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*ESTRADIOL
The Journal of Immunology, 2001, 167: 542-552.
Copyright © 2001 by The American Association of Immunologists

Estrogen Treatment Down-Regulates TNF-{alpha} Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice1

Atsushi Ito2,*,{ddagger}, Bruce F. Bebo, Jr.2,*,{dagger},{ddagger}, Agata Matejuk*,{ddagger}, Alex Zamora{ddagger}, Marc Silverman{ddagger}, Amber Fyfe-Johnson{ddagger} and Halina Offner3,*,{ddagger}

* Department of Neurology and {dagger} Neurological Sciences Institute, Oregon Health Sciences University, and {ddagger} Neuroimmunology Research, Department of Veterans Affairs, Portland, OR 97201

A shift toward Th2 cytokine production has been demonstrated during pregnancy and high dose estrogen therapy and is thought to be the primary mechanism by which estrogen suppresses the development of experimental autoimmune encephalomyelitis. However, low dose estrogen treatment is equally protective in the absence of a significant shift in cytokine production. In this study 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 experimental autoimmune encephalomyelitis in IL-4 and IL-10 knockout mice and in wild type littermate mice with a similar potency of protection. Significant disease suppression was also seen in IFN-{gamma}-deficient mice. The decrease in disease severity was accompanied by a concomitant reduction in the number of proinflammatory cytokine- and chemokine-producing cells in the CNS. Although there was no apparent increase in compensatory Th2 cytokine production in cytokine-deficient mice, there was a profound decrease in the frequency of TNF-{alpha}-producing cells in the CNS and the periphery. Therefore, we propose that one mechanism by which estrogen protects females from the development of cell-mediated autoimmunity is through a hormone-dependent regulation of TNF-{alpha} production.




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