TAILIEUCHUNG - Báo cáo khoa học: Caspase-8- and JNK-dependent AP-1 activation is required for Fas ligand-induced IL-8 production

Despite a dogma that apoptosis does not induce inflammation, Fas ligand (FasL), a well-known death factor, possesses pro-inflammatory activity. For example, FasL induces nuclear factorjB (NF-jB) activity and interleukin 8 (IL-8) production by engagement of Fas in human cells. | ễFEBS Journal Caspase-8- and JNK-dependent AP-1 activation is required for Fas ligand-induced IL-8 production Norihiko Matsumoto Ryu Imamura and Takashi Suda Division of Immunology and Molecular Biology Cancer Research Institute Kanazawa University Japan Keywords AP-1 caspase-8 Fas ligand IL-8 MAP kinase Correspondence T. Suda Division of Immunology and Molecular Biology Cancer Research Institute Kanazawa University 13-1 Takaramachi Kanazawa Ishikawa 920-0934 Japan Fax 81 76 234 4525 Tel 81 76 265 2736 E-mail sudat@ Received 6 November 2006 revised 5 March 2007 accepted 6 March 2007 doi Despite a dogma that apoptosis does not induce inflammation Fas ligand FasL a well-known death factor possesses pro-inflammatory activity. For example FasL induces nuclear factor kB NF-kB activity and interleukin 8 IL-8 production by engagement of Fas in human cells. Here we found that a dominant negative mutant of c-Jun a component of the activator protein-1 AP-1 transcription factor inhibits FasL-induced AP-1 activity and IL-8 production in HEK293 cells. Selective inhibition of AP-1 did not affect NF-kB activation and vice versa indicating that their activations were not sequential events. The FasL-induced AP-1 activation could be inhibited by deleting or introducing the lymphoproliferation Ipr -type point mutation into the Fas death domain DD knocking down the Fas-associ-ated DD protein FADD abrogating caspase-8 expression with small interfering RNAs or using inhibitors for pan-caspase and caspase-8 but not caspase-1 or caspase-3. Furthermore wildtype but not a catalytically inactive mutant of caspase-8 reconstituted the FasL-induced AP-1 activation in caspase-8-deficient cells. Fas ligand induced the phosphorylation of two of the three major mitogen-activated protein kinases MAPKs extracellular signal-regulated kinase ERK and c-Jun N-terminal kinase JNK but not p38 MAPK. Unexpectedly an inhibitor for JNK but not for MAPK .

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