodes the transmembrane domain and the beginning of the intracellular domain. Exon 7 covers the rest of the intracellular domain and the 3 -UTR. The positions of the introns are also conserved. There are several deviations from the rule. The TF gene apparently lacks exon 7. It has a short intracellular domain of 21 a.a. with no function assigned to it. Three splice variants has been reported for the human IFNAR2 gene, resulting in three distinct protein products, IFN-␣R2a, IFN-␣R2b, and IFN-␣R2c [82–84]. IFN-␣R2a is derived by skipping exon 6. IFN-␣R2b is encoded by the transcript lacking exon 7. When all exons are present, IFN-␣R2c, which appears to be the functional membrane-bound form is produced. Alternative splicing of the murine IFNAR2 gene is also observed, producing both a membrane-bound and soluble receptor; however, the details of alternative splicing patterns differ for human and murine IFNAR2 genes [85]. Because IFN-␣R1 has four FNIII tandem domains (see before), the IFNAR1 gene has four additional exons (exons 2 , 3 , 4 and 5 ), encoding the additional module of the IFN-␣R1 extracellular domain.

236

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

Fig. 7. Schematic structure of the genes for IL-10-related cytokines and their receptors. Thick colored bars represent proteins. Arrows indicate relative positions of former introns. Transcripts are schematically shown as strings of lines (exons, ex) interrupted by dotted lines (introns). The coding region of cytokine genes is contained within five exons (A and B). IL-19 and IL-22 transcripts have one additional exon (ex1a) upstream of exon 1 (ex1). IL-19 transcripts demonstrate two alternative variants of ex1a (ex1a1 (A) and ex1a2 (B)). IL-24 transcripts have two additional exons (ex1a and ex1b) upstream of ex1 (B). Ex1a can be spliced out in some of IL-24 transcripts (A). When ex1a2 or ex1a are present in IL-19 or IL-24 transcripts respectively, an additional Met codon (Metupstream , MUP ) appears in frame with the Met codon (M) encoded within ex1 (B). Translation from MUP results in elongated abnormal signal peptide for IL-19 and IL-24 proteins (IL-19L and IL-24L ). Otherwise, translation of IL-19 and IL-24 transcripts starts from M generating proteins with canonical signal peptide (A). Hydropathy plot of IL-19L is shown in correlation with the schematic structure of IL-19 and IL-19L proteins (D). Arrows indicate positions of MUP and M codons. Receptor genes contain seven exons with the exception of the IL-22BP gene which has 5 exons and encodes soluble receptor (C). There are several splice variants for IL-22BP and IL-20R1 described in the text and not presented on the figure. SP and TM represent signal peptide and the transmembrane domain, respectively.

IL-22BP is the only soluble receptor from the class II cytokine receptor family [26,24]. Lacking the transmembrane and intracellular domains, the coding region of the IL-22BP gene derives from only five exons (exons 1–5). However, the gene for IL-22BP has an additional exon 1a encoding an extended 5 -UTR (Fig. 7C). In addition, there is an alternative splicing pattern which either inserts exon 3a between exons 3 and 4 creating a longer splice variant, or eliminates the exon 4, creating a prematurely terminated short protein. These two splicing events, insertion of exon 3a and skipping exon 4, can also occur in one transcript, creating an intermediate splice variant. Several ESTs indicate that there are two splice variants of the IL-20R1 transcript with spliced out exon 3 and with eliminated part of exon 4 in addition to entire exon 3 [70]. Both events result in the generation of short polypeptides due to frame shifting.

