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The immunopharmacological properties of transforming growth factor beta
International Immunopharmacology 5 (2005) 1771 – 1782 www.elsevier.com/locate/intimp
Brief review
The immunopharmacological properties of transforming growth factor beta Yingying Le a,*, Xiaojing Yu a, Lingfei Ruan a,b, Oumei Wang a,b, Dongfei Qi a,b, Jingjing Zhu a, Xiaofeng Lu a, Yan Kong a,b, Kun Cai a,b, Shanshan Pang a,b, Xianglin Shi a, Ji Ming Wang c a
c
Laboratory of Immunologic and Inflammatory Diseases, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, P.R. China b Graduate School of the Chinese Academy of Sciences, Shanghai, 200031, P.R. China Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD21702, USA Received 24 May 2005; received in revised form 28 June 2005; accepted 18 July 2005
Abstract Transforming growth factor-h (TGF-h) family members are multifunctional molecules, which play pivotal roles in regulating cell proliferation, differentiation, migration, development, tissue remodeling and repair. These events are closely associated with host immune responses and inflammation. Despite some controversies on their function in controlling dendritic and T regulatory cell development and activity, the importance of TGF-hs in the progress of autoimmunity and inflammatory diseases has been well appreciated and new aspects of their contribution continue to be recognized. Since one of the major biological properties of TGF-hs is its capacity to potently suppress immune responses, they are considered as candidates for the development of therapeutic agents to fend off undesirable damage associated with immune and inflammatory conditions. D 2005 Elsevier B.V. All rights reserved. Keywords: Transforming growth factor beta; Inflammation; Alzheimer’s disease
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular genetics and signaling pathways of TGF-h . . . . . . . Biological functions of TGF-hs . . . . . . . . . . . . . . . . . . Involvement of TGF-hs in autoimmune and inflammatory diseases The role of TGF-hs in the pathogenesis of Alzheimer’s disease . .
* Corresponding author. Tel.: +86 21 54920901; fax: +86 21 54920291. E-mail address: [email protected] (Y. Le). 1567-5769/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.intimp.2005.07.006
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6. TGF-h in tumor growth and metastasis 7. Perspectives . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .
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1. Introduction Transforming growth factor-h (TGF-h) was first characterized as a protein that stimulated colony formation by normal rat kidney cells [1]. Since this is a classical measurement of cellular transformation, TGF-h was thus named to illustrate its originally discovered biological action. Now, TGF-hs are recognized as the prototype of multifunctional growth factors. Virtually every cell type in the body, including epithelial, endothelial, hematopoietic, neuronal, and connective-tissue cells, produces TGF-h and expresses receptor for it. TGF-hs regulate a variety of important cell and tissue functions, such as cell growth and differentiation, chemotaxis, apoptosis, angiogenesis, immune responses, extracellular matrix production, and hematopoiesis [2,3]. Increases or decreases in the production of TGF-hs have been linked to numerous disease states, including altered proinflammatory responses, atherosclerosis, and fibrotic diseases of the kidney, liver, and lung. Mutations in the genes for TGF-h, its receptors, or intracellular signaling molecules associated with TGF-h may cause abnormal production of members of this cytokine family and skewed cell responses, which contribute to the pathogenesis of certain diseases, in particular malignant tumors and hereditary hemorrhagic telangiectasia. Thus, TGF-h and its associated signaling molecules constitute important immunopharmacological targets for the development of therapeutics. The purpose of this review is to provide a briefing on the genetics, signaling pathways and biological functions of TGF-h, with emphasis on the role of TGF-h in autoimmune, inflammatory, neurodegenerative diseases and cancer.
2. Molecular genetics and signaling pathways of TGF-B There are currently five isoforms of TGF-h with 65–80% identity at the amino acid level. TGF-hs 1–3
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are expressed in mammals and it has been proposed that TGF-h4 in chicken and TGF-h5 in Xenopus are homologues of mammalian TGF-h1 [4]. In human, genes coding for the three isoforms are located on different chromosomes, 19q13, 1q41, and 14q24, respectively [5]. Despite a high degree of sequence homology among TGF-h proteins, genes for three mammalian isoforms each has distinct promoter and 5V and 3V untranslated regions that regulate transcription [6–8]. Because of this feature, a given stimulus may affect the expression of each individual isoform differently in vivo. TGF-h1, TGF-h2, and TGF-h3 all arise from precursor proteins, which are processed to produce latent TGF-h complexes that are secreted by the producing cells [9,10]. Either before or after secretion, TGF-hs can associate with other proteins to form higher molecular weight complexes [11,12]. For TGFhs to signal through cellular receptors, the latent complexes must first be activated. The process of activation is still not well understood; however, proteolytic enzymes such as plasmin, cathepsin and thrombospondin-1 have all been shown to possess the capacity to activate latent TGF-h1 complexes [13–15]. TGF-h is found in all tissues, but is particularly abundant in bone, lung, kidney and placental tissue. Many cell types produce TGF-h1 normally in its latent form, with human platelets and mammalian bone marrow being the richest sources [16]. In addition, antigen specific T cells and activated macrophages produce both active and latent TGF-h1 [17]. TGF-h2 is also produced by many cell types and its highest concentration is found in porcine (but not human) platelets and mammalian bones. TGF-h3 has been detected mainly in cells of the mesenchymal origin, in human, pig, and birds, suggesting that this protein may function differently than TGF-h1 or TGF-h2 [16]. Biological activities of TGF-h are mediated through a heterodimeric transmembrane receptor complex of type I (RI) and type II (RII) subunits of serine/ threonine kinases. The other cell surface receptors, the type III receptor and endoglin are high molecular
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weight proteoglycans that bind TGF-h with high affinity, but do not transduce signals due to the lack of kinase domains. They nevertheless function as presenters of TGF-h to the RII receptor [2]. The current model proposes that binding of TGF-h to RII induces the assembly of an RII–RI heterodimer and transphosphorylation of RI, which activates the RI protein kinase followed by phosphorylation of adaptor proteins Smad2 or Smad3. Phosphorylated Smad2 or Smad3 recruits Smad4, and the resulting complex translocates from the cytoplasm into the nucleus, where Smad complex interacts in a cell-specific manner, in concert with various other transcription factors, to regulate the transcription of genes that are TGF-hresponsive (Fig. 1). Activation of TGF-hRI/II also regulates gene expression by directly activating MAPKs and NF-nB or attenuating other stimulants
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such as LPS induced MAPKs and NF-nB activation [18] (Fig. 1).
3. Biological functions of TGF-Bs TGF-hs elicit a wide range of biological responses in various cells of different organs [2,3]. The regulatory role of TGF-h in cell proliferation is dependent on the type of the cells it interacts with. For epithelial, endothelial, and hematopoietic cells, TGF-h is a potent inhibitor of proliferation. It arrests cell cycle in the G1 phase by stimulating the production of cyclin-dependent protein kinase inhibitor p15 and by inhibiting the function or production of essential cell cycle regulators, especially the cyclin-dependent protein kinases 2 and 4 as well as cyclins A and
Fig. 1. TGF-h signaling and its cross talk with LPS induced intracellular events. TGF-h binds either to type III TGF-h receptor (RIII)/endoglin, which presents it to the type II TGF-h receptor (RII), or directly to RII on the cell membrane. The binding of TGF-h to RII results in association of RI with RII and the phosphorylation of RI. The phosphorylation of RI activates the RI kinase which then phosphorylates the transcription factor Smad2 or Smad3. The phosphorylated Smad2 or Smad3 couples Smad4 and the complex translocates into the nucleus to bind with other transcription factors for regulating the transcription of TGF-h target genes. Activation of TGF-hRI/II also regulates gene expression by directly activating MAPKs and NF-nB or attenuating the pathways of other stimulants such as LPS.
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E [19]. These changes result in decreased phosphorylation of a retinoblastoma gene product, Rb, which then binds to and sequester members of the E2F family of transcription factors. Sequestered E2F is unable to stimulate the expression of genes such as c-myc and b-myb that regulate the progression and completion of the cell cycle. The essential role of TGF-h in the regulation of cell proliferation and differentiation, embryonic development, and angiogenesis has been demonstrated by targeted deletion of the genes encoding members of its signaling pathways in mice. Disruption of both TGF-h2 and TGFh3 genes results in perinatal lethality. TGF-h2 null mice exhibit a broad range of developmental abnormalities, including cardiac, lung, craniofacial, limb, eye, ear and urogenital defects [20]. TGF-h3 gene ablation results exclusively in defective palatogenesis and delayed pulmonary development [21,22]. Polymorphisms in TGF-h3 gene have been linked to the development of cleft palate in humans [23]. TGF-h directly stimulates angiogenesis in vivo, which is blocked by TGF-h antibodies [24]. In mice, deletion of either TGF-h1 or type II TGF-h receptor results in decreased vasculogenesis associated with defective differentiation of capillary endothelium and inade-
quate capillary-tube formation [25–28] (Table 1). The many other phenotypic characteristics of TGFh1 knockout mice will be discussed. TGF-h is one of the most potent regulators of the production and deposition of extracellular matrix. It stimulates the production and affects the adhesive properties of the extracellular matrix by two major mechanisms [3]. First, TGF-h stimulates fibroblasts and other cells to produce extracellular-matrix and cell-adhesion proteins, including collagen, fibronectin, and integrins. Second, TGF-h decreases the production of enzymes that degrade the extracellular matrix, including collagenase, heparinase, and stromelysin, but increases the level of proteins that inhibit matrix-degrading proteolytic enzymes, including plasminogen-activator inhibitor type 1 and tissue inhibitor of metalloprotease. These changes are essential for maintaining a balanced production of extracellularmatrix proteins and for differential regulation of the adhesive properties of specific cell types. A well characterized in vivo activity of TGF-h is its ability to mediate a wound-healing cascade which accelerates tissue repair [34]. At the site of a peripheral wound, degranulation of platelets releases a bolus of TGF-h1, which attracts and activates monocytes,
Table 1 Consequences of TGF-h and TGF-h receptor gene depletion Gene targeting
Major phenotypes
References
TGF-h1 KO
Mice die either at around 10.5 days postcoitus or 3 weeks postpartum. Defective vasculogenesis, hematopoiesis and endothelial differentiation; multifocal inflammation. Perinatal lethality; multiple developmental defects, including cardiac, lung, limb, craniofacial, spinal column, eye, inner ear, urogenital defects. Perinatal lethality; defective palatogenesis; delayed pulmonary development. Embryonic lethality around 10.5 days postcoitus due to defects in the yolk sac hematopoiesis and vasculogenesis.
[25,27,28]
TGF-h2 KO TGF-h3 KO TGF-h RII KO TGF-h RII conditional KO In mammary epithelium
In colonic epithelium In fibroblasts In Col2a expressing cells In B cells
Lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. Shortened latency of tumor formation and increased pulmonary metastases when crossed with mouse mammary tumor virus-polyomavirus middle T antigen transgenic mouse. Increased formation and progression of azoxymethane-induced adenomas and adenocarcinomas. Intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach associated with an increased abundance of stromal cells. Defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Reduced life span of conventional B cells, expansion of peritoneal B-1 cells; B cell hyperplasia in Peyer’s patches; elevated serum immunoglobulin, and substantial IgG3 responses to a normally weak immunogen.
[20] [21,22] [26]
[29]
[30] [31] [32] [33]
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lymphocytes and neutrophils to contain infection, then promotes apoptosis and clearance of infiltrating leukocytes by tissue macrophages that produce antiinflammatory cytokines. Autoinduction of TGF-h in a number of cell types also maintains high levels of this growth factor in the wound bed where it induces angiogenesis and production of extracellular matrix to promote tissue repair [34,35]. If wound-healing processes fail to resolve at the appropriate stages or in the case of chronic injury, the formation of excessive granulomatous tissues may cause fibrotic disease.
4. Involvement of TGF-Bs in autoimmune and inflammatory diseases Epidermal Langerhans cells (LC) like bone marrow-derived immature dendritic cells (DC) play a critical role in the capture and processing of foreign antigens. This requires LC to have the capacity to migrate to regional lymph nodes where they become mature and present antigens to T cells. The development and differentiation of LC requires TGF-h1 [36], as indicated by in vitro experiments showing that the presence of TGF-h1 is necessary for CD34+ hemopoietic progenitor cells to develop into LC. In vivo, TGF-h1-deficient mice lack epidermal LC, but contain functional LC precursors that, upon transplantation into wild type mice, are capable of differentiating into LC. Thus, it appears that stimulation of LC precursors in peripheral organs by TGF-h1 in a paracrine manner is sufficient for LC differentiation, which provides strong evidence for the capacity of TGF-h1 to efficiently promote adaptive immunity. While TGF-h1 may act as a stimulant it suppresses the growth and differentiation of most immune cell lineages including B and T cells [37]. TGF-h is produced by most immune cell lineages and acts as a chemoattractant for monocytes/macrophages and inhibits immune cell activation by blocking antigen presentation and/or production of interleukins [37,38]. Gene targeting mouse model has confirmed and extended the understanding of the pivotal role played by TGF-h in immune cell homeostasis. TGF-h1 knockout mice exhibit a profound self-targeting multifocal inflammatory responses mediated by lymphocytes and characterized by overproduction of auto-
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antibodies that kill the animals at very early stages of life [27,39,40]. This phenotype manifests multiple characteristics, including a T cell-specific component whereby TGF-h control of proliferation and differentiation of T cells is lost [41,42]. In addition, apoptotic T cells are a major source of TGF-h [43], and moreover, TGF-h controls B cell proliferation, maturation and selectively upregulates IgA expression [44]. Furthermore, knocking-out one of the major signaling effectors of the TGF-h pathway, the Smad3, results in early post-natal death due to leukocytosis and impaired mucosal immunity that leads to severe chronic infection [45,46]. Therefore, a critical normal function of TGF-h in the immune system is suppression of lymphocyte proliferation and differentiation, therefore preventing detrimental autoimmune responses and regulating proper immune cell populations during pathologic states. TGF-h exerts potent immunosuppressive effects by inhibiting the expression of proinflammatory cytokines such as TNFa and IL-1 by immune cells [47], and blocking the induction of adhesion molecules such as ICAM-1 and VCAM-1 by cytokines [48,49]. In TGF-h deficient mice, the levels of class II MHC mRNA are elevated and mice die from cardiac, pulmonary, and gastric inflammation. Treatment of such mice with anti-inflammatory and immune suppressive agents have been shown to prolong animal life by reducing the levels of infiltrating immune cells in inflamed organs and the severity of inflammation [27]. Smad3-deficient mice develop chronic mucosal infection due to impairment of T-cell activation and mucosal immunity [46]. In contrast, in mice that are both TGF-h and class II MHC deficient, manifestations of autoimmune disease are diminished [50], suggesting that MHC class II molecules are essential for the development of autoimmunity in TGF-h1 deficient mice. Based on these results, TGF-h has been considered as a prominent candidate for control of autoimmune and chronic inflammatory diseases [51]. TGF-h1 is expressed abundantly in rheumatoid arthritis (RA) synovium. This suggests that TGF-h1 per se or in combination with other cytokines may play an important role in the progression of RA. There are several hypothetical ways by which TGF-h may promote RA pathogenesis. First, TGF-h surprisingly stimulates the expression of inflammatory cytokines
