Gene interactions and pathways from curated databases and text-mining
FEBS J 2007, PMID: 17403042

Caspase-8- and JNK-dependent AP-1 activation is required for Fas ligand-induced IL-8 production.

Matsumoto, Norihiko; Imamura, Ryu; Suda, Takashi

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.

Diseases/Pathways annotated by Medline MESH: MAP Kinase Signaling System
Document information provided by NCBI PubMed

Text Mining Data

IL-8 → Fas ligand: " Caspase-8- and JNK dependent AP-1 activation is required for Fas ligand induced IL-8 production "

IL-8 → AP-1: " Caspase-8- and JNK dependent AP-1 activation is required for Fas ligand induced IL-8 production "

interleukin 8 (IL-8) → FasL: " For example, FasL induces nuclear factor kappaB (NF-kappaB) activity and interleukin 8 (IL-8) production by engagement of Fas in human cells "

nuclear factor kappaB (NF-kappaB) → FasL: " For example, FasL induces nuclear factor kappaB (NF-kappaB) activity and interleukin 8 (IL-8) production by engagement of Fas in human cells "

AP-1 → FasL: " 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 "

IL-8 → FasL: " 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 "

NF-kappaB — AP-1: " Selective inhibition of AP-1 did not affect NF-kappaB activation and vice versa, indicating that their activations were not sequential events "

AP-1 → FasL: " 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 "

AP-1 → FasL: " Furthermore, wildtype, but not a catalytically inactive mutant, of caspase-8 reconstituted the FasL induced AP-1 activation in caspase-8-deficient cells "

AP-1 → FasL: " Unexpectedly, an inhibitor for JNK but not for MAPK/ERK kinase inhibited the FasL induced AP-1 activation and IL-8 production "

IL-8 → FasL: " Unexpectedly, an inhibitor for JNK but not for MAPK/ERK kinase inhibited the FasL induced AP-1 activation and IL-8 production "

AP-1 → FasL: " 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 "

IL-8 → FasL: " 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 "

IL-8 → AP-1: " 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 "

Manually curated Databases

No curated data.