Proinflammatory Cytokines in the Pathogenesis of Inflammatory Bowel Diseases
2011; Elsevier BV; Volume: 140; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2011.02.016
ISSN1528-0012
Autores Tópico(s)IL-33, ST2, and ILC Pathways
ResumoThe cytokine responses characterizing the inflammatory bowel diseases are the key pathophysiologic elements that govern the initiation, evolution, and, ultimately, the resolution of these forms of inflammation. Studies during the last 2 decades now provide a detailed (but not yet complete) picture of the nature of these responses. The first tier of cytokine responses are governed by the T-cell differentiation patterns dominating the disease. In Crohn's disease, the major cytokines arise from T-helper cell (Th) 1 and Th17 CD4+ T-cell differentiation and consist of interferon-γ and interleukin (IL)-17/IL-22 generated by these types of differentiation. The relative importance of these cytokines to Crohn's inflammation is still unclear, although evidence is mounting that interferon-γ is primus inter pare (first among equals). In contrast, in ulcerative colitis, a Th2-like differentiation process is paramount, which results in expansion of natural killer T cells producing IL-13 (and perhaps IL-5). These disease-specific cytokine patterns give rise to a second tier of cytokines that span the Th1/Th17–Th2 divide and act as upstream facilitators and downstream mediators of inflammation. These cytokines include the well-known tumor necrosis factor–α, IL-1β, IL-6 triumphirate, as well as a more recently studied cytokine known as TL1A (tumor necrosis factor–like ligand). In this review, we will explore this cytokine landscape with the view of providing an understanding of how recent and future anticytokine therapies actually function. The cytokine responses characterizing the inflammatory bowel diseases are the key pathophysiologic elements that govern the initiation, evolution, and, ultimately, the resolution of these forms of inflammation. Studies during the last 2 decades now provide a detailed (but not yet complete) picture of the nature of these responses. The first tier of cytokine responses are governed by the T-cell differentiation patterns dominating the disease. In Crohn's disease, the major cytokines arise from T-helper cell (Th) 1 and Th17 CD4+ T-cell differentiation and consist of interferon-γ and interleukin (IL)-17/IL-22 generated by these types of differentiation. The relative importance of these cytokines to Crohn's inflammation is still unclear, although evidence is mounting that interferon-γ is primus inter pare (first among equals). In contrast, in ulcerative colitis, a Th2-like differentiation process is paramount, which results in expansion of natural killer T cells producing IL-13 (and perhaps IL-5). These disease-specific cytokine patterns give rise to a second tier of cytokines that span the Th1/Th17–Th2 divide and act as upstream facilitators and downstream mediators of inflammation. These cytokines include the well-known tumor necrosis factor–α, IL-1β, IL-6 triumphirate, as well as a more recently studied cytokine known as TL1A (tumor necrosis factor–like ligand). In this review, we will explore this cytokine landscape with the view of providing an understanding of how recent and future anticytokine therapies actually function. View Large Image Figure ViewerDownload Hi-res image Download (PPT) In the past 2 decades, studies of the cytokines driving the inflammatory bowel diseases (IBDs) and other forms of mucosal inflammation has borne ample fruit, both in providing us with major insights into the mechanism of these diseases and in pointing us in the direction of new therapies. In this review, we will focus on the main cytokine responses in Crohn's disease (CD) and ulcerative colitis (UC) that initiate and sustain inflammation, leaving the task of discussing the regulatory cytokines that oppose such inflammation to other reviewers. With the discovery in the late 1980s that T helper (Th) cells differentiate into Th1 and Th2 cells,1Mosmann T.R. Cherwinski H. Bond M.W. et al.Two types of murine helper T cell clone I. Definition according to profiles of lymphokine activities and secreted proteins.J Immunol. 