Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of proteins. The role of PPARs in regulating the transcription of genes involved in glucose and lipid metabolism has been extensively characterized. Interestingly, PPARs have also been demonstrated to mediate inflammatory responses. Microglia participate in pathology associated with multiple sclerosis (MS). Upon activation, microglia produce molecules including NO and TNF-alpha that can be toxic to CNS cells including myelin-producing oligodendrocytes and neurons, which are compromised in the course of MS. Previously, we and others demonstrated that PPAR-gamma agonists including 15d-PGJ(2) are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-gamma modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ(2) is a more potent inhibitor of microglial activation than thiazolidinediones, which are currently used to treat diabetes. Furthermore, 15d-PGJ2 acts cooperatively with 9-cis retinoic acid, the ligand for the retinoid X receptor (RXR), in inhibiting microglial cell activation. This suggests that 15d-PGJ2 and 9-cis RA inhibit cell activation through the formation of PPAR-gamma/RXR heterodimers. Interestingly, PGA,, which like 15d-PGJ2 is a cyclopentenone prostaglandin, but which unlike 15d-PGJ2 does not bind PPAR-gamma, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ2 inhibits microglial cell activation by P PAR-gamma-dependent as well as PPAR-gamma-independent mechanisms. The studies further suggest that the PPAR-gamma agonist 15d-PGJ2 in combination with retinoids may be effective in the treatment of MS. (c) 2004 Elsevier B.V. All rights reserved.