Induction of RIP-2 kinase by proinflammatory cytokines is mediated via NF-kappaB signaling pathways and involves a novel feed-forward regulatory mechanism.
The transcription factor NF-kappaB (nuclear factor kappaB) is a central mediator of inflammatory and apoptotic signaling in the cell. The protein kinase RIP-2 is a member of the CARD protein family (caspase activation and recruitment domain, also known as CARD3, Ripk2, CARDIAK, RICK, and CCK), and has been shown to be an activator of NF-kappaB. In this study, it was demonstrated by transcriptional profiling and protein expression analysis that the inflammatory cytokines TNF-alpha, IL-1 beta, and IFN-gamma induced RIP-2 transcription and translation in endothelial cells. Two mechanistically distinct inhibitors of NF-kappaB signaling, sulfasalazine (NF-kappaB inhibitor) and WY-14643 [PPAR alpha (peroxisome proliferator-activated receptor alpha) agonist] that interfere with the transcription factor RELA (p65), suppressed TNF-alpha induced RIP-2 gene expression, which indicated that NF-kappaB signaling was involved in the cytokine-induced transcriptional activation of RIP-2 gene expression. Consistent with these observations, multiple NF-kappaB response elements were found in the upstream regions of the human and mouse RIP-2 genes. NF-kappaB-mediated regulation of RIP-2 gene and protein expression suggests an additional step in the regulation of NF-kappaB function as RIP-2 has been shown to positively modulate NF-kappaB by binding IKK gamma (I kappaB kinase gamma), a component of the IKK complex. These findings support a positive feed-forward mechanism of NF-kappaB regulation that involves NF-kappaB-dependent induction of RIP-2 transcription and a subsequent increase in RIP-2 protein levels in response to inflammatory cytokines. Elevated RIP-2 protein levels are then available to promote NF-kappaB function via interaction with IKK gamma. RIP-2 is the first reported NF-kappaB-dependent protein kinase that positively regulates NF-kappaB activity.
Yin
Xixi
X
Department of Medicine, St. Luke's and Roosevelt Hospital, 1111 Amsterdam Avenue, New York, NY 10025, USA. xixiyin2004@yahoo.com
Krikorian
Paul
P
Logan
Thomas
T
Csizmadia
Vilmos
V
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000502:physiology*; D025461:Feedback, Physiological; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D018836:Inflammation Mediators; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics*; D015398:Signal Transduction; D015533:Transcriptional Activation
D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; C506253:RIPK2 protein, human; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D051550:I-kappa B Kinase
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