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

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