PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

Abstract

Background and purpose: Nitric oxide (NO) production through the inducible nitric oxide synthase (iNOS) pathway is increased in response to pro-inflammatory cytokines and bacterial products. In inflammation, NO has pro-inflammatory and regulatory effects. Peroxisome proliferator-activated receptors (PPARs), members of the nuclear steroid receptor superfamily, regulate not only metabolic but also inflammatory processes. The aim of the present study was to investigate the role of PPARa in the regulation of NO production and iNOS expression in activated macrophages. Experimental approach: The effects of PPARa agonists were investigated on iNOS mRNA and protein expression, on NO production and on the activation of transcription factors NF-kB and STAT1 in J774 murine macrophages exposed to bacterial lipopolysaccharide (LPS). Key results: PPARa agonists GW7647 and WY14643 reduced LPS-induced NO production in a dose-dependent manner as measured by the accumulation of nitrite into the culture medium. However, PPARa agonists did not alter LPS-induced iNOS mRNA expression or activation of NF-kB or STAT1 which are important transcription factors for iNOS. Nevertheless, iNOS protein levels were reduced by PPARa agonists in a time-dependent manner. The reduction was markedly greater after 24 h incubation than after 8 h incubation. Treatment with the proteasome inhibitors, lactacystin or MG132, reversed the decrease in iNOS protein levels caused by PPARa agonists. Conclusions and implications:The results suggest that PPARa agonists reduce LPS-induced iNOS expression and NO production in macrophages by enhancing iNOS protein degradation through the proteasome pathway. The results offer an additional mechanism underlying the anti-inflammatory effects of PPARa agonists.

PPAR-α activation reduced LPS-induced inflammation in alveolar epithelial cells

“…This phenomenon may be explained by several reasons: PPAR-α mRNA and protein are expressed in AEC at stable levels that remained unaffected by LPS stimulation and thus might be the cause for a reduced PPAR-α activation in-vitro. Several studies could so far show in different cell types that an in-vitro activation by WY-14643 is principally possible [12,32]. Our results implicate for the first time that PPAR-α activation in AEC by fibrates necessarily is dependent on the presence of a functional living organism.…”

Differential effects of LY294002 and wortmannin on inducible nitric oxide synthase expression in glomerular mesangial cells

“…iNOS proteins are substantially regulated by proteolytic degradation. Diverse factors such as an EP4 antagonist (AH23848), PPARα agonists, and transforming growth factor-β1 inhibit iNOS-stimulated NO production by promoting iNOS protein degradation [5][6][7]. iNOS is targeted for degradation either through proteasome or calpain pathways [4].…”

PPARα mediates the anti‐inflammatory effect of simvastatin in an experimental model of zymosan‐induced multiple organ failure

“…PPARa binds a diverse set of ligands including arachidonic acid metabolites and synthetic fibrate drugs (Sher et al, 1993). In addition, PPARa plays a pivotal role in the regulation of lipid metabolism, and it also exerts pronounced anti-inflammatory activities by negatively interfering with pro-inflammatory signalling pathways including NF-kB (Marx et al, 2004;Okamoto et al, 2005;Paukkeri et al, 2007;Becker et al, 2008). We and others have reported that activation of PPARa resulted in significant anti-inflammatory effects in various experimental models (Becker et al, 2008), including ours .…”