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such as TNFa and IL-1h by synovial cells [52]. Second, the production and activity of metalloproteinases are increased by TGF-h [52,53]. Third, TGF-h1 is chemotactic and may attract inflammatory cells to synovial tissue [54]. Fourth, TGF-h accelerates synovial hypertrophy since it induces fibroblast proliferation and reduces their apoptosis [55]. Finally, TGF-h is an inducer of VEGF therefore contributing indirectly to angiogenesis in arthritic synovium [56]. In asthmatic airways, TGF-h1 is an important fibrogenic and immunomodulatory factor that may cause structural changes [57]. Inflammatory cells infiltrating bronchial mucosa, and structural cells of the airway wall including fibroblasts, epithelial, endothelial and smooth muscle cells all of which are TGF-h producers. These diverse cell types increase the levels of TGF-h as observed in bronchoalveolar lavage fluid from asthmatic patients. Elevated TGF-h has been implied in the remodeling of the airway wall, which is related to subepithelial fibrosis. Interestingly, in vitro as well as in vivo studies have documented dual roles of TGF-h in airway diseases, functioning either as a pro- or an anti-inflammatory cytokine on infiltrating inflammatory cells. These apparently contradictory results may well be the consequences of using different experimental conditions. More clearcut conclusions concerning the effects of TGF-h may be obtainable from studies using systemic or conditional gene depletion approaches. Regulatory T (TR) cells are a subset of T cells that function to down-regulate immune responses. Reductions in TR cells are known to cause organ-specific autoimmune diseases in animal models. Different populations of TR cells have been described, including thymic derived CD4+CD25+ TR cells and TR cells induced in the periphery by exposure to antigen. A transcription factor, Foxp3, has been identified as a specific molecular marker for TR cells and its expression is essential for programming TR cell development and function [58]. TGF-h appears to play a broad role in TR activity. High concentrations of TGF-h enhance the regulatory function of TCR-stimulated CD25 CD4+ T cells in vitro [58,59]. However, in vivo, TGF-h seems to be dispensable for thymic TR cell development but is involved in the maintenance of peripheral TR cell number and functionality [60,61]. TGF-h might act directly on potentially pathogenic T cells to inhibit their differentiation
and effector function [62] or to induce their differentiation into Foxp3+ TR cells, or a combination of both [60,61]. CD4+CD25+ TR cells express membranebound and/or secreted TGF-h1, and blockade of TGF-h1 by anti-TGF-h1 antibody or recombinant latency-associated peptide of TGF-h1 dampens the ability of these cells to suppress CD25 T cell proliferation and B cell Ig production. This suggests that TGF-h1 produced by CD4+CD25+ T cells mediates the suppressor activity of these cells [63]. However, it has also been reported that neutralization of TGF-h1 with either monoclonal antibody or soluble TGF-hRII-Fc did not reverse in vitro suppression by resting or activated CD4+CD25+ TR cells. Responder T cells from Smad3 / or dominant-negative TGF-h type RII transgenic mice were as susceptible to CD4+CD25+mediated suppression as T cells from wild-type mice. Furthermore, CD4+CD25+ TR cells from neonatal TGF-h1 / mice were as suppressive as the cells from TGF-h1+/+ mice. These results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-h1 [64]. As the phenotype of freshly isolated CD4+CD25+ TGF-h1 / TR cells is distinct from their counterparts from wild type, the TGF-h1 null CD4+CD25+ TR cell populations are unique and/or may express alternative regulatory molecules. Although there are temporal, spatial and functional differences in distribution between TGF-h1 and its homologues TGF-h2 and TGF-h3 in vivo, both TGFh2 and TGF-h3 exhibit suppression in vitro and may play a role in the absence of TGF-h1. Collectively, these results demonstrate an important role for TGFh1 in TR cell biology and suggest additional applications for targeting TGF-h1 signal transduction pathway as means of therapeutic immune modulation.
5. The role of TGF-Bs in the pathogenesis of Alzheimer’s disease Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neuronal loss that causes progressive loss of cognitive function. Neuropathological hallmarks of AD include the presence of amyloid plaques, neurofibrillary tangles, and gliosis. Animal and clinical studies have implicated a number of pro- and anti-inflammatory cytokines as integral to AD pathogenesis [65]. Among those cytokines, TGF-
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h emerged as an important factor in regulating inflammatory responses in AD. A genetic polymorphism of the TGF-h1 gene was found to be associated with a higher risk to the development of AD [66]. In AD patients, TGF-h levels were elevated in sera and cerebrospinal fluid, and the levels of TGF-h in serum correlate with disease severity [67,68]. Postmortem brain tissue analyses of AD patients showed an increased expression of TGF-h1 that was correlated with the degree of cerebral amyloid angiopathy [69]. TGF-h1 was immunohistochemically detected in neurofibrillary tangles and some senile plaques, particularly those located in the dentate gyrus of the hippocampus and the entorhinal cortex [70,71]. TGF-h2 levels are significantly elevated in the brains of AD patients, and were localized to glial cells and tangle-bearing neurons [71,72]. In in vitro experiments, TGF-h2, produced by microglia, a mononuclear phagocyte lineage cell type in the brain, was found to be associated with amyloid precursor protein (APP) [73]. These findings lead to the hypothesis that TGF-h may regulate APP synthesis, its processing by proteolytic enzymes, plaque formation, astroglial responses and neuronal cell death. In a model of long-term infusion of Ah into the rat brain, co-administration of TGF-h was found to be a requirement for plaque formation [74]. In addition, TGF-h1 substantially increased the in vitro expression of APP mRNA and protein by astrocytes and microglia [75,76]. Overexpression of TGF-h1 in transgenic mice induces higher level expression of APP, increases Ah generation in cerebral tissues [77], and accelerates amyloid-beta deposition in cerebral blood vessels and meninges [69]. Aged transgenic mice containing Swedish double mutations of APP695 which in human are associated with early onset AD dementia, display TGF-h1 immunoreactive astrocytes in the brain in close proximity to Ah deposits [78]. Co-expression of TGF-h1 in transgenic mice overexpressing APP accelerated the deposition of amyloid-beta peptide, a major component of the senile plaques [69]. These results suggest a marked influence of TGF-h1 on APP metabolism and processing, albeit with as yet unclear mechanisms. Despite its potentially detrimental role in amyloid deposition in AD, there are also reports indicating that TGF-h may be neuroprotective at certain stages of the disease. TGF-h1 has been shown to provide protec-
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tion for human fetal neuronal cells against the cytotoxicity of Ah peptides [79]. All three TGF-h isoforms have been reported to reduce the damage of rat hippocampal neurons by Ah or its active fragments [69,80,81], TGF-h1 was also implicated in Ah clearance from the brain parenchyma to the cerebral blood vasculature in aged hAPP/TGF-h1 double transgenic mice by microglia. Increased astroglial TGF-h1 production in such mice activates microglia in the hippocampus and cortex. These mice exhibit 75% reduction in parenchymal amyloid plaques, and with significantly lower levels of Ah deposition [82]. Recently, TGF-h1 has been shown to regulate the expression of Ah receptors on microglial cells. The bulk of the evidence suggests that inflammatory responses elicited by elevated Ah peptides play an important role in the progression of AD. In AD brain, microglia accumulate at the sites of Ah peptide deposition. In vitro, Ah peptides activate mononuclear phagocytes to release neurotoxic mediators. A number of cell surface molecules have been reported to act as putative receptors for Ah peptides, among which the G protein coupled formyl peptide receptorlike 1 (FPRL1) and its mouse homologue FPR2 [83] have been shown to be expressed by activated microglial cells and to mediate the chemotactic activity of a 42 amino acid form of Ah (Ah42), a major component of AD plaques [84,85]. FPRL1 also participates in Ah internalization in macrophages and its cytotoxicity for neuronal cells [86,87]. In murine-microglial cells, the bacterial endotoxin LPS and TNFa increased the expression of functional mFPR2 [88,89], whereas TGF-h1 was capable of attenuating LPS-induced signaling cascade and the resultant up-regulation of mFPR2 [18]. The inhibitory effect of TGF-h1 required the participation of Smad3 and the transcription coactivator p300 [18], and in addition, TGF-h1 enhanced MAPK phosphorylation in microglial cells which became refractory to subsequent stimulation by LPS. TGF-h1 also directly inhibited the function of mFPR2 in microglial cells activated by LPS, and in human monocytes which constitutively express functional FPRL1. TGF-h1 decreased the FPRL1 gene expression and the cell responses to FPRL1 agonists including Ah42 (Le Y., unpublished observation). Taken together, TGF-h1 in the AD brain may dynamically affect the accumulation, redistribution, and clearance of Ah. Furthermore, TGF-h1, by reg-
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ulating the expression of mFPR2 in microglial cells, may profoundly affect the proinflammatory responses mediated by Ah42. A tight temporal-spatial balance of TGF-h1 production may determine the outcome of its influence on AD pathogenesis. Further elucidation of the signaling pathways by which TGF-h exerts its effect in AD may identify specific targets for therapeutic intervention.
