Hormone regulation of microglial cell activation: relevance to multiple sclerosis

Previously, we and others demonstrated that PPAR-γ agonists including 15d-PGJ2 are effective in the treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. PPAR-γ modulation of EAE may occur, at least in part, by inhibition of microglial cell activation. Here, we indicate that 15d-PGJ2 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-γ/RXR heterodimers. Interestingly, PGA2, which like 15d-PGJ2 is a cyclopentenone prostaglandin, but which unlike 15d-PGJ2 does not bind PPAR-γ, is a potent inhibitor of microglial cell activation. Collectively, these studies suggest that 15d-PGJ2 inhibits microglial cell activation by PPAR-γ-dependent as well as PPAR-γ-independent mechanisms. The studies further suggest that the PPAR-γ agonist 15d-PGJ2 in combination with retinoids may be effective in the treatment of MS.