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 factor kappaB (NF-kappaB) 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-kappaB 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.
Matsumoto
Norihiko
N
Division of Immunology and Molecular Biology, Cancer Research Institute, Kanazawa University, Japan.
Imamura
Ryu
R
Suda
Takashi
T
D000818:Animals; D053181:Caspase 8 / Q000378:metabolism / Q000502:physiology*; D002384:Catalysis; D002460:Cell Line; D053222:Fas Ligand Protein / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D053222:Fas Ligand Protein; D016209:Interleukin-8; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D053181:Caspase 8