Agonists for the peroxisome proliferator‐activated receptor‐α and the retinoid X receptor inhibit inflammatory responses of microglia

Abstract

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), the animal model of multiple sclerosis (MS). In the present study we investigated the effects of PPAR-alpha agonists on primary mouse microglia, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR-alpha agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO production by cytokine-stimulated microglia in a dose-dependent manner. However, fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and ciprofibrate. In LPS-stimulated microglia, only fenofibrate and WY 14,643 significantly suppressed NO production. Additionally, PPAR-alpha agonists inhibited the secretion of the proinflammatory cytokines IL-1beta, TNF-alpha, IL-6, and IL-12 p40 and the chemokine MCP-1 by LPS-stimulated microglia. Retinoid X receptors (RXRs) physically interact with PPAR-alpha receptors, and the resulting heterodimers regulate the expression of PPAR-responsive genes. Interestingly, the RXR agonist 9-cis retinoic acid (9-cis RA) inhibited NO production by LPS-stimulated microglia. Furthermore, a combination of 9-cis RA and the PPAR-alpha agonist fenofibrate cooperatively inhibited NO production by these cells. A combination of these agonists also selectively inhibited the expression of proinflammatory cytokines including IL-1beta, TNF-alpha, and IL-6 by LPS-stimulated microglia. Collectively, these results raise the possibility that PPAR-alpha and RXR agonists might have benefit as a therapy in MS, where activated microglia are believed to contribute to disease pathology.

Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-β

“…Earlier we have demonstrated that gemfibrozil attenuates the expression of inducible nitric-oxide synthase in human astrocytes (22). Others have also shown an anti-inflammatory effect of gemfibrozil in other cells (23,24). In the current work, we present evidence that gemfibrozil markedly stimulated the expression of myelin-specific genes (MOG, PLP, CNPase, and MBP) in human primary oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures.…”

Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes

“…Interestingly, RXRs also physically interact with PPAR ligands. We have previously demonstrated that PPAR and RXR ligands act cooperatively in suppressing inflammatory responses (Lovett-Racke et al, 2004;Xu et al, 2006a;Xu et al, 2005b). Future studies will compare the profile of genes regulated by PPAR relative to LXR agonists.…”

“…PPAR-γ ligands also suppress inflammation and pathology in animal models of atherosclerosis, arthritis, inflammatory bowel disease and MS (Diab et al, 2002;Feinstein et al, 2002;Kawahito et al, 2000;Li et al, 2000;Natarajan and Bright, 2002;Niino et al, 2001;Su et al, 1999). Like PPAR-γ agonists, PPAR-α agonists suppress the function of T cells and CNS glia in vitro (Lovett-Racke et al, 2004;Xu et al, 2006a;Xu et al, 2005b). In addition, these agonists are effective in the treatment of EAE (Lovett-Racke et al, 2004).…”

Peroxisome Proliferator-Activated Receptor-γ Agonists Suppress the Production of IL-12 Family Cytokines by Activated Glia

“…For example, we (13) and others (14 -16) have demonstrated that administration of PPAR-␥ agonists inhibits the clinical signs of experimental autoimmune encephalomyelitis (EAE), suggesting that these agonists may be effective in the treatment of MS. In addition, we have demonstrated that PPAR-␣ agonists also suppress the development of EAE and suppress the expression of proinflammatory cytokines and chemokines by glia (17)(18)(19).…”