5. Concluding remarks All these novel cytokines compose the family of IL10-related cytokines. They are likely to possess pleiotropic,

cell specific and, perhaps, species-specific activities as IL-10 itself does [9]. Several IL-10-related cytokines could be involved in skin development and functioning. IL-20 transgenic mice are characterized by hyperproliferation of keratinocytes [1]. Rat IL-24/C49A is expressed in normal rat skin at a low level, and its expression is up-regulated in the wound [6]. Human IL-24/MDA-7 is expressed by normal melanocytes and enhanced proliferation of normal human skin fibroblast correlates with increased expression of IL-24 mRNA [6,10,11]. Both IL-20 and IL-24 and also IL-19 are capable of signaling through the same IL-20 receptor complex which is expressed in skin [1,17,18]. These three cytokines activate Stat3 in cytokine-responsive cells. It is noteworthy that mice with keratinocyte-targeted deletion of the Stat3 gene develop practically normal skin, however, they have impaired wound healing [86]. All these suggest that at least IL-19, IL-20 and IL-24 can participate in regulating proliferation and differentiation of various skin cells. However, the skin is not only a constitutively regenerating, self-repairing organ, it also provides an environment and signals for the immune system to generate proper immune response to

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

various pathogens and antigens. IL-10 itself has potential actions in various cutaneous disorders by regulating various aspects of inflammatory and immune responses in the skin [87,88]. Thus, several IL-10-related cytokines may play important and perhaps overlapping roles in regulating proper skin functioning, including inflammatory processes, by modulating the expression of inflammatory mediators in the skin and perhaps acting directly on immune cells. The fact that IL-19, IL-22 and IL-24 can be produced by various immune cells in response to different stimuli supports this proposal. The EST database demonstrates that several receptors for IL-10-related cytokines are expressed in leukocytes [70] and, thus, certain subsets of leukocytes can respond to these cytokines. However, immunomodulatory activities of IL-10-related cytokines remains to be demonstrated. Linkage to cancer development under certain conditions may also be proposed for IL-10-related cytokines. Stat3 activation is a common motif of IL-10-related cytokine signaling. Constitutively active Stat3 is capable of driving cellular transformation [89]. Thus, if cells would simultaneously express one of these cytokines and its functional receptor, then this could cause an autocrine loop maintaining constitutive activation of Stat3 that may result in transformation. Such a scenario may occur in ras-transformed cells [7]. In addition, the cmvIL-10 gene is collinear with a region of the CMV genome which was reported to be able to transform rodent cells [90–93]. IL-22 is clearly involved in the regulation of inflammatory responses. Its mRNA expression is induced by LPS injection in multiple mouse organs [21]. IL-22 has direct and tissue-specific effects in upregulating expression of several proteins such as APP and PAP1 known to be involved in inflammatory responses [21,23,27]. These secreted proteins, as well as IL-22 itself being induced in a particular organ, can then go to circulation and cause a systemic effect. In this respect, it is interesting to note that one of the reported activities for PAP1 is its protective effect on leukocyte-mediated lung injury [94]. The IL-22 gene locus has been potentially linked to asthma and atopy by genetic studies [73]. IL-22 is also induced by IL-9, a Th2 cytokine active on T and B lymphocytes, mast cells, and eosinophils, and potentially involved in allergy and asthma [95–97]. Lung tissue expresses a low, albeit detectable, level of IL-22R1 [27]. Expression of IL-22BP was also detected by in situ hybridization in the mononuclear cells of inflammatory infiltration sites in several tissues including lung and skin [63]. IL-22 may also be active in skin because IL-22R1 is expressed in G361 melanoma and HaCaT keratinocyte cell lines [25,18], and several melanoma cell lines respond to IL-22 [21]. Whether lung and skin tissues respond directly to IL-22 or can be affected by some of IL-22-induced proteins remains to be determined. Nevertheless, it seems likely that IL-10-related cytokines may act as important modulators of inflammatory responses in a variety of tissues. So far IL-19, IL-20 and IL-24 demonstrate more tissue-restricted action then IL-22 does, which is achieved through tissue-restricted expres-

