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Caspase‐8‐ and JNK‐dependent AP‐1 activation is required for Fas ligand‐induced IL‐8 production
Author(s) -
Matsumoto Norihiko,
Imamura Ryu,
Suda Takashi
Publication year - 2007
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2007.05772.x
Subject(s) - fas ligand , caspase 8 , fadd , mapk/erk pathway , kinase , microbiology and biotechnology , death domain , activator (genetics) , chemistry , protein kinase a , caspase , biology , apoptosis , programmed cell death , biochemistry , receptor
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 κB (NF‐κB) 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‐κB 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 (lpr) ‐type point mutation into the Fas death domain (DD), knocking down the Fas‐associated 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/ERK kinase inhibited the FasL‐induced AP‐1 activation and IL‐8 production. These results demonstrate that FasL‐induced AP‐1 activation is required for optimal IL‐8 production, and this process is mediated by FADD, caspase‐8, and JNK.