1986; 136: 2348-2357Crossref PubMed Google Scholar producing different sets of cytokines, it was quickly established that CD differed from UC in that CD seemed to be a Th1 cytokine-mediated disease characterized by increased production of interferon (IFN)-γ, whereas UC seemed to be a Th2 cytokine-mediated disease characterized by increased production of interleukin (IL)-5 production and normal IFN-γ production.2Braese E. Braegger C.P. Corrigan C.J. et al.Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa.Immunology. 1993; 78: 127-131PubMed Google Scholar, 3Fuss I.J. Neurath M. Boirivant M. et al.Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5.J Immunol. 1996; 157: 1261-1270PubMed Google Scholar One caveat, however, was that production of the signature cytokine of the Th2 response (IL-4) was not increased in UC and it was clear that the latter was a “Th2-like” disease rather than a fully Th2 disease (see Figure 1). Support for these concepts came from studies of several murine models of IBD resembling CD, particularly trinitrobenzene sulfonic acid (TNBS)–induced colitis and cell transfer–induced colitis, which showed that inflammation was reversed by treatment with anti–IL-12p40—an antibody directed against a cytokine initially identified as IL-12, the master cytokine driving the Th1 response.4Neurath M.F. Fuss I. Kelsall B.L. et al.Antibodies to interleukin 12 abrogate established experimental colitis in mice.J Exp Med. 1995; 182 (1291–1290)Crossref PubMed Scopus (1213) Google Scholar, 5Liu Z. Beboes K. Heremans H. et al.Role of interleukin-12 in the induction of mucosal inflammation and abrogation of regulatory T cell function in chronic experimental colitis.Eur J Immunol. 2001; 31: 1550-1560Crossref PubMed Scopus (53) Google Scholar These findings, along with the fact that patients with CD exhibited increased lamina propria IL-12 production as compared to controls,6Fuss I.J. Becker C. Yang Z. et al.Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regulated by treatment with anti-IL-12 p40 monoclonal antibody.Inflamm Bowel Dis. 2006; 12: 9-15Crossref PubMed Scopus (282) Google Scholar, 7Hart A.L. Al-Hassi H.O. 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Elson C.O. et al.Anti-interleukin-12 antibody for active Crohn's disease.N Engl J Med. 2004; 351: 2069-2079Crossref PubMed Scopus (764) Google Scholar, 10Sandborn W.J. Feagan B.G. Fedorak R.N. et al.A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn's disease.Gastroenterology. 2008; 135: 1130-1141Abstract Full Text Full Text PDF PubMed Scopus (645) Google Scholar These results not only formed the basis of a new therapy for CD, they also represented incontrovertible evidence that a cytokine containing a p40 chain played a major pathogenic role in this disease. Parallel studies of UC, which will be discussed here at greater length, verified that UC was a Th2-like disease because it was associated with increased IL-13 production (but not IL-4 production) by natural killer T (NKT) cells, rather than by conventional T cells.11Fuss I.J. Heller F. Boirivant M. et al.Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis.J Clin Invest. 2004; 113: 1490-1497Crossref PubMed Scopus (672) Google Scholar As is the case with CD, analysis of the pattern of T-cell differentiation was predictive of the basic cytokines causing UC-type inflammation. The concept that CD was an IL-12−driven Th1 inflammation did not remain unchallenged for long: about the time anti−IL-12p40 was shown to be effective in the treatment of CD, a new set of cytokines, the Th17 cytokines (IL-17 and IL-23), was shown to function as effectors in various autoimmune disease models.12Oppman B. Lesley R. Blom B. et al.Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.Immunity. 2000; 13: 715-725Abstract Full Text Full Text PDF PubMed Scopus (2340) Google Scholar, 13Aggarwal S. Ghilardi N. 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Buonocore S. et al.Interleukin-23 drives innate and T cell-mediated intestinal inflammation.J Exp Med. 2006; 203: 2473-2483Crossref PubMed Scopus (699) Google Scholar, 17Kullberg M.C. Jankovic D. Feng C.G. et al.IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis.J Exp Med. 2006; 203: 2485-2494Crossref PubMed Scopus (487) Google Scholar The idea that a Th17 response rather than a Th1 response was the major engine of inflammation in CD did not contradict the previously observed effect of anti−IL-12p40 in experimental and human CD because both IL-12 and IL-23 are heterodimers of which one chain is p4012; thus, anti−IL-12p40 can neutralize both IL-12 and IL-23. To fully understand how Th17 T-cell responses are involved in experimental colitis or CD, it is important to take a moment to review certain salient features of Th17 immunobiology. First, IL-12 has a very different relation to IFN-γ than does IL-23 to IL-17. IL-12 is the major inducer of Th1 cells producing IFN-γ via direct interaction with IL-12 receptors on undifferentiated T cells18Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity.Ann Rev Immunol. 