237

sion of IL-20R2, the receptor chain required for signaling by IL-19, IL-20 and IL-24. Extensive receptor sharing by IL-10-related cytokines also indicates that they should have overlapping activities. Importantly, IL-20 and IL-24 should possess a set of IL-22-specific biological activities because IL-22R1 is one of the receptors utilized by IL-20 and IL-24 for signaling. IL-22R1 is the R1 type receptor and its intracellular domain is responsible for mediating IL-22-specific biological activities [25]. This speculation is supported by the observation that, in HaCaT cells, IL-20 induces expression of several proteins involved in inflammation [1]. Thus, it seems likely that IL-22 can be produced by and is active on multiple tissues. Therefore, IL-22 induced in an isolated inflammation site may enter the circulation and cause a systemic effect. However, there are two mechanisms regulating this effect. Because IL-22 binding to the IL-10R2 chain expressed alone does not lead to signaling, it may prevent the introduction of IL-22 into the circulation (local regulation). In addition, IL-22BP secreted by mononuclear cells in the site of inflammation also inhibits IL-22 action (systemic regulation). Action of IL-19, IL-20 and IL-24 is limited by the pattern of IL-20R2 expression, which is confined to certain tissues [1]. In addition, production of IL-19 and IL-24 with long abnormal signal peptide limits their secretion and may target these proteins to the cellular membrane and/or to the cytosol. This may provide a mechanism for limiting the action of these cytokines to the level of cell-to-cell contacts. Alternatively, cytokines can be released in the case of cellular injury such as skin damage caused by either trauma or immune cell attack. The “classical” approach in science when a biological function preceded the discovery of the gene encoding this function has been reversed in the Genomic Era. IL-10-related cytokines as well as their receptors were identified using the power of genomics; and subsequently the hunt for the functions has begun. We are just beginning an exploration of the biology, physiology and molecular biology of these molecules. Immediately on the agenda must be a more comprehensive determination of the expression and distribution of these IL-10-related cytokines and their receptors, in terms of development and differentiation, mature tissue distribution, and responses to biologic or environmental stimuli. The questions are many. What are their major functions? Do IL-19, IL-20, IL-22 and IL-24 share functions? If so, which, and why? What is their distribution in other animals? Knockout and transgenic animals should provide important clues in the near future, but a view which integrates these molecules into the overall picture of inflammation and immunity will doubtless require more subtle and imaginative experiments.

Acknowledgements I thank Jerome Langer and Grant Gallagher for the critical review of the text and helpful suggestions. This study was

238

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

supported in part by RO1 AI51139-01 from the National Institute of Allergy and Infectious Diseases and by American Heart Association Grant AHA#9730247N.

