Female sex steroids: effects upon microglial cell activation

Multiple sclerosis occurs more commonly in females than males. However, the mechanisms resulting in gender differences in multiple sclerosis are unkno wn. Activated microglia are believed to contribute to multiple sclerosis pa thology, perhaps in part due to production of nitric oxide (NO) and TNF-alp ha, molecules which can be toxic to cells including oligodendrocytes. The c urrent study demonstrates that the female sex steroids estriol, beta -estra diol and progesterone inhibit Lipopolysaccharide (LPS)induction of nitric o xide (NO) production by primary rat microglia and by the mouse N9 microglia l cell line. These hormones act by inhibiting the production of inducible n itric oxide synthase (iNOS) which catalyses the synthesis of NO. Estriol li kely inhibits iNOS gene expression since the hormone blocks LPS induction o f iNOS RNA levels. The pro-inflammatory cytokines IFN-gamma and TNF-alpha a re believed to be important modulators of multiple sclerosis. Here, we demo nstrate that estrogens and progesterone also inhibit NO production by micro glial cells activated in response to these cytokines. Activated microglia e licit TNF-alpha. in addition to NO and we further demonstrate that estrogen s and progesterone repress TNF-alpha production by these cells. Finally, es triol and progesterone, at concentrations consistent with late pregnancy, i nhibit NO and TNF-alpha production by activated microglia, suggesting that hormone inhibition of microglial cell activation may contribute to the decr eased severity of multiple sclerosis symptoms commonly associated with preg nancy. (C) 2000 Elsevier Science B.V. All rights reserved.