ERK5 activation inhibits inflammatory responses via peroxisome proliferator-activated receptor delta (PPARdelta) stimulation.
Peroxisome proliferator-activated receptors (PPAR) decrease the production of cytokine and inducible nitric-oxide synthase (iNOS) expression, which are associated with aging-related inflammation and insulin resistance. Recently, the involvement of the induction of heme oxygenase-1 (HO-1) in regulating inflammation has been suggested, but the exact mechanisms for reducing inflammation by HO-1 remains unclear. We found that overexpression of HO-1 and [Ru(CO)(3)Cl(2)](2), a carbon monoxide (CO)-releasing compound, increased not only ERK5 kinase activity, but also its transcriptional activity measured by luciferase assay with the transfection of the Gal4-ERK5 reporter gene. This transcriptional activity is required for coactivation of PPARdelta by ERK5 in C2C12 cells. [Ru(CO)(3)Cl(2)](2) activated PPARdelta transcriptional activity via the MEK5/ERK5 signaling pathway. The inhibition of NF-kappaB activity by ERK5 activation was reversed by a dominant negative form of PPARdelta suggesting that ERK5/PPARdelta activation is required for the anti-inflammatory effects of CO and HO-1. Based on these data, we propose a new mechanism by which CO and HO-1 mediate anti-inflammatory effects via activating ERK5/PPARdelta, and ERK5 mediates CO and HO-1-induced PPARdelta activation via its interaction with PPARdelta.
Woo
Chang-Hoon
CH
Cardiovascular Research Institute, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Massett
Michael P
MP
Shishido
Tetsuro
T
Itoh
Seigo
S
Ding
Bo
B
McClain
Carolyn
C
Che
Wenyi
W
Vulapalli
Sreesatya Raju
SR
Yan
Chen
C
Abe
Jun-ichi
J
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002248:Carbon Monoxide / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D004789:Enzyme Activation; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology*; D008024:Ligands; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
D000893:Anti-Inflammatory Agents; D008024:Ligands; D016328:NF-kappa B; D047494:PPAR delta; D002248:Carbon Monoxide; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D048054:Mitogen-Activated Protein Kinase 7