References [1] Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, et al. Interleukin-20: discovery, receptor identification, and role in epidermal function. Cell 2001;104:9–19. [2] Dumoutier L, Louahed J, Renauld JC. Cloning and characterization of IL-10-related T-cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol 2000;164:1814–9. [3] Gallagher G, Dickensheets H, Eskdale J, Izotova LS, Mirochnitchenko OV, Peat JD, et al. Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun 2000;1:442–50. [4] Jiang H, Lin JJ, Su ZZ, Goldstein NI, Fisher PB. Subtraction hybridization identifies a novel melanoma differentiation associated gene, MDA-7, modulated during human melanoma differentiation, growth and progression. Oncogene 1995;11:2477–86. [5] Knappe A, Hor S, Wittmann S, Fickenscher H. Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri. J Virol 2000;74:3881–7. [6] Soo C, Shaw WW, Freymiller E, Longaker MT, Bertolami CN, Chiu R, et al. Cutaneous rat wounds express c49a, a novel gene with homology to the human melanoma differentiation associated gene, MDA-7. J Cell Biochem 1999;74:1–10. [7] Zhang R, Tan Z, Liang P. Identification of a novel ligand–receptor pair constitutively activated by ras oncogenes. J Biol Chem 2000;275:24436–43. [8] Schaefer G, Venkataraman C, Schindler U. Cutting edge: FISP (IL-4-induced secreted protein), a novel cytokine-like molecule secreted by Th2 cells. J Immunol 2001;166:5859–63. [9] Moore KW, de Waal MR, Coffman RL, O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683– 765. [10] Ekmekcioglu S, Ellerhorst J, Mhashilkar AM, Sahin AA, Read CM, Prieto VG, et al. Down-regulated melanoma differentiation associated gene (MDA-7) expression in human melanomas. Int J Cancer 2001;94:54–9. [11] Huang EY, Madireddi MT, Gopalkrishnan RV, Leszczyniecka M, Su Z, Lebedeva IV, et al. Genomic structure, chromosomal localization and expression profile of a novel melanoma differentiation associated (MDA-7) gene with cancer specific growth suppressing and apoptosis inducing properties. Oncogene 2001;20:7051–63. [12] Su ZZ, Madireddi MT, Lin JJ, Young CS, Kitada S, Reed JC, et al. The cancer growth suppressor gene MDA-7 selectively induces apoptosis in human breast cancer cells and inhibits tumor growth in nude mice. Proc Natl Acad Sci USA 1998;95:14400–5. [13] Jiang H, Su ZZ, Lin JJ, Goldstein NI, Young CS, Fisher PB. The melanoma differentiation associated gene MDA-7 suppresses cancer cell growth. Proc Natl Acad Sci USA 1996;93:9160–5. [14] Madireddi MT, Su ZZ, Young CS, Goldstein NI, Fisher PB. MDA-7, a novel melanoma differentiation associated gene with promise for cancer gene therapy. Adv Exp Med Biol 2000;465:239–61. [15] Mhashilkar AM, Schrock RD, Hindi M, Liao J, Sieger K, Kourouma F, et al. Melanoma differentiation associated gene-7 (MDA-7): a novel anti-tumor gene for cancer gene therapy. Mol Med 2001;7:271–82. [16] Saeki T, Mhashilkar A, Chada S, Branch C, Roth JA, Ramesh R. Tumor-suppressive effects by adenovirus-mediated MDA-7 gene transfer in non-small cell lung cancer cell in vitro. Gene Ther 2000;7:2051–7.

[17] Dumoutier L, Leemans C, Lejeune D, Kotenko SV, Renauld JC. Cutting edge: Stat activation by IL-19, IL-20 and MDA-7 through IL-20 receptor complexes of two types. J Immunol 2001;167:3545– 9. [18] Wang M, Tan Z, Zhang R, Kotenko SV, Liang P. Interleukin24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J Biol Chem 2002;277: 7341–7. [19] Yamaguchi Y, Yoshikawa K. Cutaneous wound healing: an update. J Dermatol 2001;28:521–34. [20] Gharaee-Kermani M, Phan SH. Role of cytokines and cytokine therapy in wound healing and fibrotic diseases. Curr Pharm Des 2001;7:1083–103. [21] Dumoutier L, Van Roost E, Colau D, Renauld JC. Human interleukin-10-related T-cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc Natl Acad Sci USA 2000;97:10144–9. [22] Xie MH, Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chem 2000;275:31335–9. [23] Pittman DD, Goad B, Lambert AJ, Clark E, Tan XY, Spaulding V, et al. IL-22 is a tightly-regulated IL10-like molecule that induces an acute-phase response and renal tubular basophilia. Genes Immun 2001;2:172. [24] Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, et al. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J Immunol 2001;166:7096–103. [25] Kotenko SV, Izotova LS, Mirochnitchenko OV, Esterova E, Dickensheets H, Donnelly RP, et al. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta) is a common chain of both the IL-10 and IL-22 (IL-10-related T-cell-derived inducible factor, IL-TIF) receptor complexes. J Biol Chem 2001;276:2725–32. [26] Dumoutier L, Lejeune D, Colau D, Renauld JC. Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T-cell-derived inducible factor/IL-22. J Immunol 2001;166:7090–5. [27] Aggarwal S, Xie MH, Maruoka M, Foster J, Gurney AL. Acinar cells of the pancreas are a target of interleukin-22. J Interferon Cytokine Res 2001;21:1047–53. [28] Dusetti NJ, Tomasini R, Azizi A, Barthet M, Vaccaro MI, Fiedler F, et al. Expression profiling in pancreas during the acute phase of pancreatitis using cDNA microarrays. Biochem Biophys Res Commun 2000;277:660–7. [29] Carroccio A, Iovanna JL, Iacono G, Li PM, Montalto G, Cavataio F, et al. Pancreatitis-associated protein in patients with celiac disease: serum levels and immunocytochemical localization in small intestine. Digestion 1997;58:98–103. [30] Iovanna JL, Ferec C, Sarles J, Dagorn JC. The pancreatitisassociated protein (PAP). A new candidate for neonatal screening of cystic fibrosis. CR Acad Sci III 1994;317:561–4. [31] Iovanna J, Orelle B, Keim V, Dagorn JC. Messenger RNA sequence and expression of rat pancreatitis-associated protein, a lectin-related protein overexpressed during acute experimental pancreatitis. J Biol Chem 1991;266:24664–9. [32] Fickenscher H, Fleckenstein B. Herpesvirus saimiri. Philos Trans R Soc Lond B Biol Sci 2001;356:545–67. [33] Lin H, Mosmann TR, Guilbert L, Tuntipopipat S, Wegmann TG. Synthesis of T helper 2-type cytokines at the maternal–fetal interface. J Immunol 1993;151:4562–73. [34] Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal–fetal relationship: is successful pregnancy a TH2 phenomenon. Immunol Today 1993;14:353–6. [35] Kotenko SV, Pestka S. Viral IL-10 variants. In: Oppenheim JJ, Feldmann M, editors. Cytokine Reference. Academic Press, New York, 2001.

