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The Journal of Immunology, 2005, 175: 5716-5723.
Copyright © 2005 by The American Association of Immunologists

Estrogen Receptor {alpha} (ER{alpha}) Deficiency in Macrophages Results in Increased Stimulation of CD4+ T Cells while 17{beta}-Estradiol Acts through ER{alpha} to Increase IL-4 and GATA-3 Expression in CD4+ T Cells Independent of Antigen Presentation1

K. Chad Lambert*,§, Edward M. Curran{dagger},§, Barbara M. Judy{dagger},§, Gregg N. Milligan{dagger}, Dennis B. Lubahn{ddagger},§ and D. Mark Estes2,*,{dagger},§

* Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65211; {dagger} Department of Pediatrics, University of Texas Medical Branch, Sealy Center for Vaccine Development, Galveston, TX 77555; {ddagger} Department of Biochemistry, University of Missouri, Columbia, MO 65211; and § University of Missouri Center for Phytonutrient and Phytochemical Research, Columbia, MO 65211

The effects of 17{beta}-estradiol (E2) on immune function have been extensively reported. The effects are dependent on concentration and duration of exposure and potential differences in signaling between the known E2 receptors, estrogen receptors (ER) {alpha} and ER{beta}. Through the use of ER-deficient mice, we and others have begun to demonstrate the role of the two known receptors in modulating immune functional activities. Previous studies have shown that cells of the innate immune system have altered function (bactericidal capacity) and patterns of cytokine expression (increased proinflammatory cytokine expression) through amelioration of ER{alpha} signaling. In this study, we extend these studies to analysis of T cell differentiation and proliferation in APC-dependent and APC-independent in vitro assay systems. Our results demonstrate that ER{alpha} deficiency in splenic macrophages, but not CD11c+ splenic dendritic cells pulsed with OVA significantly enhances proliferative responses and IFN-{gamma} production by transgenic OVA peptide-specific (OT-II) CD4+ T cells when compared with Ag-pulsed APC from wild-type littermates. The addition of E2 in this culture system did not significantly affect the production of IFN-{gamma}. In addition, when purified CD4+ T cells from ER{alpha}-deficient and wild-type littermates were stimulated with anti-CD3/CD28 Ab in the absence of E2, there were no significant differences in IFN-{gamma} or IL-4 production. However, the addition of E2 significantly increased IL-4 secretion, as well as increased GATA-3 mRNA levels from ER{alpha}-replete CD4+ T cells, while this effect was abrogated in ER{alpha}-deficient CD4+ T cells.




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