1995; 13: 251-276Crossref PubMed Scopus (2257) Google Scholar; in contrast, transforming growth factor−β (TGF-β) and IL-6 (or IL-21) are the major inducers of Th17 cells producing IL-17 (and IL-22 as well) and the function of IL-23 is to interact with already differentiated Th17 cells (now expressing an IL-23 receptor) to cause stabilization and/or expansion of Th17 cells.19Veldhoen M. Hocking R.J. Atkins C.J. et al.TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.Immunity. 2006; 24: 179-189Abstract Full Text Full Text PDF PubMed Scopus (3099) Google Scholar, 20McGeachy M.J. Chen Y. 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Chen Y. et al.TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology.Nat Immunol. 2007; 8: 1390-1397Crossref PubMed Scopus (1274) Google Scholar In addition, it has recently been shown that Th17 cells induced in the presence of IL-1β have a unique messenger RNA profile and an increased capacity to induce inflammation.24Ghoreschi K. Laurence A. Yang X.P. et al.Generation of pathogenic T(H)17 cells in the absence of TGF-β signaling.Nature. 2010; 467: 967-971Crossref PubMed Scopus (1140) Google Scholar Thus, not all Th17 cells are equal. Second, because Th17 cells usually require TGF-β for differentiation, a cytokine also involved in regulatory T-cell differentiation, it is not surprising that Th17 cells and regulatory T cells have a “ying-yang” relationship, wherein development of one type of cell is reciprocal to development of the other type of cell. This is seen in the fact that induction of Foxp3 expression, the signature protein of regulatory T cells, inhibits RORγt function, the main IL-17 transcription factor. Similarly, the induction of Th17 cells inhibits Foxp3 expression.25Zhou L. Littman D.R. Transcriptional regulatory networks in Th17 cell differentiation.Curr Opin Immunol. 2009; 21: 146-152Crossref PubMed Scopus (161) Google Scholar, 26Yang X.O. Pappu B.P. Nurieva R. et al.T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.Immunity. 2008; 28: 29-39Abstract Full Text Full Text PDF PubMed Scopus (1345) Google Scholar Another manifestation of the relationship between Th17 cells and regulatory T cells is that the latter cells produce large amounts of TGF-β and can induce naïve CD4+ cells to become IL-17−producing cells in an inflammatory milieu that contains IL-6, or can themselves be converted into Th17 cells under these circumstances.27Xu L. Kitani A. Fuss I. et al.Cutting edge: regulatory T cells induce CD4+CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta.J Immunol. 2007; 178: 6725-6729PubMed Google Scholar, 28Zhou L. Lopes J.E. Chong M.M. et al.TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.Nature. 2008; 453: 236-240Crossref PubMed Scopus (1573) Google Scholar, 29Koenen J.H. Smeets R.L. Vink P.M. et al.Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells.Blood. 2008; 112: 2340-2352Crossref PubMed Scopus (624) Google Scholar, 30Yang X.O. Nrurieva R. Martinez G.J. et al.Molecular antagonism and plasticity of regulatory and inflammatory T cell programs.Immunity. 2008; 29: 44-56Abstract Full Text Full Text PDF PubMed Scopus (947) Google Scholar This “plasticity” of IL-17−producing cells and regulatory T cells indicates that Th17 responses in IBD may morph into regulatory responses (and vice versa), depending on the character of the inflammation. A third and final feature of Th17 development is that induction of IL-17 gives rise to IL-17−producing T cells, as well as cells producing both IL-17 and IFN-γ; in addition, there is evidence that in a milieu lacking TGF-β, IL-12 and IL-23 tend to act on cells initially producing IL-17 to become cells producing IFN-γ.31Harrington L.E. Hatton R.D. Mangan P.R. et al.Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.Nat Immunol. 