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240 [36] Moore KW, Vieira P, Fiorentino DF, Trounstine ML, Khan TA, Mosmann TR. Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein-Barr virus gene BCRFI. Science 1990;248:1230–4. [37] Hsu DH, de Waal M, Fiorentino DF, Dang MN, Vieira P, de Vries J, et al. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1. Science 1990;250:830–2. [38] Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci USA 2000;97:1695–700. [39] Lockridge KM, Zhou SS, Kravitz RH, Johnson JL, Sawai ET, Blewett EL, et al. Primate cytomegalovirus encode and express an IL-10-like protein. Virology 2000;268:272–80. [40] Fleming SB, McCaughan CA, Andrews AE, Nash AD, Mercer AA. A homolog of interleukin-10 is encoded by the poxvirus orf virus. J Virol 1997;71:4857–61. [41] Lee HJ, Essani K, Smith GL. The genome sequence of Yaba-like disease virus, a yatapoxvirus. Virology 2001;281:170–92. [42] Bazan JF. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 1990;87:6934–8. [43] Thoreau E, Petridou B, Kelly PA, Djiane J, Mornon JP. Structural symmetry of the extracellular domain of the cytokine/growth hormone/prolactin receptor family and interferon receptors revealed by hydrophobic cluster analysis. FEBS Lett 1991;282:26–31. [44] Carmeliet P, Collen D. Tissue factor. Int J Biochem Cell Biol 1998;30:661–7. [45] Domanski P, Colamonici OR. The type-I interferon receptor. The long and short of it. Cytokine Growth Factor Rev 1996;7:143–51. [46] Mogensen KE, Lewerenz M, Reboul J, Lutfalla G, Uzé G. The type I interferon receptor: structure, function, and evolution of a family business. J Interferon Cytokine Res 1999;19:1069–98. [47] Kirchhofer D, Nemerson Y. Initiation of blood coagulation: the tissue factor/factor VIIa complex. Curr Opin Biotechnol 1996;7:386–91. [48] Pestka S, Kotenko SV, Muthukumaran G, Izotova LS, Cook JR, Garotta G. The interferon gamma (IFN-gamma) receptor: a paradigm for the multichain cytokine receptor. Cytokine Growth Factor Rev 1997;8:189–206. [49] Bach EA, Aguet M, Schreiber RD. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol 1997;15:563–91. [50] Kotenko SV, Pestka S. Jak–Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene 2000;19:2557–65. [51] Prejean C, Colamonici OR. Role of the cytoplasmic domains of the type I interferon receptor subunits in signaling. Semin Cancer Biol 2000;10:83–92. [52] Lutfalla G, Gardiner K, Uzé G. A new member of the cytokine receptor gene family maps on chromosome 21 at less than 35 kb from IFNAR. Genomics 1993;16:366–73. [53] Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S. Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J 1997;16:5894–903. [54] Ealick SE, Cook WJ, Vijay-Kumar S, Carson M, Nagabhushan TL, Trotta PP, et al. Three-dimensional structure of recombinant human interferon-gamma. Science 1991;252:698–702. [55] Walter MR, Nagabhushan TL. Crystal structure of interleukin-10 reveals an interferon gamma-like fold. Biochemistry 1995;34: 12118–25. [56] Zdanov A, Schalk-Hihi C, Gustchina A, Tsang M, Weatherbee J, Wlodawer A. Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon gamma. Structure 1995;3:591–601. [57] Josephson K, Logsdon NJ, Walter MR. Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site. Immunity 2001;15:35–46.

