期刊
JOURNAL OF IMMUNOLOGY
卷 197, 期 8, 页码 3120-3129出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1600690
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- NIAAA NIH HHS [U01 AA021857] Funding Source: Medline
- NIDDK NIH HHS [P30 DK048522, R01 DK078586, R01 DK067215, K08 DK109141] Funding Source: Medline
Receptor-interacting protein kinase (RIPK) 1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-kappa B and regulation of caspase-dependent apoptosis and RIPK3/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis. We examined the effect of RIPK1 antisense knockdown on immune-mediated liver injury in C57BL/6 mice caused by alpha-galactosylceramide (alpha GalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated alpha GalCer-mediated liver injury and induced lethality. This was associated with increased hepatic inflammation and massive apoptotic death of hepatocytes, as indicated by TUNEL staining and caspase-3 activation. Pretreatment with zVAD.fmk, a pan-caspase inhibitor, or neutralizing Abs against TNF, almost completely protected against the exacerbated liver injury and lethality. Primary hepatocytes isolated from RIPK1-knockdown mice were sensitized to TNF-induced cell death that was completely inhibited by adding zVAD.fmk. The exacerbated liver injury was not due to impaired hepatic NF-kappa B activation in terms of I kappa B alpha phosphorylation and degradation in in vivo and in vitro studies. Lack of RIPK1 kinase activity by pretreatment with necrostatin-1, a RIPK1 kinase inhibitor, or in the RIPK1 kinase-dead knock-in (RIPK1(D138N)) mice did not exacerbate alpha GalCer-mediated liver injury. Furthermore, RIPK3-knockout and MLKL-knockout mice behaved similarly as wild-type control mice in response to alpha GalCer, with or without knockdown of RIPK1, excluding a switch to RIPK3/MLKL-mediated necroptosis. Our findings reveal a critical kinase-independent platform role for RIPK1 in protecting against TNF/caspase-dependent apoptosis of hepatocytes in immune-mediated liver injury.
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