6. TGF-B in tumor growth and metastasis TGF-h has been considered as an important regulator of carcinogenesis, with either suppressive or promoting activities depending on developmental stages and cellular context of the tumor. During the early phase of epithelial tumorigenesis, TGF-h inhibits primary tumor development and growth by inducing tumor cell cycle arrest that may lead to apoptosis. However, in late stages of tumor progression, since tumor cells may evade the growth inhibition exerted by TGF-h, due to inactivation of intracellular signaling pathway or aberrant activation of cell cycle machinery, the presence of TGF-h is often associated with tumor progression. Since TGF-h is a potent growth inhibitor of most cell types, perturbations of TGF-h signaling cascade result in malignant transformation and tumor progression. It has been reported that decreased expression of TGF-h receptor II (RII) in epithelial cells is an important step in their malignant transformation resulting from the activation of Ras protein and from antigenpresenting cell (APC) mutations [90,91]. Down-regulation of RII was observed in 13% human colon carcinoma specimens with microsatellite instability [92]. Mutations in RII have been identified in patients with hereditary nonpolyposis colon cancer [93]. Depletion of RII in mouse colonic epithelium increased the formation and progression of azoxymethane-induced adenoma and adenocarcinoma [30]. Depletion of RII in mouse fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both in association with increased abundance of stromal cells [31]. Mutations of Smad4 have been found in patients with pancreatic carcinoma and those with advanced colon carcinoma [94,95]. Hypomorphic TGF-h signaling in TGF-h+/ mice is associated with increased
tumor development [96], and hypomorphic TGF-h RI(6A) allele in human is associated with the development of a variety of cancers [97]. These observations suggest that TGF-h receptor signaling plays an important role in homeostasis and resistance to malignant transformation of epithelial cells. TGF-h induces extracellular matrix accumulation, angiogenesis, and immunosuppression, indicating that TGF-h may facilitate the progression of tumors under certain conditions. TGF-h expression is increased in a variety of tumor types. Studies of colorectal carcinoma have documented that high-level expression of TGF-h1 in primary tumor is associated with advanced tumor stage and is an independent prognostic factor [98]. Inhibiting TGF-h activity reduces the rate of tumor progression and in particular, metastasis, in certain experimental tumor models. TGF-h is also thought to increase the ability of malignant cells to metastasize by altering cytoskeletal architecture, known as epithelial-to-mesenchymal transition. In fact, evidence suggests that autocrine TGF-h expression by tumor cells is critical for epithelial-to-fibroblastoid conversion in mammary cells [99] and in keratinocytes [100]. Although TGF-h overexpression in mouse keratinocytes inhibits the growth of carcinogen-induced benign skin tumors, it promotes the progression of advanced lesions of the malignant phenotype [101]. TGF-hinduced mesenchymal transition in Ha-Ras-transformed mammary epithelial cells disrupts cell–cell adhesion and causes the loss of epithelial polarity [102]. It is believed that the ability of an epithelial cell to use TGF-h as a growth-promoting factor and a trigger for invasive phenotype is a result of complicated alteration in many cellular and nuclear elements, including the absence or disruption of cyclindependent kinase inhibitors. This imbalance in cell cycle regulators may be the key element that dictates cellular responses to TGF-h either for growth-inhibition or for stimulation.
7. Perspectives TGF-h is an immunoregulatory cytokine. Despite its multiple roles in autoimmune and inflammatory processes, it has been experimentally deployed as a potential therapeutic agent to control autoimmune
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and chronic inflammatory diseases [103]. TGF-h has also been implicated as one of the key regulators of regulatory T cells that are crucial for maintaining balanced immune responses. Nevertheless, its overproduction contributes to persistent inflammation, thus antagonists of TGF-h delivered locally break the cycle of leukocyte recruitment and subsequent fibrosis. On the other hand, systemic administration of TGF-h by injections of the protein or by gene transfer inhibits inflammatory pathogenesis. In addition, enhanced levels of circulating TGF-h appear to be instrumental during the development of oral tolerance and in immunosuppression caused by cyclosporin treatment. The multiplicity of actions of TGFhs and their virtually ubiquitous expression call for more rigorous investigation of their roles in health and disease states and more importantly, careful evaluation of their potential as immunopharmacological agents. Acknowledgement The authors thank their colleagues at Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, P.R. China, and National Cancer Institute at Frederick, the National Institutes of Health, USA, for contributions to the studies. References [1] Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A 1981;78:5339 – 43. [2] Govinden R, Bhoola KD. Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther 2000;98:257 – 65. [3] Massague J. The transforming growth factor-beta family. Annu Rev Cell Biol 1990;6:597 – 641. [4] Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res 1994;5: 99 – 118. [5] Roberts AB. Molecular and cell biology of TGF-beta. Miner Electrolyte Metab 1998;24:111 – 9. [6] Kim SJ, Jeang KT, Glick AB, Sporn MB, Roberts AB. Promoter sequences of the human transforming growth factor-beta 1 gene responsive to transforming growth factor-beta 1 autoinduction. J Biol Chem 1989;264:7041 – 5.
