Interferon-??-induced activation of c-Jun NH₂-terminal kinase mediates apoptosis through up-regulation of CD95 in CH31 B lymphoma cells

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• 作者：Takada ; Eiko ; Shimo ; Kuniaki ; Hata ; Kikumi ; Abiake ; Maira ; Mukai ; Yasuo ; Moriyama ; Masami ; Heasley ; Lynn ; et. al.
• 关键词：IFN ; interferon ; TNF ; tumor necrosis factor ; TRAIL ; TNF-related apoptosis-inducing ligand ; FADD ; Fas-associated protein with death domain ; DISC ; death-inducing signaling complex ; ERK ; extracellular signal-regulated kinase ; p38 MAPK ; p38 mitogen-activated
• 刊名：Experimental Cell Research
• 出版年：2005
• 出版时间：April 1, 2005
• 年：2005
• 卷：304
• 期：2
• 页码：518-530
• 全文大小：746 K

文摘

Type I interferon (IFN)-induced antitumor action is due in part to apoptosis, but the molecular mechanisms underlying IFN-induced apoptosis remain largely unresolved. In the present study, we demonstrate that IFN-?? induced apoptosis and the loss of mitochondrial membrane potential (????m) in the murine CH31 B lymphoma cell line, and this was accompanied by the up-regulation of CD95, but not CD95-ligand (CD95-L), tumor necrosis factor (TNF), or TNF-related apoptosis-inducing ligand (TRAIL). Pretreatment with anti-CD95-L mAb partially prevented the IFN-??-induced loss of ????m, suggesting that the interaction of IFN-??-up-regulated CD95 with CD95-L plays a crucial role in the induction of fratricide. IFN-?? induced a sustained activation of c-Jun NH₂-terminal kinase 1 (JNK1), but not extracellular signal-regulated kinases (ERKs). The IFN-??-induced apoptosis and loss of ????m were substantially compromised in cells overexpressing a dominant-negative form of JNK1 (dnJNK1), and it was slightly enhanced in cells carrying a constitutively active JNK construct, MKK7???JNK1 fusion protein. The IFN-??-induced up-regulation of CD95 together with caspase-8 activation was also abrogated in the dnJNK1 cells while it was further enhanced in the MKK7???JNK1 cells. The levels of cellular FLIP (c-FLIP), competitively interacting with caspase-8, were down-regulated by stimulation with IFN-?? but were reversed by the proteasome inhibitor lactacystin. Collectively, the IFN-??-induced sustained activation of JNK mediates apoptosis, at least in part, through up-regulation of CD95 protein in combination with down-regulation of c-FLIP protein.