PPAR gamma AND eNOS CONTRIBUTE TO THE RESOLUTION OF CHRONIC INFLAMMATION.

Abstract

Chronic inflammation follows defined phases of induction, inflammation, and resolution. The resolution phase requires cycloxygenase-2 (COX-2) activity. This study aims to address what other molecules are required for a functional resolution phase. We demonstrated that in murine collagen-induced arthritis the transcription factor, PPARgamma plays a role in the resolution phase. Inhibition of COX-2 activity results in fewer PPARgamma positive cells in the arthritic synovium. Treatment with a PPARgamma antagonist, SR202, alone, also disrupts the process of resolution. PPARgamma antagonist treatment results in a decrease in eNOS phosphorylation within the arthritic synovium. These observations indicate that PPARgamma may function to regulate eNOS activity. The source of pro-resolving nitric oxide is eNOS but not, iNOS. The effect of COX-2 inhibition on the resolution phase is ameliorated by injection of a PGE2 analog. Restoration of PGE2 levels results in an increase in PPARgamma positive cells in the arthritic synovium which correlates with this restoration of resolution. Thus, this study provides in vivo evidence for the pro-resolving role of PPARgamma and its relationship with PGE2 and eNOS.