Peroxisome proliferator-activated receptor-α and retinoid X receptor agonists inhibit inflammatory responses of astrocytes

Abstract

The peroxisome proliferator-activated receptor-α (PPAR-α) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR-α agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In the present study, we investigated the effects of PPAR-α agonists on primary mouse astrocytes, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-α agonists fenofibrate, and WY 14643 inhibited NO production by LPS-stimulated astrocytes in a dose-dependent manner. Additionally, PPAR-α agonists inhibited the secretion of the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 by LPS-stimulated astrocytes. Fenofibrate inhibited NF-κB DNA binding activity, suggesting a mechanism by which PPAR-α agonists may regulate the expression of genes encoding these pro-inflammatory molecules. Retinoid X receptors (RXRs) physically interact with PPAR-α receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, a combination of 9-cis RA and the PPAR-α agonists fenofibrate or gemfibrozil cooperatively inhibited NO, TNF-α, IL-1β, IL-6, and MCP-1 production by these cells. Collectively, these results raise the possibility that PPAR-α and RXR agonists might be effective in the treatment of MS, where activated astrocytes are believed to contribute to disease pathology.