ERK5 activation inhibits inflammatory responses via peroxisome proliferator-activated receptor δ (PPARδ) 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 PPAR delta by ERK5 in C2C12 cells. [Ru(CO)(3)Cl-2](2) activated PPAR delta transcriptional activity via the MEK5/ERK5 signaling pathway. The inhibition of NF-kappa B activity by ERK5 activation was reversed by a dominant negative form of PPAR delta suggesting that ERK5/PPAR delta 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/PPAR delta, and ERK5 mediates CO and HO-1-induced PPAR delta activation via its interaction with PPAR delta.