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Brief review
The immunopharmacological properties of transforming growth factor beta Yingying Le a,*, Xiaojing Yu a, Lingfei Ruan a,b, Oumei Wang a,b, Dongfei Qi a,b, Jingjing Zhu a, Xiaofeng Lu a, Yan Kong a,b, Kun Cai a,b, Shanshan Pang a,b, Xianglin Shi a, Ji Ming Wang c a
c
Laboratory of Immunologic and Inflammatory Diseases, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, P.R. China b Graduate School of the Chinese Academy of Sciences, Shanghai, 200031, P.R. China Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD21702, USA Received 24 May 2005; received in revised form 28 June 2005; accepted 18 July 2005
Abstract Transforming growth factor-h (TGF-h) family members are multifunctional molecules, which play pivotal roles in regulating cell proliferation, differentiation, migration, development, tissue remodeling and repair. These events are closely associated with host immune responses and inflammation. Despite some controversies on their function in controlling dendritic and T regulatory cell development and activity, the importance of TGF-hs in the progress of autoimmunity and inflammatory diseases has been well appreciated and new aspects of their contribution continue to be recognized. Since one of the major biological properties of TGF-hs is its capacity to potently suppress immune responses, they are considered as candidates for the development of therapeutic agents to fend off undesirable damage associated with immune and inflammatory conditions. D 2005 Elsevier B.V. All rights reserved. Keywords: Transforming growth factor beta; Inflammation; Alzheimer’s disease
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Molecular genetics and signaling pathways of TGF-h . . . . . . . Biological functions of TGF-hs . . . . . . . . . . . . . . . . . . Involvement of TGF-hs in autoimmune and inflammatory diseases The role of TGF-hs in the pathogenesis of Alzheimer’s disease . .
* Corresponding author. Tel.: +86 21 54920901; fax: +86 21 54920291. E-mail address: [email protected] (Y. Le). 1567-5769/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.intimp.2005.07.006
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6. TGF-h in tumor growth and metastasis 7. Perspectives . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .
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1. Introduction Transforming growth factor-h (TGF-h) was first characterized as a protein that stimulated colony formation by normal rat kidney cells [1]. Since this is a classical measurement of cellular transformation, TGF-h was thus named to illustrate its originally discovered biological action. Now, TGF-hs are recognized as the prototype of multifunctional growth factors. Virtually every cell type in the body, including epithelial, endothelial, hematopoietic, neuronal, and connective-tissue cells, produces TGF-h and expresses receptor for it. TGF-hs regulate a variety of important cell and tissue functions, such as cell growth and differentiation, chemotaxis, apoptosis, angiogenesis, immune responses, extracellular matrix production, and hematopoiesis [2,3]. Increases or decreases in the production of TGF-hs have been linked to numerous disease states, including altered proinflammatory responses, atherosclerosis, and fibrotic diseases of the kidney, liver, and lung. Mutations in the genes for TGF-h, its receptors, or intracellular signaling molecules associated with TGF-h may cause abnormal production of members of this cytokine family and skewed cell responses, which contribute to the pathogenesis of certain diseases, in particular malignant tumors and hereditary hemorrhagic telangiectasia. Thus, TGF-h and its associated signaling molecules constitute important immunopharmacological targets for the development of therapeutics. The purpose of this review is to provide a briefing on the genetics, signaling pathways and biological functions of TGF-h, with emphasis on the role of TGF-h in autoimmune, inflammatory, neurodegenerative diseases and cancer.
2. Molecular genetics and signaling pathways of TGF-B There are currently five isoforms of TGF-h with 65–80% identity at the amino acid level. TGF-hs 1–3
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are expressed in mammals and it has been proposed that TGF-h4 in chicken and TGF-h5 in Xenopus are homologues of mammalian TGF-h1 [4]. In human, genes coding for the three isoforms are located on different chromosomes, 19q13, 1q41, and 14q24, respectively [5]. Despite a high degree of sequence homology among TGF-h proteins, genes for three mammalian isoforms each has distinct promoter and 5V and 3V untranslated regions that regulate transcription [6–8]. Because of this feature, a given stimulus may affect the expression of each individual isoform differently in vivo. TGF-h1, TGF-h2, and TGF-h3 all arise from precursor proteins, which are processed to produce latent TGF-h complexes that are secreted by the producing cells [9,10]. Either before or after secretion, TGF-hs can associate with other proteins to form higher molecular weight complexes [11,12]. For TGFhs to signal through cellular receptors, the latent complexes must first be activated. The process of activation is still not well understood; however, proteolytic enzymes such as plasmin, cathepsin and thrombospondin-1 have all been shown to possess the capacity to activate latent TGF-h1 complexes [13–15]. TGF-h is found in all tissues, but is particularly abundant in bone, lung, kidney and placental tissue. Many cell types produce TGF-h1 normally in its latent form, with human platelets and mammalian bone marrow being the richest sources [16]. In addition, antigen specific T cells and activated macrophages produce both active and latent TGF-h1 [17]. TGF-h2 is also produced by many cell types and its highest concentration is found in porcine (but not human) platelets and mammalian bones. TGF-h3 has been detected mainly in cells of the mesenchymal origin, in human, pig, and birds, suggesting that this protein may function differently than TGF-h1 or TGF-h2 [16]. Biological activities of TGF-h are mediated through a heterodimeric transmembrane receptor complex of type I (RI) and type II (RII) subunits of serine/ threonine kinases. The other cell surface receptors, the type III receptor and endoglin are high molecular
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weight proteoglycans that bind TGF-h with high affinity, but do not transduce signals due to the lack of kinase domains. They nevertheless function as presenters of TGF-h to the RII receptor [2]. The current model proposes that binding of TGF-h to RII induces the assembly of an RII–RI heterodimer and transphosphorylation of RI, which activates the RI protein kinase followed by phosphorylation of adaptor proteins Smad2 or Smad3. Phosphorylated Smad2 or Smad3 recruits Smad4, and the resulting complex translocates from the cytoplasm into the nucleus, where Smad complex interacts in a cell-specific manner, in concert with various other transcription factors, to regulate the transcription of genes that are TGF-hresponsive (Fig. 1). Activation of TGF-hRI/II also regulates gene expression by directly activating MAPKs and NF-nB or attenuating other stimulants
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such as LPS induced MAPKs and NF-nB activation [18] (Fig. 1).
3. Biological functions of TGF-Bs TGF-hs elicit a wide range of biological responses in various cells of different organs [2,3]. The regulatory role of TGF-h in cell proliferation is dependent on the type of the cells it interacts with. For epithelial, endothelial, and hematopoietic cells, TGF-h is a potent inhibitor of proliferation. It arrests cell cycle in the G1 phase by stimulating the production of cyclin-dependent protein kinase inhibitor p15 and by inhibiting the function or production of essential cell cycle regulators, especially the cyclin-dependent protein kinases 2 and 4 as well as cyclins A and
Fig. 1. TGF-h signaling and its cross talk with LPS induced intracellular events. TGF-h binds either to type III TGF-h receptor (RIII)/endoglin, which presents it to the type II TGF-h receptor (RII), or directly to RII on the cell membrane. The binding of TGF-h to RII results in association of RI with RII and the phosphorylation of RI. The phosphorylation of RI activates the RI kinase which then phosphorylates the transcription factor Smad2 or Smad3. The phosphorylated Smad2 or Smad3 couples Smad4 and the complex translocates into the nucleus to bind with other transcription factors for regulating the transcription of TGF-h target genes. Activation of TGF-hRI/II also regulates gene expression by directly activating MAPKs and NF-nB or attenuating the pathways of other stimulants such as LPS.
