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The journal of immunology : official journal of the American Association of Immunologists v.197 no.8, 2016년, pp.3120 - 3129   SCI SCIE
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Knockdown of RIPK1 Markedly Exacerbates Murine Immune-Mediated Liver Injury through Massive Apoptosis of Hepatocytes, Independent of Necroptosis and Inhibition of NF-κB

Suda, Jo (Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 ); Dara, Lily (Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 ); Yang, Luoluo (Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 ); Aghajan, Mariam (Ionis Pharmaceuticals, Carlsbad, CA 92008 ); Song, Yong (and ); Kaplowitz, Neil (YSL Bioprocess Development Co., Pomona, CA 91767 ); Liu, Zhang-Xu (Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033 );
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    Receptor-interacting protein kinase (RIPK)1 has an essential role in the signaling pathways triggered by death receptors through activation of NF-κB 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 α-galactosylceramide (αGalCer), a specific activator for invariant NKT cells. We found that knockdown of RIPK1 markedly exacerbated αGalCer-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-κB activation in terms of IκBα 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 αGalCer-mediated liver injury. Furthermore, RIPK3-knockout and MLKL-knockout mice behaved similarly as wild-type control mice in response to αGalCer, 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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