Down-regulation of protein kinase C? inhibits inducible nitric oxide synthase expression through IRF1.

ABSTRACT: In inflammation, pro-inflammatory cytokines and bacterial products induce the production of high amounts of NO by inducible nitric oxide synthase (iNOS) in inflammatory and tissue cells. NO is an effector molecule in innate immunity, and it also has regulatory and pro-inflammatory/destructive effects in the inflammatory process. Protein kinase C? (PKC?) is an important signaling protein regulating B lymphocyte functions, but less is known about its effects in innate immunity and inflammatory gene expression. In the present study we investigated the role of PKC? in the regulation of iNOS expression in inflammatory conditions. NO production and iNOS expression were induced by LPS or a combination of cytokines IFN?, IL-1?, and TNF?. Down-regulation of PKC? by siRNA and inhibition of PKC? by rottlerin suppressed NO production and iNOS expression in activated macrophages and fibroblasts. PKC? directed siRNA and inhibition of PKC? by rottlerin suppressed also the expression of transcription factor IRF1, possibly through inhibition of STAT1 activation. Accordingly, down-regulation of IRF1 by siRNA reduced iNOS expression in response to inflammatory stimuli. In addition, inhibition of PKC? showed anti-inflammatory effects in carrageenan induced paw inflammation in mice as did iNOS inhibitor L-NIL. These results suggest that inhibitors of PKC? have anti-inflammatory effects in disease states complicated by enhanced NO production through iNOS pathway.

SUBMITTER: Leppanen T 

PROVIDER: S-EPMC3541401 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature