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

Abstract

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.

Tumor‐specific cytotoxic T cell generation and dendritic cell function are differentially regulated by interleukin 27 during development of anti‐tumor immunity

“…10-12 Induction of IL-10 production by activated T cells is responsible for IL-27-mediated regulation of inflammation. [33][34][35] Through this IL-10 production and a direct suppressive mechanism as yet to be determined, IL-27 also has a suppressive effect on immune cells other than T cells, such as NK/NKT cells, 29,30 macrophages, 31 and DCs. 13 WSX-1 2/2 DCs lacking IL-27-mediated suppression were more potent than WT DCs in generation of Th1-biased anti-protozoan immunity.…”

“…WSX-1 2/ 2 deficient mice developed severe immunopathology over WT mice in various experimental settings. [29][30][31][32] Suppression of Th17 differentiation is partly responsible for the anti-inflammatory effect of IL-27. 10-12 Induction of IL-10 production by activated T cells is responsible for IL-27-mediated regulation of inflammation.…”

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

“…It was previously demonstrated using WSX-1-deficient mice that IL-27/WSX-1 is important for suppression of proinflammatory cytokine production in certain infections with Toxoplasma gondii (5,14), Trypanosoma cruzi (15), and Trichuris muris (16), Con A-induced hepatitis (17), and experimental autoimmune encephalomyelitis (18). We and other groups recently demonstrated that IL-27 inhibits primary IL-2 production mediated through CD28 signaling from naive CD4 ϩ T cells (19,20) and that SOCS3, whose expression is induced by IL-27, plays a critical role in the inhibition in a negative feedback mechanism (20).…”

“…Several previous studies using mice lacking one of the IL-27R subunits, T cell cytokine receptor (10)/ WSX-1 (11), revealed that IL-27 plays multiple roles including positive and negative regulation of immune responses (12,13). Namely, IL-27 regulates not only proinflammatory responses including the early initiation of Th1 responses, but also antiinflammatory responses including the suppression of cellular activation and proinflammatory cytokine production such as IFN-␥, IL-2, TNF-␣, IL-4, IL-13, and IL-17 in certain infections with Toxoplasma gondii (5,14), Trypanosoma cruzi (15), and Trichuris muris (16), Con A-induced hepatitis (17), and experimental autoimmune encephalomyelitis (18). However, the molecular mechanism whereby IL-27 regulates pro-and anti-inflammatory immune responses remains largely unknown.…”

The IL-27 Receptor (WSX-1) Is an Inhibitor of Innate and Adaptive Elements of Type 2 Immunity

“…Thus, hyperactive CD4 ϩ T cells led to a lethal inflammatory disease during acute toxoplasmosis (15). Similarly, WSX-1 is a the negative regulator of T cell-dependent inflammation in an experimental model of hepatitis (16) and following infection with Trypanosma cruzi (17). Although these studies have collectively demonstrated that IL-27/ WSX-1 signaling can either promote or inhibit type 1 responses depending on the cytokine environment, there is little known about the role of WSX-1 in regulating type 2-mediated immunity.…”