239

[58] Walter MR, Windsor WT, Nagabhushan TL, Lundell DJ, Lunn CA, Zauodny PJ, et al. Crystal structure of a complex between interferon-gamma and its soluble high-affinity receptor [see comments]. Nature 1995;376:230–5. [59] Bach EA, Tanner JW, Marsters S, Ashkenazi A, Aguet M, Shaw AS, et al. Ligand-induced assembly and activation of the gamma interferon receptor in intacT-cells. Mol Cell Biol 1996;16:3214–21. [60] Kotenko SV, Izotova LS, Pollack BP, Mariano TM, Donnelly RJ, Muthukumaran G, et al. Interaction between the components of the interferon gamma receptor complex. J Biol Chem 1995;270:20915– 21. [61] Kotenko SV, Izotova LS, Pollack BP, Muthukumaran G, Paukku K, Silvennoinen O, et al. Other kinases can substitute for Jak2 in signal transduction by interferon-gamma. J Biol Chem 1996;271:17174– 82. [62] Kotenko SV, Izotova LS, Mirochnitchenko OV, Lee C, Pestka S. The intracellular domain of interferon-receptor 2c (IFN-R2c) chain is responsible for Stat activation. Proc Natl Acad Sci USA 1999;96:5007–12. [63] Xu W, Presnell SR, Parrish-Novak J, Kindsvogel W, Jaspers S, Chen Z, et al. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc Natl Acad Sci USA 2001;98:9511–6. [64] Gruenberg BH, Schoenemeyer A, Weiss B, Toschi L, Kunz S, Wolk K, et al. A novel, soluble homologue of the human IL-10 receptor with preferential expression in placenta. Genes Immun 2001;2:329– 34. [65] Wehinger J, Gouilleux F, Groner B, Finke J, Mertelsmann R, Weber-Nordt RM. IL-10 induces DNA binding activity of three Stat proteins (Stat1, Stat3, and Stat5) and their distinct combinatorial assembly in the promoters of selected genes. FEBS Lett 1996;394:365–70. [66] Finbloom DS, Winestock KD. IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of Stat1 alpha and Stat3 complexes in human T-cells and monocytes. J Immunol 1995;155:1079–90. [67] Weber-Nordt RM, Riley JK, Greenlund AC, Moore KW, Darnell JE, Schreiber RD. Stat3 recruitment by two distinct ligand-induced, tyrosine-phosphorylated docking sites in the interleukin-10 receptor intracellular domain. J Biol Chem 1996;271:27954–61. [68] Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JEJ, Yancopoulos GD. Choice of Stats and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 1995;267:1349–53. [69] Yan H, Krishnan K, Lim JT, Contillo LG, Krolewski JJ. Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction. Mol Cell Biol 1996;16:2074–82. [70] Data were obtained from the website of the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/) with the use of various software tools for analyzing genome and EST databases available at the site. January 2002. [71] Spencer SD, Di Marco F, Hooley J, Pitts-Meek S, Bauer M, Ryan AM, et al. The orphan receptor CRF2-4 is an essential subunit of the interleukin-10 receptor. J Exp Med 1998;187:571–8. [72] De Carli M, Berthold S, Fickenscher H, Fleckenstein IM, D’Elios MM, Gao Q, et al. Immortalization with herpesvirus saimiri modulates the cytokine secretion profile of established Th1 and Th2 human T-cell clones. J Immunol 1993;151:5022–30. [73] Cookson W. The alliance of genes and environment in asthma and allergy. Nature 1999;402:B5–11. [74] Barnes KC, Freidhoff LR, Nickel R, Chiu YF, Juo SH, Hizawa N, et al. Dense mapping of chromosome 12q13.12-q23.3 and linkage to asthma and atopy. J Allergy Clin Immunol 1999;104:485–91. [75] Barnes KC, Neely JD, Duffy DL, Freidhoff LR, Breazeale DR, Schou C, et al. Linkage of asthma and total serum IgE concentration to markers on chromosome 12q: evidence from Afro–Caribbean and Caucasian populations. Genomics 1996;37:41–50.