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E [19]. These changes result in decreased phosphorylation of a retinoblastoma gene product, Rb, which then binds to and sequester members of the E2F family of transcription factors. Sequestered E2F is unable to stimulate the expression of genes such as c-myc and b-myb that regulate the progression and completion of the cell cycle. The essential role of TGF-h in the regulation of cell proliferation and differentiation, embryonic development, and angiogenesis has been demonstrated by targeted deletion of the genes encoding members of its signaling pathways in mice. Disruption of both TGF-h2 and TGFh3 genes results in perinatal lethality. TGF-h2 null mice exhibit a broad range of developmental abnormalities, including cardiac, lung, craniofacial, limb, eye, ear and urogenital defects [20]. TGF-h3 gene ablation results exclusively in defective palatogenesis and delayed pulmonary development [21,22]. Polymorphisms in TGF-h3 gene have been linked to the development of cleft palate in humans [23]. TGF-h directly stimulates angiogenesis in vivo, which is blocked by TGF-h antibodies [24]. In mice, deletion of either TGF-h1 or type II TGF-h receptor results in decreased vasculogenesis associated with defective differentiation of capillary endothelium and inade-
quate capillary-tube formation [25–28] (Table 1). The many other phenotypic characteristics of TGFh1 knockout mice will be discussed. TGF-h is one of the most potent regulators of the production and deposition of extracellular matrix. It stimulates the production and affects the adhesive properties of the extracellular matrix by two major mechanisms [3]. First, TGF-h stimulates fibroblasts and other cells to produce extracellular-matrix and cell-adhesion proteins, including collagen, fibronectin, and integrins. Second, TGF-h decreases the production of enzymes that degrade the extracellular matrix, including collagenase, heparinase, and stromelysin, but increases the level of proteins that inhibit matrix-degrading proteolytic enzymes, including plasminogen-activator inhibitor type 1 and tissue inhibitor of metalloprotease. These changes are essential for maintaining a balanced production of extracellularmatrix proteins and for differential regulation of the adhesive properties of specific cell types. A well characterized in vivo activity of TGF-h is its ability to mediate a wound-healing cascade which accelerates tissue repair [34]. At the site of a peripheral wound, degranulation of platelets releases a bolus of TGF-h1, which attracts and activates monocytes,
Table 1 Consequences of TGF-h and TGF-h receptor gene depletion Gene targeting
Major phenotypes
References
TGF-h1 KO
Mice die either at around 10.5 days postcoitus or 3 weeks postpartum. Defective vasculogenesis, hematopoiesis and endothelial differentiation; multifocal inflammation. Perinatal lethality; multiple developmental defects, including cardiac, lung, limb, craniofacial, spinal column, eye, inner ear, urogenital defects. Perinatal lethality; defective palatogenesis; delayed pulmonary development. Embryonic lethality around 10.5 days postcoitus due to defects in the yolk sac hematopoiesis and vasculogenesis.
[25,27,28]
TGF-h2 KO TGF-h3 KO TGF-h RII KO TGF-h RII conditional KO In mammary epithelium
In colonic epithelium In fibroblasts In Col2a expressing cells In B cells
Lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. Shortened latency of tumor formation and increased pulmonary metastases when crossed with mouse mammary tumor virus-polyomavirus middle T antigen transgenic mouse. Increased formation and progression of azoxymethane-induced adenomas and adenocarcinomas. Intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach associated with an increased abundance of stromal cells. Defects in the axial skeleton without alterations in chondrocyte differentiation or embryonic development of long bones. Reduced life span of conventional B cells, expansion of peritoneal B-1 cells; B cell hyperplasia in Peyer’s patches; elevated serum immunoglobulin, and substantial IgG3 responses to a normally weak immunogen.
[20] [21,22] [26]
[29]
[30] [31] [32] [33]
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lymphocytes and neutrophils to contain infection, then promotes apoptosis and clearance of infiltrating leukocytes by tissue macrophages that produce antiinflammatory cytokines. Autoinduction of TGF-h in a number of cell types also maintains high levels of this growth factor in the wound bed where it induces angiogenesis and production of extracellular matrix to promote tissue repair [34,35]. If wound-healing processes fail to resolve at the appropriate stages or in the case of chronic injury, the formation of excessive granulomatous tissues may cause fibrotic disease.
4. Involvement of TGF-Bs in autoimmune and inflammatory diseases Epidermal Langerhans cells (LC) like bone marrow-derived immature dendritic cells (DC) play a critical role in the capture and processing of foreign antigens. This requires LC to have the capacity to migrate to regional lymph nodes where they become mature and present antigens to T cells. The development and differentiation of LC requires TGF-h1 [36], as indicated by in vitro experiments showing that the presence of TGF-h1 is necessary for CD34+ hemopoietic progenitor cells to develop into LC. In vivo, TGF-h1-deficient mice lack epidermal LC, but contain functional LC precursors that, upon transplantation into wild type mice, are capable of differentiating into LC. Thus, it appears that stimulation of LC precursors in peripheral organs by TGF-h1 in a paracrine manner is sufficient for LC differentiation, which provides strong evidence for the capacity of TGF-h1 to efficiently promote adaptive immunity. While TGF-h1 may act as a stimulant it suppresses the growth and differentiation of most immune cell lineages including B and T cells [37]. TGF-h is produced by most immune cell lineages and acts as a chemoattractant for monocytes/macrophages and inhibits immune cell activation by blocking antigen presentation and/or production of interleukins [37,38]. Gene targeting mouse model has confirmed and extended the understanding of the pivotal role played by TGF-h in immune cell homeostasis. TGF-h1 knockout mice exhibit a profound self-targeting multifocal inflammatory responses mediated by lymphocytes and characterized by overproduction of auto-
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antibodies that kill the animals at very early stages of life [27,39,40]. This phenotype manifests multiple characteristics, including a T cell-specific component whereby TGF-h control of proliferation and differentiation of T cells is lost [41,42]. In addition, apoptotic T cells are a major source of TGF-h [43], and moreover, TGF-h controls B cell proliferation, maturation and selectively upregulates IgA expression [44]. Furthermore, knocking-out one of the major signaling effectors of the TGF-h pathway, the Smad3, results in early post-natal death due to leukocytosis and impaired mucosal immunity that leads to severe chronic infection [45,46]. Therefore, a critical normal function of TGF-h in the immune system is suppression of lymphocyte proliferation and differentiation, therefore preventing detrimental autoimmune responses and regulating proper immune cell populations during pathologic states. TGF-h exerts potent immunosuppressive effects by inhibiting the expression of proinflammatory cytokines such as TNFa and IL-1 by immune cells [47], and blocking the induction of adhesion molecules such as ICAM-1 and VCAM-1 by cytokines [48,49]. In TGF-h deficient mice, the levels of class II MHC mRNA are elevated and mice die from cardiac, pulmonary, and gastric inflammation. Treatment of such mice with anti-inflammatory and immune suppressive agents have been shown to prolong animal life by reducing the levels of infiltrating immune cells in inflamed organs and the severity of inflammation [27]. Smad3-deficient mice develop chronic mucosal infection due to impairment of T-cell activation and mucosal immunity [46]. In contrast, in mice that are both TGF-h and class II MHC deficient, manifestations of autoimmune disease are diminished [50], suggesting that MHC class II molecules are essential for the development of autoimmunity in TGF-h1 deficient mice. Based on these results, TGF-h has been considered as a prominent candidate for control of autoimmune and chronic inflammatory diseases [51]. TGF-h1 is expressed abundantly in rheumatoid arthritis (RA) synovium. This suggests that TGF-h1 per se or in combination with other cytokines may play an important role in the progression of RA. There are several hypothetical ways by which TGF-h may promote RA pathogenesis. First, TGF-h surprisingly stimulates the expression of inflammatory cytokines
