Colitis in mice lacking the common cytokine receptor γ chain is mediated by IL-6-producing CD4+ T cells

Kai, Yasuyuki; Takahashi, Ichiro; Ishikawa, Hiromichi; Hiroi, Takachika; Mizushima, Tsunekazu; Matsuda, Chu; Kishi, Daisuke; Hamada, Hiromasa; Takahashi, Hiroshi; Ito, Toshinori; Yoshizaki, Kazuyuki; Kishimoto, Tadamitsu; Matsuda, Hikaru; Kiyono, Hiroshi

doi:10.1053/j.gastro.2005.01.013

Cited by 34 publications

(22 citation statements)

References 47 publications

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“…The inflammatory mediators include a number of cytokines such as TNF-α, IL-1β, IL-6, IL-12, IL-23, and IL-10. [15][16][17][18] In our present study, IL-8 and MIP-1β were remarkable parameters showing significant decrease after induction therapy with infliximab in patients with UC. 19,20 IL-8 expression increased significantly in active UC mucosa and is therefore thought to play an important role in the perpetuation of inflammation in UC.…”

Section: Discussionsupporting

confidence: 60%

“…15,17 Furthermore, blockade of IL-6 signaling by monoclonal antibodies is effective in suppressing intestinal inflammation in mouse models, which suggests IL-6 as a potential therapeutic target in IBD. 15,16 The present study has several limitations. First, we could not examine circulating infliximab concentration or antibody to infliximab, which is inevitably associated with the long-term clinical response to infliximab.…”

Section: Discussionmentioning

confidence: 86%

See 1 more Smart Citation

Changes in cytokine profile may predict therapeutic efficacy of infliximab in patients with ulcerative colitis

Sato

Chiba

Nakamura

et al. 2015

J of Gastro and Hepatol

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 86%

Changes in cytokine profile may predict therapeutic efficacy of infliximab in patients with ulcerative colitis

Sato

Chiba

Nakamura

et al. 2015

J of Gastro and Hepatol

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“…The cytokine IL-6 is known to induce STAT-3 expression in T cells and thereby control T cell resistance against apoptosis in experimental colitis (11)(12)(13). Here, we identified IRF4 as a key regulator of mucosal IL-6 production and T cell apoptosis in experimental colitis.…”

Section: Figurementioning

confidence: 80%

“…IL-6 is produced by both macrophages and T cells in IBD patients and mediates T cell resistance against apoptosis in chronic intestinal inflammation. The key functional role of IL-6 signaling was underlined by the observation that neutralizing anti-IL-6R antibodies led to suppression of established intestinal inflammation in animal models of IBD (10)(11)(12)(13). Moreover, treatment of patients with Crohn disease (CD) with a humanized, neutralizing anti-IL-6R antibody resulted in significantly higher response rates than placebo therapy, suggesting a therapeutic benefit of anti-IL-6 signaling strategies (14).…”

Section: Introductionmentioning

confidence: 99%

The transcription factor IFN regulatory factor–4 controls experimental colitis in mice via T cell–derived IL-6

Mudter¹,

Amoussina²,

Schenk³

et al. 2008

J. Clin. Invest.

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The proinflammatory cytokine IL-6 seems to have an important role in the intestinal inflammation that characterizes inflammatory bowel diseases (IBDs) such as Crohn disease and ulcerative colitis. However, little is known about the molecular mechanisms regulating IL-6 production in IBD. Here, we assessed the role of the transcriptional regulator IFN regulatory factor-4 (IRF4) in this process. Patients with either Crohn disease or ulcerative colitis exhibited increased IRF4 expression in lamina propria CD3 + T cells as compared with control patients. Consistent with IRF4 having a regulatory function in T cells, in a mouse model of IBD whereby colitis is induced in RAG-deficient mice by transplantation with CD4 + CD45RB hi T cells, adoptive transfer of wild-type but not IRF4-deficient T cells resulted in severe colitis. Furthermore, IRF4-deficient mice were protected from T cell-dependent chronic intestinal inflammation in trinitrobenzene sulfonic acid-and oxazolone-induced colitis. In addition, IRF4-deficient mice with induced colitis had reduced mucosal IL-6 production, and IRF4 was required for IL-6 production by mucosal CD90 + T cells, which it protected from apoptosis. Finally, the protective effect of IRF4 deficiency could be abrogated by systemic administration of either recombinant IL-6 or a combination of soluble IL-6 receptor (sIL-6R) plus IL-6 (hyper-IL-6). Taken together, our data identify IRF4 as a key regulator of mucosal IL-6 production in T cell-dependent experimental colitis and suggest that IRF4 might provide a therapeutic target for IBDs.

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“…Furthermore, CD4ϩ T cells from colitic mice were transferred into SCID mice, where they induced IL-6-dependent colitis. 63 An interesting study on the role of IL-6 in colitis was performed by Kitamura et al 64 In that work, the CD45RBhigh CD4ϩ transfer model was used to induce colitis. Upon transfer, IL-6 levels progressively increased correlating with the degree of colitis.…”

Section: Il-6 Signaling In Experimental Colitismentioning

confidence: 99%

Il-6 signaling in inflammatory bowel disease: Pathophysiological role and clinical relevance

Mudter

Neurath

2007

Inflammatory Bowel Diseases

359

237

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Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) occurring in the gut of genetically susceptible individuals independent of a specific pathogen. The interaction between antigen-presenting cells and the local bacterial flora contributes to an uncontrolled activation of mucosal CD4+ T lymphocytes with the consecutive release of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6, IL-12, IL-23, IL-27, and also IL-17, which is attributed to a specific, differentiated CD4+ lineage called Th17 (TH-IL17, THi). Recent data suggest that IL-6 contributes to Th17 differentiation. However, to clarify the importance of Th17 cells in IBD further data are needed. So far, CD has been attributed to a Th1-mediated disease, whereas UC exhibits a modified Th2 cytokine response. In both diseases CD4+ T cells at the site of inflammation are critically dependent on antiapoptotic IL-6 signaling. Thereby, IL-6 induces the transcription factor STAT-3 via transsignaling (activation of a cell lacking membrane-bound IL-6 receptor via soluble IL-6 receptor). STAT-3 itself induces the antiapoptotic factors bcl-2 and bcl-xL, thus resulting in T-cell resistance against apoptosis. This vicious circle of T-cell accumulation, mediated by apoptosis resistance, finally leading to chronic inflammation, can be blocked by anti-IL-6 receptor antibodies. This review highlights the role of IL-6 in IBD immunopathogenesis and its clinical relevance in IBD therapy and diagnostics.

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Colitis in mice lacking the common cytokine receptor γ chain is mediated by IL-6-producing CD4+ T cells

Cited by 34 publications

References 47 publications

Changes in cytokine profile may predict therapeutic efficacy of infliximab in patients with ulcerative colitis

Changes in cytokine profile may predict therapeutic efficacy of infliximab in patients with ulcerative colitis

The transcription factor IFN regulatory factor–4 controls experimental colitis in mice via T cell–derived IL-6

Il-6 signaling in inflammatory bowel disease: Pathophysiological role and clinical relevance

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