The IL-27R (WSX-1) Is Required to Suppress T Cell Hyperactivity during Infection

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Administration of Con A induces liver injury that is considered to be an experimental model for human autoimmune or viral hepatitis, where immunopathology plays roles mediated by activated lymphocytes, especially NK1.1+ CD3+ NKT cells, and inflammatory cytokines, including IFN-γ and IL-4. In the present study we investigated the role of WSX-1, a component of IL-27R, in Con A-induced hepatitis by taking advantage of WSX-1 knockout mice. WSX-1-deficient mice were more susceptible to Con A treatment than wild-type mice, showing serum alanine aminotransferase elevation and massive necrosis in the liver. Although the development of NKT cells appeared normal in WSX-1 knockout mice, purified NKT cells from the knockout mice produced more IFN-γ and IL-4 than those from wild-type mice in response to stimulation with Con A both in vitro and in vivo. In addition, hyperproduction of proinflammatory cytokines, including IL-1, IL-6, and TNF-α, was observed in the knockout mice after Con A administration. These data revealed a novel role for WSX-1 as an inhibitory regulator of cytokine production and inflammation in Con A-induced hepatitis.

Section: Discussionsupporting

confidence: 84%

Section: Hyperproduction Of Proinflammatory Cytokines By Wsx-1-deficimentioning

confidence: 84%

Section: Discussionmentioning

confidence: 98%

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Hyperproduction of Proinflammatory Cytokines by WSX-1-Deficient NKT Cells in Concanavalin A-Induced Hepatitis

Yamanaka

Hamano

Miyazaki

et al. 2004

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“…The cytokine receptor WSX-1/T cell cytokine receptor, which is homologous to the IL-12R␤2 subunit, and a commonly used cytokine receptor for the IL-6 family, gp130, constitute a functional signal-transducing receptor for IL-27 (1,2). IL-27 activates JAK1, Ϫ2, TYK2, STAT1, -2, -3, -4, and -5 in naive CD4 ϩ T cells (3)(4)(5)(6), and enhances proliferation in naive but not memory CD4 ϩ T cells (1). IL-27 also induces expression of T-box expressed in T cells (Tbet), 4 a master transcriptional regulator for Th1 differentiation (7), and subsequent IL-12R␤2, but down-regulates expression of a Th2-specific transcriptional factor, GATA3, and synergizes with IL-12 in primary IFN-␥ production (1,3,4,6).…”

Section: Stat3 Is Indispensable To Il-27-mediated Cell Proliferation mentioning

confidence: 99%

STAT3 Is Indispensable to IL-27-Mediated Cell Proliferation but Not to IL-27-Induced Th1 Differentiation and Suppression of Proinflammatory Cytokine Production

Owaki

Asakawa

Morishima

et al. 2008

IL-27, a member of the IL-6/IL-12 family, activates both STAT1 and STAT3 through its receptor, which consists of WSX-1 and gp130 subunits, resulting in augmentation of Th1 differentiation and suppression of proinflammatory cytokine production. In the present study, we investigated the role of STAT3 in the IL-27-mediated immune functions. IL-27 induced phosphorylation of STAT1, -2, -3 and -5 in wild-type naive CD4+ T cells, but failed to induce that of STAT3 and STAT5 in STAT3-deficient cohorts. IL-27 induced not only proinflammatory responses including up-regulation of ICAM-1, T-box expressed in T cells, and IL-12Rβ2 and Th1 differentiation, but also anti-inflammatory responses including suppression of proinflammatory cytokine production such as IL-2, IL-4, and IL-13 even in STAT3-deficient naive CD4+ T cells. In contrast, IL-27 augmented c-Myc and Pim-1 expression and induced cell proliferation in wild-type naive CD4+ T cells but not in STAT3-deficient cohorts. Moreover, IL-27 failed to activate STAT3, augment c-Myc and Pim-1 expression, and induce cell proliferation in pro-B BaF/3 transfectants expressing mutant gp130, in which the putative STAT3-binding four Tyr residues in the YXXQ motif of the cytoplasmic region was replaced by Phe. These results suggest that STAT3 is activated through gp130 by IL-27 and is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production. Thus, IL-27 may be a cytokine, which activates both STAT1 and STAT3 through distinct receptor subunits, WSX-1 and gp130, respectively, to mediate its individual immune functions.

“…IL-27 also promotes the production of IL-10 by various effector CD4 + T cell populations, including Th1 and Th2 cells and CD4 + T cells polarized under Th17-inducing conditions (20)(21)(22)(23)(24)(25). In line with these disparate roles, IL-27 signaling is essential for the generation of early protective T cell responses during Leishmania major (9) and bacillus Calmette-Guérin (8) infections but is required for the suppression of Th1-and Th17-mediated inflammation during Toxoplasma gondii, Trypanosoma cruzi, Mycobacterium tuberculosis, Leishmania donovani, and nonhealing L. major infections (17,(26)(27)(28)(29)(30)(31).…”

mentioning

confidence: 99%

Essential Role for IL-27 Receptor Signaling in Prevention of Th1-Mediated Immunopathology during Malaria Infection

Findlay

Greig

Stumhofer

et al. 2010

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109

123

Successful resolution of malaria infection requires induction of proinflammatory immune responses that facilitate parasite clearance; however, failure to regulate this inflammation leads to immune-mediated pathology. The pathways that maintain this immunological balance during malaria infection remain poorly defined. In this study, we demonstrate that IL-27R–deficient (WSX-1−/−) mice are highly susceptible to Plasmodium berghei NK65 infection, developing exacerbated Th1-mediated immune responses, which, despite highly efficient parasite clearance, lead directly to severe liver pathology. Depletion of CD4+ T cells—but not CD8+ T cells—prevented liver pathology in infected WSX-1−/− mice. Although WSX-1 signaling was required for optimal IL-10 production by CD4+ T cells, administration of rIL-10 failed to ameliorate liver damage in WSX-1−/− mice, indicating that additional, IL-10–independent, protective pathways are modulated by IL-27R signaling during malaria infection. These data are the first to demonstrate the essential role of IL-27R signaling in regulating effector T cell function during malaria infection and reveal a novel pathway that might be amenable to manipulation by drugs or vaccines.