2005; 6: 1123-1132Crossref PubMed Scopus (3920) Google Scholar, 32Mangan P.R. Harrington L.E. O'Quinn D.B. et al.Transforming growth factor-beta induces development of the T(H)17 lineage.Nature. 2006; 441: 231-234Crossref PubMed Scopus (2669) Google Scholar, 33Lee Y.K. Turner H. Maynard C.L. et al.Late developmental plasticity in the T helper 17 lineage.Immunity. 2009; 30: 92-107Abstract Full Text Full Text PDF PubMed Scopus (847) Google Scholar This capacity of at least some Th17 T cells to produce IFN-γ is consonant with the heterogeneity of Th17 cells mentioned here and may facilitate their pathologic potential. The initial studies assessing the importance of Th17 responses in experimental colitis and CD used the previously mentioned cell-transfer colitis model. This model consists of inflammation developing in immunodeficient mice (either recombination activating gene [RAG]−deficient or severe combined immune-deficient [SCID] mice) after adaptive transfer of naïve CD4+ T cells (CD45RBhigh T cells) that develop into proinflammatory effector cells in the absence of a mature (CD45RBlow T cells) cell population that contain regulatory T cells.34Powrie F. Correa-Oliveira R. Mauze S. et al.Regulatory interactions between CD45RBhigh and CD45RBlow CD4+ T cells are important for the balance between protective and pathogenic cell-mediated immunity.J Exp Med. 1994; 179: 589-600Crossref PubMed Scopus (566) Google Scholar, 35Powrie F. Mason D. OX-22 high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22 low subset.J Exp Med. 1990; 172: 1701-1708Crossref PubMed Scopus (356) Google Scholar To put these studies into prospective, one should be aware that anti−IFN-γ administration leads to complete amelioration of cell-transfer colitis and transfer of CD45RBhigh (colitis-inducing) cells unable to synthesize IFN-γ because they lack a key factor (T-bet) necessary for IFN-γ production, does not initiate colitis.36Powrie F. Leach M.W. Mauze S. et al.Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells.Immunity. 1994; 1: 553-562Abstract Full Text PDF PubMed Scopus (1019) Google Scholar, 37Neurath M.F. Weigmann B. Finotto S. et al.The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.J Exp Med. 2002; 195: 1129-1143Crossref PubMed Scopus (527) Google Scholar In addition, the percentage of cells in the inflamed lamina propria of this model producing IFN-γ alone is 15−25 times higher than the percentage of cells producing IL-17 alone and 10 times higher than those producing both IL-17 and IFN-γ.38Griseri T. Asquith M. Thompson C. et al.OX40 is required for regulatory T cell-mediated control of colitis.JEM. 2010; 207: 699-709Crossref PubMed Scopus (134) Google Scholar, 39Mikami Y. Kanai T. Sujino T. et al.Competition between colitogenic Th1 and Th17 cells contributes to the amelioration of colitis.Eur J Immunol. 2010; 40: 2409-2422Crossref PubMed Scopus (34) Google Scholar These facts strongly suggest that the dominant effector cell driving cell-transfer colitis is an IFN-γ−producing cell that is likely originating mainly from a Th1 response not a Th17 response. Nevertheless, certain influential studies have appeared presenting compelling evidence that a Th17 response is, in fact, the key effector cell response in this colitis model. In the first of 3 such studies, it was shown that RAG-deficient mice also deficient in IL-23p19 (and thus deficient in IL-23) did not develop colitis upon transfer of naïve T cells, whereas the same mice also deficient in IL-12p35 (and thus deficient in IL-12) did develop colitis upon transfer.16Hue S. Ahern P. Buonocore S. et al.Interleukin-23 drives innate and T cell-mediated intestinal inflammation.J Exp Med. 2006; 203: 2473-2483Crossref PubMed Scopus (699) Google Scholar, 40Uhlig H.H. McKenzie B.S. Huie S. et al.Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology.Immunity. 2006; 25: 309-318Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar Correspondingly, proinflammatory cytokine production (TNF-α and IFN-γ) was greatly reduced in the IL-23p19−deficient mice, whereas it was only moderately reduced in the IL-12p35−deficient mice. Interestingly, while the IL-12p35−deficient mice exhibited greatly increased levels of IL-17, they also exhibited increased levels of IFN-γ. This suggests that the inflammation in IL-12p35−deficient mice may have been due, as least in part, to the previously mentioned IFN-γ component of the Th17 response, which in the absence of the p35 chain comprising part of the inhibitory cytokine, IL-35, is exaggerated.41Collison L.W. Workman C.J. Kuo T.T. et al.The inhibitory cytokine IL-35 contributes to regulatory T-cell function.Nature. 