Critical role of interleukin 5 and eosinophils in concanavalin A–induced hepatitis in mice

Louis, Hubert; Moine, Alaín Le; Flamand, Véronique; Nagy, Nathalie; Quertinmont, Eric; Paulart, Frédéric; Abramowicz, Daniel; Moine, Olivier Le; Goldman, Michel; Devière, Jacques

doi:10.1053/gast.2002.33620

Cited by 64 publications

(62 citation statements)

References 48 publications

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“…Previous studies have shown that Con A activates hepatic resident NKT cells to produce IL-4 (5, 6); IL-4, in turn, acts on NKT cells in an autocrine fashion to induce Fas ligand (FasL) expression on these cells, which subsequently promotes hepatocyte cell death (i.e., cytotoxicity), possibly by interacting with Fas-expressing hepatocytes. In agreement with this concept is the observation that Fas, FasL, and IL-4 exert proinflammatory effects during Con A-induced hepatitis since mice deficient in any of the aforementioned mediators are resistant to Con A-induced liver damage (7)(8)(9).…”

mentioning

confidence: 64%

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Mencarelli

Renga²,

Migliorati³

et al. 2009

The Journal of Immunology

136

110

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Immune-mediated liver diseases including autoimmune and viral hepatitis are a major health problem worldwide. In this study, we report that activation of the farnesoid X receptor (FXR), a member of the ligand-activated nuclear receptor superfamily and bile sensor highly expressed in the liver, attenuates liver injury in a model of autoimmune hepatitis induced by Con A. We found that FXR gene ablation results in a time-dependent increase of liver expression (up to 20-fold in a 9-mo-old mouse) of osteopontin, a NKT cell-derived extracellular matrix protein and immunoregulatory cytokine. In comparison to wild-type, FXR−/− mice are more susceptible to Con A-induced hepatitis and react to Con A administration by an unregulated production of osteopontin. Administering wild-type mice with a synthetic FXR agonist attenuated Con A-induced liver damage and liver expression of the osteopontin gene. By in vitro studies, we found that FXR is expressed by primarily isolated NKT cells and its ablation favors ostepontin production in response to Con A. Chromatin immunoprecipitation assay and coimmunoprecipitation experiments demonstrate that the short heterodimer partner (SHP), a nuclear receptor and FXR target, was expressed by NKT cell hybridomas and increased in response to FXR activation. FXR activates SHP that interacts with and inhibits c-Jun binding to the osteopontin promoter. These data indicate that in NKT cells, FXR activation causes a SHP-mediated inhibition of osteopontin production. These data support the notion that the bile acid sensor FXR regulates the activation of liver NKT cells.

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mentioning

confidence: 64%

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

Mencarelli

Renga²,

Migliorati³

et al. 2009

The Journal of Immunology

136

110

View full text Add to dashboard Cite

show abstract

“…1). Although NKT cells are the primary source of IFN-␥ and IL-4, and presumably IL-5 (19), cytokines such as TNF-␣, IL-1, and IL-6 are probably produced by Kupffer cells in the liver (8) in response to IFN-␥ and IL-4 produced by NKT cells. As macrophages are positive for the expression of WSX-1 by RT-PCR (22), it is possible that WSX-1-deficient macrophages (Kupffer cells) are also more sensitive to stimulation and are prone to overproduction of inflammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

“…Next we examined cytokine expression by liver MNC after Con A injection by RT-PCR analyses and found that in addition to IFN-␥ and IL-4 described above, the expression of IL-5 and TNF-␣, cytokines reportedly involved in Con A hepatitis (17,19), was unexpectedly higher in the knockout than in wild-type mice (data not shown).…”

Section: Hyperproduction Of Proinflammatory Cytokines In Con A-treatementioning

confidence: 96%

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

Yamanaka

Hamano

Miyazaki

et al. 2004

The Journal of Immunology

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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.

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“…NKT cells rapidly secrete a large amount of IL-4, IL-5, IFN-␥, and TNF-␣, all of which have been shown to play essential roles in Con A-induced liver injury. 3,[7][8][9][10][11][12] We next wanted to know whether IL-15 influences these cytokines' production. As shown in Fig.…”

Section: Il-15 Prevents Mice From Con A-induced Livermentioning

confidence: 99%

“…Concanavalin A (Con A)-induced hepatitis is a well-established experimental murine model, 1 being characterized by markedly increased serum levels of transaminase and simultaneous infiltration of T cells, eosinophils, 2,3 and Kupffer cells 4 into the liver. The hepatic natural killer T (NKT) cells play essential roles in the Con A-induced liver injury by releasing a variety of cytokines, including interleukin 4 (IL-4), IL-5, interferon gamma (IFN-␥), and tumor necrosis factor alpha (TNF-␣).…”

mentioning

confidence: 99%

Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism

Sun

Wei

et al. 2006

Hepatology

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Critical role of interleukin 5 and eosinophils in concanavalin A–induced hepatitis in mice

Cited by 64 publications

References 48 publications

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

The Bile Acid Sensor Farnesoid X Receptor Is a Modulator of Liver Immunity in a Rodent Model of Acute Hepatitis

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

Interleukin-15 prevents concanavalin A-induced liver injury in mice via NKT cell-dependent mechanism

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