240

S.V. Kotenko / Cytokine & Growth Factor Reviews 13 (2002) 223–240

[76] Nickel R, Wahn U, Hizawa N, Maestri N, Duffy DL, Barnes KC, et al. Evidence for linkage of chromosome 12q15-q24.1 markers to high total serum IgE concentrations in children of the German Multicenter Allergy Study. Genomics 1997;46:159–62. [77] Wilkinson J, Thomas NS, Morton N, Holgate ST. Candidate gene and mutational analysis in asthma and atopy. Int Arch Allergy Immunol 1999;118:265–7. [78] Hayden C, Pereira E, Rye P, Palmer L, Gibson N, Palenque M, et al. Mutation screening of interferon-gamma (IFN-gamma) as a candidate gene for asthma. Clin Exp Allergy 1997;27:1412–6. [79] Schoenmakers EF, Geurts JM, Kools PF, Mols R, Huysmans C, Bullerdiek J, et al. A 6-Mb yeast artificial chromosome contig and long-range physical map encompassing the region on chromosome 12q15 frequently rearranged in a variety of benign solid tumors. Genomics 1995;29:665–78. [80] Wanschura S, Kazmierczak B, Schoenmakers E, Meyen E, Bartnitzke S, Van de V, et al. Regional fine mapping of the multiple-aberration region involved in uterine leiomyoma, lipoma, and pleomorphic adenoma of the salivary gland to 12q15. Genes Chromosomes Cancer 1995;14:68–70. [81] Dumoutier L, Van Roost E, Ameye G, Michaux L, Renauld JC. IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes Immun 2000;1:488–94. [82] Domanski P, Witte M, Kellum M, Rubinstein M, Hackett R, Pitha P, et al. Cloning and expression of a long form of the beta subunit of the interferon alpha beta receptor that is required for signaling. J Biol Chem 1995;270:21606–11. [83] Lutfalla G, Holland SJ, Cinato E, Monneron D, Reboul J, Rogers NC, et al. Mutant U5A cells are complemented by an interferon-alpha beta receptor subunit generated by alternative processing of a new member of a cytokine receptor gene cluster. EMBO J 1995;14:5100–8. [84] Novick D, Cohen B, Rubinstein M. The human interferon alpha/beta receptor: characterization and molecular cloning. Cell 1994;77:391– 400. [85] Hardy MP, Owczarek CM, Trajanovska S, Liu X, Kola I, Hertzog PJ. The soluble murine type I interferon receptor Ifnar-2 is present in serum, is independently regulated, and has both agonistic and antagonistic properties. Blood 2001;97:473–82. [86] Sano S, Itami S, Takeda K, Tarutani M, Yamaguchi Y, Miura H, et al. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. EMBO J 1999;18:4657–68. [87] Asadullah K, Sabat R, Wiese A, Docke WD, Volk HD, Sterry W. Interleukin-10 in cutaneous disorders: implications for its pathophysiological importance and therapeutic use. Arch Dermatol Res 1999;291:628–36. [88] Asadullah K, Friedrich M, Hanneken S, Rohrbach C, Audring H, Vergopoulos A, et al. Effects of systemic interleukin-10 therapy on psoriatic skin lesions: histologic, immunohistologic, and molecular biology findings. J Invest Dermatol 2001;116:721–7. [89] Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, et al. Stat3 as an oncogene. Cell 1999;98:295–303. [90] Razzaque A, Jahan N, McWeeney D, Jariwalla RJ, Jones C, Brady J, et al. Localization and DNA sequence analysis of the transforming domain (mtrII) of human cytomegalovirus. Proc Natl Acad Sci USA 1988;85:5709–13.

