Contribution of Fas ligand to T cell-mediated hepatic injury in mice

Seino, Ken‐ichiro; Kayagaki, Nobuhiko; Takeda, Kazuyoshi; Fukao, Katashi; Okumura, Ko; Yagita, Hideo

doi:10.1053/gast.1997.v113.pm9322527

Cited by 135 publications

(107 citation statements)

References 7 publications

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“…Intravenous injection of phytohemagglutin (PHA) results in a CD95-dependent autoimmune hepatitis (Seino et al, 1997). This syndrome is caused by induction of CD95 ligand on lymphocytes upon PHA stimulation and migration of these lymphocytes to the liver.…”

Section: Asm In Autoimmune Syndromesmentioning

confidence: 99%

“…This syndrome is caused by induction of CD95 ligand on lymphocytes upon PHA stimulation and migration of these lymphocytes to the liver. Since hepatocytes constitutively express CD95, they are killed by apoptosis upon contact with the CD95 ligand-positive T cells, resulting in autoimmune hepatitis (Seino et al, 1997). ASM-deficient mice were protected against the adverse effects of PHA injections despite normal upregulation of CD95 on their T cells, and the livers in ASM knockout mice were almost free of apoptotic cells (Kirschnek et al, 2000).…”

Section: Asm In Autoimmune Syndromesmentioning

confidence: 99%

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Raft ceramide in molecular medicine

2003

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Section: Asm In Autoimmune Syndromesmentioning

confidence: 99%

Section: Asm In Autoimmune Syndromesmentioning

confidence: 99%

Raft ceramide in molecular medicine

2003

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“…The 26-kDa membrane-bound precursor form of 17-kDa sTNF and both TNFRs have been shown to be central for the development of Con A hepatitis (16). Additional mediators such as the Fas ligand/Fas system or perforin/granzyme have been described either to contribute (17,18) or not to contribute (19,18) to liver injury induced by Con A. However, mTNF-, Fas ligand-, and perforinmediated direct hepatotoxic effects require cell-to-cell contact between hepatocytes and leukocytes.…”

Section: Tnf-␣-induced Expression Of Adhesion Molecules In the Liver mentioning

confidence: 99%

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

Wolf

Hallmann

Sass

et al. 2001

The Journal of Immunology

108

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TNF-α has been clearly identified as central mediator of T cell activation-induced acute hepatic injury in mice, e.g., Con A hepatitis. In this model, liver injury depends on both TNFRs, i.e., the 55-kDa TNFR1 as well as the 75-kDa TNFR2. We show in this report that the hepatic TNFRs are not transcriptionally regulated, but are regulated by receptor shedding. TNF directly mediates hepatocellular death by activation of TNFR1 but also induces the expression of inflammatory proteins, such as cytokines and adhesion molecules. Here we provide evidence that resistance of TNFR1−/− and TNFR2−/− mice against Con A hepatitis is not due to an impaired production of the central mediators TNF and IFN-γ. Con A injection results in a massive induction of ICAM-1, VCAM-1, and E-selectin in the liver. Lack of either one of both TNFRs did not change adhesion molecule expression in the livers of Con A-treated mice, presumably reflecting the fact that other endothelial cell-activating cytokines up-regulated adhesion molecule expression. However, treatment of TNFR1−/− and TNFR2−/− mice with murine rTNF revealed a predominant role for TNFR1 for the induction of hepatic adhesion molecule expression. Pretreatment with blocking Abs against E- and P-selectin or of ICAM−/− mice with anti-VCAM-1 Abs failed to prevent Con A hepatitis, although accumulation of the critical cell population, i.e., CD4+ T cells was significantly inhibited. Hence, up-regulation of adhesion molecules during acute hepatitis unlikely contributes to organ injury but rather represents a defense mechanism.

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“…ConA-induced hepatitis is also thought to be a model of immunologically induced hepatocyte injury, and its histological features resemble those of viral-or drug-induced acute hepatitis in humans. 1,7,[25][26][27][28][29][30] In this mode, hepatocyte cell death induced by ConA is caused by necrosis and apoptosis. Hence, apoptosis and Th1 cytokine release were thought to be key factors.…”

Section: Discussionmentioning

confidence: 99%

“…4 We also know that the stimulation of Fas on hepatocytes by anti-Fas antibodies causes severe damage to hepatocytes by apoptotic cell death. 31 Earlier results showed that liver necroapoptosis induced by ConA is mediated by TNF-a and IFN-g. 1,4,5,7,[25][26][27][28][29][30]32 On TNF-a receptor crosstalk, the death domain of the TNF-a receptor 1 associates with TNF receptor 1-associated protein (TRADD), causing Fas-associated death domain (FADD) recruitment. FADD in turn activates upstream caspase-8, and the effector caspases involved in apoptosis, caspase-9 and -3.…”

Section: Discussionmentioning

confidence: 99%

CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

et al. 2003

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Activated cytotoxic T-cell-mediated hepatocyte apoptosis via Fas/Fas-ligand and perforin/granzyme pathways are believed to involve the model of concanavalin A (ConA)-induced hepatitis. The purpose of the present study is to investigate whether the cytokine response modifier A (crmA) gene effectively inhibits the hepatocyte apoptosis of ConAinduced hepatitis. We examined survival rates, liver pathology, immune histological changes, and cytokine profiles from mice receiving the recombinant adenovirus vectors containing cre and/or crmA genes, transferred to the liver 3 days before ConA injection, and a crmA gene nonexpression control group. Injection of ConA into mice rapidly led to massive hepatocyte apoptosis, and infiltration of leukocytes, especially CD11b + inflammatory cells. In contrast, liver damage was dramatically reduced in the mice that expressed the crmA gene. However, infiltration by CD4 + cells was not affected. The survival of the mice increased significantly to 100% in the treated group versus the control group. Furthermore, we demonstrated that interleukin (IL)-18 plays an important role in ConA-induced hepatitis, and that crmA expression significantly inhibited IL-18 secretion. Our results showed that the crmA gene effectively inhibits apoptosis induced by ConA hepatitis. This indicates a potential therapeutic usage of crmA for protection from cellular damage due to hepatitis.

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Contribution of Fas ligand to T cell-mediated hepatic injury in mice

Cited by 135 publications

References 7 publications

Raft ceramide in molecular medicine

Raft ceramide in molecular medicine

TNF-α-Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1—Relevance for Concanavalin A-Induced Hepatitis

CrmA gene expression protects mice against concanavalin-A-induced hepatitis by inhibiting IL-18 secretion and hepatocyte apoptosis

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