Estrogen treatment down-regulates TNF-alpha production and reduces the severity of experimental autoimmune encephalomyelitis in cytokine knockout mice

A shift toward Th2 cytokine production has been demonstrated during pregnan cy and high dose estrogen therapy and is thought to be the primary mechanis m by which estrogen suppresses the development of experimental autoimmune e ncephalomyelitis. However, low dose estrogen treatment is equally protectiv e in the absence of a significant shift in cytokine production. In this stu dy cytokine-deficient mice were treated with estrogen to determine whether a shift in Th2 cytokine production was required for the protective effects of hormone therapy. Estrogen effectively suppressed the development of expe rimental autoimmune encephalomyelitis in IL-4 and IL-10 knockout mice and i n wild type littermate mice with a similar potency of protection. Significa nt disease suppression was also seen in IFN-gamma -deficient mice. The decr ease in disease severity was accompanied by a concomitant reduction in the number of proinflammatory cytokine- and chemokine-producing cells in the CN S. Although there was no apparent increase in compensatory Th2 cytokine pro duction in cytokine-deficient mice, there was a profound decrease in the fr equency of TNF-alpha -producing cells in the CNS and the periphery. Therefo re, we propose that one mechanism by which estrogen protects females from t he development of cell-mediated autoimmunity is through a hormone-dependent regulation of TNF-a production. The Journal of Immunology, 2001.