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such as TNFa and IL-1h by synovial cells [52]. Second, the production and activity of metalloproteinases are increased by TGF-h [52,53]. Third, TGF-h1 is chemotactic and may attract inflammatory cells to synovial tissue [54]. Fourth, TGF-h accelerates synovial hypertrophy since it induces fibroblast proliferation and reduces their apoptosis [55]. Finally, TGF-h is an inducer of VEGF therefore contributing indirectly to angiogenesis in arthritic synovium [56]. In asthmatic airways, TGF-h1 is an important fibrogenic and immunomodulatory factor that may cause structural changes [57]. Inflammatory cells infiltrating bronchial mucosa, and structural cells of the airway wall including fibroblasts, epithelial, endothelial and smooth muscle cells all of which are TGF-h producers. These diverse cell types increase the levels of TGF-h as observed in bronchoalveolar lavage fluid from asthmatic patients. Elevated TGF-h has been implied in the remodeling of the airway wall, which is related to subepithelial fibrosis. Interestingly, in vitro as well as in vivo studies have documented dual roles of TGF-h in airway diseases, functioning either as a pro- or an anti-inflammatory cytokine on infiltrating inflammatory cells. These apparently contradictory results may well be the consequences of using different experimental conditions. More clearcut conclusions concerning the effects of TGF-h may be obtainable from studies using systemic or conditional gene depletion approaches. Regulatory T (TR) cells are a subset of T cells that function to down-regulate immune responses. Reductions in TR cells are known to cause organ-specific autoimmune diseases in animal models. Different populations of TR cells have been described, including thymic derived CD4+CD25+ TR cells and TR cells induced in the periphery by exposure to antigen. A transcription factor, Foxp3, has been identified as a specific molecular marker for TR cells and its expression is essential for programming TR cell development and function [58]. TGF-h appears to play a broad role in TR activity. High concentrations of TGF-h enhance the regulatory function of TCR-stimulated CD25 CD4+ T cells in vitro [58,59]. However, in vivo, TGF-h seems to be dispensable for thymic TR cell development but is involved in the maintenance of peripheral TR cell number and functionality [60,61]. TGF-h might act directly on potentially pathogenic T cells to inhibit their differentiation
and effector function [62] or to induce their differentiation into Foxp3+ TR cells, or a combination of both [60,61]. CD4+CD25+ TR cells express membranebound and/or secreted TGF-h1, and blockade of TGF-h1 by anti-TGF-h1 antibody or recombinant latency-associated peptide of TGF-h1 dampens the ability of these cells to suppress CD25 T cell proliferation and B cell Ig production. This suggests that TGF-h1 produced by CD4+CD25+ T cells mediates the suppressor activity of these cells [63]. However, it has also been reported that neutralization of TGF-h1 with either monoclonal antibody or soluble TGF-hRII-Fc did not reverse in vitro suppression by resting or activated CD4+CD25+ TR cells. Responder T cells from Smad3 / or dominant-negative TGF-h type RII transgenic mice were as susceptible to CD4+CD25+mediated suppression as T cells from wild-type mice. Furthermore, CD4+CD25+ TR cells from neonatal TGF-h1 / mice were as suppressive as the cells from TGF-h1+/+ mice. These results demonstrate that CD4+CD25+ suppressor function can occur independently of TGF-h1 [64]. As the phenotype of freshly isolated CD4+CD25+ TGF-h1 / TR cells is distinct from their counterparts from wild type, the TGF-h1 null CD4+CD25+ TR cell populations are unique and/or may express alternative regulatory molecules. Although there are temporal, spatial and functional differences in distribution between TGF-h1 and its homologues TGF-h2 and TGF-h3 in vivo, both TGFh2 and TGF-h3 exhibit suppression in vitro and may play a role in the absence of TGF-h1. Collectively, these results demonstrate an important role for TGFh1 in TR cell biology and suggest additional applications for targeting TGF-h1 signal transduction pathway as means of therapeutic immune modulation.
5. The role of TGF-Bs in the pathogenesis of Alzheimer’s disease Alzheimer’s disease (AD) is a neurodegenerative disease characterized by neuronal loss that causes progressive loss of cognitive function. Neuropathological hallmarks of AD include the presence of amyloid plaques, neurofibrillary tangles, and gliosis. Animal and clinical studies have implicated a number of pro- and anti-inflammatory cytokines as integral to AD pathogenesis [65]. Among those cytokines, TGF-
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h emerged as an important factor in regulating inflammatory responses in AD. A genetic polymorphism of the TGF-h1 gene was found to be associated with a higher risk to the development of AD [66]. In AD patients, TGF-h levels were elevated in sera and cerebrospinal fluid, and the levels of TGF-h in serum correlate with disease severity [67,68]. Postmortem brain tissue analyses of AD patients showed an increased expression of TGF-h1 that was correlated with the degree of cerebral amyloid angiopathy [69]. TGF-h1 was immunohistochemically detected in neurofibrillary tangles and some senile plaques, particularly those located in the dentate gyrus of the hippocampus and the entorhinal cortex [70,71]. TGF-h2 levels are significantly elevated in the brains of AD patients, and were localized to glial cells and tangle-bearing neurons [71,72]. In in vitro experiments, TGF-h2, produced by microglia, a mononuclear phagocyte lineage cell type in the brain, was found to be associated with amyloid precursor protein (APP) [73]. These findings lead to the hypothesis that TGF-h may regulate APP synthesis, its processing by proteolytic enzymes, plaque formation, astroglial responses and neuronal cell death. In a model of long-term infusion of Ah into the rat brain, co-administration of TGF-h was found to be a requirement for plaque formation [74]. In addition, TGF-h1 substantially increased the in vitro expression of APP mRNA and protein by astrocytes and microglia [75,76]. Overexpression of TGF-h1 in transgenic mice induces higher level expression of APP, increases Ah generation in cerebral tissues [77], and accelerates amyloid-beta deposition in cerebral blood vessels and meninges [69]. Aged transgenic mice containing Swedish double mutations of APP695 which in human are associated with early onset AD dementia, display TGF-h1 immunoreactive astrocytes in the brain in close proximity to Ah deposits [78]. Co-expression of TGF-h1 in transgenic mice overexpressing APP accelerated the deposition of amyloid-beta peptide, a major component of the senile plaques [69]. These results suggest a marked influence of TGF-h1 on APP metabolism and processing, albeit with as yet unclear mechanisms. Despite its potentially detrimental role in amyloid deposition in AD, there are also reports indicating that TGF-h may be neuroprotective at certain stages of the disease. TGF-h1 has been shown to provide protec-
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tion for human fetal neuronal cells against the cytotoxicity of Ah peptides [79]. All three TGF-h isoforms have been reported to reduce the damage of rat hippocampal neurons by Ah or its active fragments [69,80,81], TGF-h1 was also implicated in Ah clearance from the brain parenchyma to the cerebral blood vasculature in aged hAPP/TGF-h1 double transgenic mice by microglia. Increased astroglial TGF-h1 production in such mice activates microglia in the hippocampus and cortex. These mice exhibit 75% reduction in parenchymal amyloid plaques, and with significantly lower levels of Ah deposition [82]. Recently, TGF-h1 has been shown to regulate the expression of Ah receptors on microglial cells. The bulk of the evidence suggests that inflammatory responses elicited by elevated Ah peptides play an important role in the progression of AD. In AD brain, microglia accumulate at the sites of Ah peptide deposition. In vitro, Ah peptides activate mononuclear phagocytes to release neurotoxic mediators. A number of cell surface molecules have been reported to act as putative receptors for Ah peptides, among which the G protein coupled formyl peptide receptorlike 1 (FPRL1) and its mouse homologue FPR2 [83] have been shown to be expressed by activated microglial cells and to mediate the chemotactic activity of a 42 amino acid form of Ah (Ah42), a major component of AD plaques [84,85]. FPRL1 also participates in Ah internalization in macrophages and its cytotoxicity for neuronal cells [86,87]. In murine-microglial cells, the bacterial endotoxin LPS and TNFa increased the expression of functional mFPR2 [88,89], whereas TGF-h1 was capable of attenuating LPS-induced signaling cascade and the resultant up-regulation of mFPR2 [18]. The inhibitory effect of TGF-h1 required the participation of Smad3 and the transcription coactivator p300 [18], and in addition, TGF-h1 enhanced MAPK phosphorylation in microglial cells which became refractory to subsequent stimulation by LPS. TGF-h1 also directly inhibited the function of mFPR2 in microglial cells activated by LPS, and in human monocytes which constitutively express functional FPRL1. TGF-h1 decreased the FPRL1 gene expression and the cell responses to FPRL1 agonists including Ah42 (Le Y., unpublished observation). Taken together, TGF-h1 in the AD brain may dynamically affect the accumulation, redistribution, and clearance of Ah. Furthermore, TGF-h1, by reg-
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ulating the expression of mFPR2 in microglial cells, may profoundly affect the proinflammatory responses mediated by Ah42. A tight temporal-spatial balance of TGF-h1 production may determine the outcome of its influence on AD pathogenesis. Further elucidation of the signaling pathways by which TGF-h exerts its effect in AD may identify specific targets for therapeutic intervention.