2007; 450: 566-569Crossref PubMed Scopus (1567) Google Scholar In a recent update of these findings, it was shown that transfer of naïve T cells lacking the IL-23 receptor also failed to generate colitis.42Ahern P.P. Schiering C. Buonocore S. et al.Interleukin-23 drives intestinal inflammation through direct activity on T cells.Immunity. 2010; 33: 279-288Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar In addition, signaling through this receptor enhanced intestinal T-cell proliferation and accumulation of IL-17−producing cells, especially those producing both IL-17 and IFN-γ, which again could be a particularly proinflammatory Th17-cell subpopulation. Finally, the lack of T-cell expansion in mice reconstituted by IL-23R−deficient T cells could be overcome by cotransfer of T cells bearing IL-23R, indicating that a factor produced by cells bearing the receptor can drive cell proliferation of cells lacking the receptor. Overall then, cell-transfer colitis was shown in studies of both IL-23−deficient mice and IL-23R−deficient mice to exhibit greatly diminished colitis. In the second study, SCID mice were initially transferred antigen-specific (ie, flagellin-specific) T cells, ie, memory T cells rather than naïve T cells, as in the usual cell-transfer colitis study. Interestingly, in this case, the lamina propria of the inflamed colon contained a 5:1 preponderance of IL-17−producing cells vs IFN-γ−producing cells, quite the opposite of what is seen with the transfer of naïve cells.43Elson C.O. Cong Y. Weaver C.T. et al.Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice.Gastroenterology. 2007; 132: 2359-2370Abstract Full Text Full Text PDF PubMed Scopus (395) Google Scholar This could conceivably be explained by the fact that memory cells are more responsive to IL-23 than to IL-12.12Oppman B. Lesley R. Blom B. et al.Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12.Immunity. 2000; 13: 715-725Abstract Full Text Full Text PDF PubMed Scopus (2340) Google Scholar Next, SCID mice were transferred previously polarized Th1 or Th17 flagellin-specific T cells producing mainly IFN-γ and IL-17, respectively. It was found that the mice transferred Th17 cells developed severe colitis, whereas the mice transferred Th1 cells developed little if any colitis. In addition, treatment of the Th17-reconstituted mice with anti−IL-23p19 either prevented colitis or reduced already established colitis. These studies suggest that Th17 cells, but not Th1 cells, mediate inflammation in a modified cell-transfer colitis model. Two points about these results require further consideration. First, the inflamed colons of mice transferred Th17 cells and exhibiting colitis contained cells producing large amounts of IFN-γ, even though at the time of cell administration they were producing mainly IL-17. Thus, the mice reconstituted with Th17 cells could conceivably have had inflammation driven by both IL-17 and IFN-γ. Second, the lack of inflammation in the mice transferred IFN-γ cells is discordant with earlier cell-transfer colitis studies already discussed in which colitis was shown to be reversed by treatment with anti–IFN-γ36; this could conceivably be explained by the fact that a memory rather than a naïve population was transferred to the SCID mice and that this memory cell population was subject to inhibition by regulatory T cells. In the third study of the role of IL-17 in transfer-colitis, it was shown that although transfer of T cells lacking the capacity to produce any individual Th17 cytokine (ie, IL-17A, IL-17F or IL-22) to RAG1-deficient mice led to full-blown colitis, transfer of T cells from an RORγt-deficient mice, that is, mice lacking a transcription factor necessary for production of all of these Th17 cytokines fail to develop colitis. Thus, although IL-17A and IL-17F are redundant, at least one member of the IL-17 cytokine family was required for the occurrence of colitis.44Leppkes M. Becker C. Ivanov I.I. et al.RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.Gastroenterology. 