[91] Jahan N, Razzaque A, Brady J, Rosenthal LJ. The human cytomegalovirus mtrII colinear region in strain Tanaka is transformation defective. J Virol 1989;63:2866–9. [92] Inamdar A, Thompson J, Kashanchi F, Doniger J, Brady JN, Rosenthal LJ. Identification of two promoters within human cytomegalovirus morphologic transforming region II. Intervirology 1992;34:146–53. [93] Muralidhar S, Doniger J, Mendelson E, Araujo JC, Kashanchi F, Azumi N, et al. Human cytomegalovirus mtrII oncoprotein binds to p53 and down-regulates p53-activated transcription. J Virol 1996;70:8691–700. [94] Heller A, Fiedler F, Schmeck J, Luck V, Iovanna JL, Koch T. Pancreatitis-associated protein protects the lung from leukocyte-induced injury. Anesthesiology 1999;91:1408–14. [95] Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of interleukin-9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med 1998;188:1307–20. [96] Levitt RC, McLane MP, MacDonald D, Ferrante V, Weiss C, Zhou T, et al. IL-9 pathway in asthma: new therapeutic targets for allergic inflammatory disorders. J Allergy Clin Immunol 1999;103:S485–91. [97] McLane MP, Haczku A, van de Rijn M, Weiss C, Ferrante V, MacDonald D, et al. Interleukin-9 promotes allergen-induced eosinophilic inflammation and airway hyperresponsiveness in transgenic mice. Am J Respir Cell Mol Biol 1998;19:713–20. [98] Vieira P, de Waal-Malefyt R, Dang MN, Johnson KE, Kastelein R, Fiorentino DF, et al. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci USA 1991;88:1172–6. [99] Aguet M, Dembic Z, Merlin G. Molecular cloning and expression of the human interferon-gamma receptor. Cell 1988;55:273–80. [100] Soh J, Donnelly RJ, Kotenko S, Mariano TM, Cook JR, Wang N, et al. Identification and sequence of an accessory factor required for activation of the human interferon gamma receptor. Cell 1994;76:793–802. [101] Uzé G, Lutfalla G, Gresser I. Genetic transfer of a functional human interferon alpha receptor into mouse cells: cloning and expression of its cDNA. Cell 1990;60:225–34. [102] Scarpati EM, Wen D, Broze GJJ, Miletich JP, Flandermeyer RR, Siegel NR, et al. Human tissue factor: cDNA sequence and chromosome localization of the gene. Biochemistry 1987;26:5234– 8. [103] Fisher KL, Gorman CM, Vehar GA, O’Brien DP, Lawn RM. Cloning and expression of human tissue factor cDNA. Thromb Res 1987;48:89–99. [104] Spicer EK, Horton R, Bloem L, Bach R, Williams KR, Guha A, et al. Isolation of cDNA clones coding for human tissue factor: primary structure of the protein and cDNA. Proc Natl Acad Sci USA 1987;84:5148–52. [105] Morrissey JH, Fakhrai H, Edgington TS. Molecular cloning of the cDNA for tissue factor, the cellular receptor for the initiation of the coagulation protease cascade. Cell 1987;50:129–35. [106] Liu Y, Wei SH, Ho AS, de Waal M, Moore KW. Expression cloning and characterization of a human IL-10 receptor. J Immunol 1994;152:1821–9.