6. TGF-B in tumor growth and metastasis TGF-h has been considered as an important regulator of carcinogenesis, with either suppressive or promoting activities depending on developmental stages and cellular context of the tumor. During the early phase of epithelial tumorigenesis, TGF-h inhibits primary tumor development and growth by inducing tumor cell cycle arrest that may lead to apoptosis. However, in late stages of tumor progression, since tumor cells may evade the growth inhibition exerted by TGF-h, due to inactivation of intracellular signaling pathway or aberrant activation of cell cycle machinery, the presence of TGF-h is often associated with tumor progression. Since TGF-h is a potent growth inhibitor of most cell types, perturbations of TGF-h signaling cascade result in malignant transformation and tumor progression. It has been reported that decreased expression of TGF-h receptor II (RII) in epithelial cells is an important step in their malignant transformation resulting from the activation of Ras protein and from antigenpresenting cell (APC) mutations [90,91]. Down-regulation of RII was observed in 13% human colon carcinoma specimens with microsatellite instability [92]. Mutations in RII have been identified in patients with hereditary nonpolyposis colon cancer [93]. Depletion of RII in mouse colonic epithelium increased the formation and progression of azoxymethane-induced adenoma and adenocarcinoma [30]. Depletion of RII in mouse fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both in association with increased abundance of stromal cells [31]. Mutations of Smad4 have been found in patients with pancreatic carcinoma and those with advanced colon carcinoma [94,95]. Hypomorphic TGF-h signaling in TGF-h+/ mice is associated with increased
tumor development [96], and hypomorphic TGF-h RI(6A) allele in human is associated with the development of a variety of cancers [97]. These observations suggest that TGF-h receptor signaling plays an important role in homeostasis and resistance to malignant transformation of epithelial cells. TGF-h induces extracellular matrix accumulation, angiogenesis, and immunosuppression, indicating that TGF-h may facilitate the progression of tumors under certain conditions. TGF-h expression is increased in a variety of tumor types. Studies of colorectal carcinoma have documented that high-level expression of TGF-h1 in primary tumor is associated with advanced tumor stage and is an independent prognostic factor [98]. Inhibiting TGF-h activity reduces the rate of tumor progression and in particular, metastasis, in certain experimental tumor models. TGF-h is also thought to increase the ability of malignant cells to metastasize by altering cytoskeletal architecture, known as epithelial-to-mesenchymal transition. In fact, evidence suggests that autocrine TGF-h expression by tumor cells is critical for epithelial-to-fibroblastoid conversion in mammary cells [99] and in keratinocytes [100]. Although TGF-h overexpression in mouse keratinocytes inhibits the growth of carcinogen-induced benign skin tumors, it promotes the progression of advanced lesions of the malignant phenotype [101]. TGF-hinduced mesenchymal transition in Ha-Ras-transformed mammary epithelial cells disrupts cell–cell adhesion and causes the loss of epithelial polarity [102]. It is believed that the ability of an epithelial cell to use TGF-h as a growth-promoting factor and a trigger for invasive phenotype is a result of complicated alteration in many cellular and nuclear elements, including the absence or disruption of cyclindependent kinase inhibitors. This imbalance in cell cycle regulators may be the key element that dictates cellular responses to TGF-h either for growth-inhibition or for stimulation.
7. Perspectives TGF-h is an immunoregulatory cytokine. Despite its multiple roles in autoimmune and inflammatory processes, it has been experimentally deployed as a potential therapeutic agent to control autoimmune
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and chronic inflammatory diseases [103]. TGF-h has also been implicated as one of the key regulators of regulatory T cells that are crucial for maintaining balanced immune responses. Nevertheless, its overproduction contributes to persistent inflammation, thus antagonists of TGF-h delivered locally break the cycle of leukocyte recruitment and subsequent fibrosis. On the other hand, systemic administration of TGF-h by injections of the protein or by gene transfer inhibits inflammatory pathogenesis. In addition, enhanced levels of circulating TGF-h appear to be instrumental during the development of oral tolerance and in immunosuppression caused by cyclosporin treatment. The multiplicity of actions of TGFhs and their virtually ubiquitous expression call for more rigorous investigation of their roles in health and disease states and more importantly, careful evaluation of their potential as immunopharmacological agents. Acknowledgement The authors thank their colleagues at Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, P.R. China, and National Cancer Institute at Frederick, the National Institutes of Health, USA, for contributions to the studies. References [1] Roberts AB, Anzano MA, Lamb LC, Smith JM, Sporn MB. New class of transforming growth factors potentiated by epidermal growth factor: isolation from non-neoplastic tissues. Proc Natl Acad Sci U S A 1981;78:5339 – 43. [2] Govinden R, Bhoola KD. Genealogy, expression, and cellular function of transforming growth factor-beta. Pharmacol Ther 2000;98:257 – 65. [3] Massague J. The transforming growth factor-beta family. Annu Rev Cell Biol 1990;6:597 – 641. [4] Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res 1994;5: 99 – 118. [5] Roberts AB. Molecular and cell biology of TGF-beta. Miner Electrolyte Metab 1998;24:111 – 9. [6] Kim SJ, Jeang KT, Glick AB, Sporn MB, Roberts AB. Promoter sequences of the human transforming growth factor-beta 1 gene responsive to transforming growth factor-beta 1 autoinduction. J Biol Chem 1989;264:7041 – 5.
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