2009; 136: 256-267Abstract Full Text Full Text PDF Scopus (370) Google Scholar Further confirmatory studies showed that RAG1-deficient mice that fail to develop colitis upon transfer of RORγt-deficient cells, do develop colitis if administered exogenous IL-17A.44Leppkes M. Becker C. Ivanov I.I. et al.RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.Gastroenterology. 2009; 136: 256-267Abstract Full Text Full Text PDF Scopus (370) Google Scholar One possible discrepancy in these data was that transfer of RORγt-deficient T cells also led to a great reduction in the production of IFN-γ, suggesting that it was really the IFN-γ produced during a Th17 response that was mediating the inflammation. However, this possibility seemed to be at least partly negated by the fact that RAG1-deficient mice transferred IL-17F−deficient T cells, thus manifesting colitis due to IL-17A alone, exhibit decreased colitis when treated with anti−IL-17A.44Leppkes M. Becker C. Ivanov I.I. et al.RORgamma-expressing Th17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F.Gastroenterology. 2009; 136: 256-267Abstract Full Text Full Text PDF Scopus (370) Google Scholar The various studies discussed here appear to offer definitive evidence that at least one major type of experimental colitis, cell-transfer colitis, requires a Th17 response to support development of colonic inflammation. However, before we accept this conclusion we need to consider studies probing the impact of Th17 responses on regulatory T-cell responses. In an initial study of this question, it was shown that the transfer of naïve T cells to immune-deficient (RAG1-deficient) mice also lacking IL-23p19 (ie, mice able to mount a Th1 but not a Th17 response) only develop colitis if they have a concomitant IL-10 or TGF-β deficiency and thus cannot mount a regulatory T-cell response.45Izcue A. Hue S. Buonocore S. et al.Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis.Immunity. 2008; 28: 559-570Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar In addition, IL-23p19−deficient mice exhibit increased numbers of regulatory T cells (Foxp3+ T cells) in the colon and transfer of naïve T cells into RAG1-deficient/IL-23p19−deficient mice that also lack Foxp3+ T cells develop colitis despite the absence of IL-23p19 (and the ability to mount a Th17 response). Similar findings were found in a second study, in which it was shown that RAG1-deficient mice reconstituted with IL-23R−deficient T cells also exhibit increased numbers of Foxp3+ T cells in the colon, which was then shown to be a result of the lack of a negative effect of IL-23 on these cells.42Ahern P.P. Schiering C. Buonocore S. et al.Interleukin-23 drives intestinal inflammation through direct activity on T cells.Immunity. 2010; 33: 279-288Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar These findings strongly suggest that IL-23 suppresses regulatory T-cell development and thus introduce the possibility that mice that lack IL-23 fail to develop colitis, not because they cannot produce a key effector cytokine (IL-17), but rather because they have a dominant regulatory T-cell response. In the same vein, the inability of transferred polarized Th1 cells to cause colitis could be due to the fact that, in the absence of Th17 cells, Th1 cells are subject to suppression by regulatory T cells. Additional questions about the role of Th17 responses in colitis models are raised by more recent studies of cell-transfer colitis, as well as studies of TNBS-colitis and dextran sodium sulfate (DSS)-colitis. In these cell-transfer colitis studies, it was found that transfer of T-cell populations from IL-17−deficient mice to immunodeficient mice led to earlier onset of colitis and higher levels of IFN-γ production than transfer of cell populations from wild-type mice.46O'Connor Jr, O. Kamanaka M. Booth C. et al.A protective function for interleukin 17A in T cell-mediated intestinal inflammation.Nat Immunol. 2009; 10: 603-609Crossref PubMed Scopus (648) Google Scholar These findings could be explained by the fact that Th1 cells bear IL-17 receptors and IL-17 signaling via these receptors inhibits Th1 differentiation by suppressing expression of T-bet, a factor necessary for Th1 T-cell development.46O'Connor Jr, O. Kamanaka M. Booth C. et al.A protective function for interleukin 17A in T cell-mediated intestinal inflammation.Nat Immunol. 2009; 10: 603-609Crossref PubMed Sco
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