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Prolactin Suppresses Glucocorticoid-Induced Thymocyte Apoptosis in Vivo

College of Pharmacy (N.K., D.J.B., A.R.B.) and Department of Molecular and Cellular Physiology (N.D.H., A.R.B.), University of Cincinnati Medical Center, Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: Arthur R. Buckley, College of Pharmacy, 3223 Eden Avenue, Cincinnati, Ohio 45267-0004. E-mail: Arthur.Buckley{at}uc.edu; or Nelson D. Horseman, Department of Molecular and Cellular Physiology, 4260 Medical Sciences Building, 231 Bethesda Avenue, Cincinnati, Ohio 45267-0576. E-mail: Nelson.Horseman{at}uc.edu.

The hypothesis that prolactin (PRL) functions as an immunomodulator was based on studies showing lymphocyte PRL receptors, and its effects on growth, differentiation, and apoptosis in lymphoid cells. However, studies of PRL (PRL-/-) and PRL receptor knockout mice indicated that PRL was not required for immune system development or function under basal conditions. Because PRL maintains survival in glucocorticoid (GC)-treated Nb2-T lymphocytes in vitro, and PRL and GCs are elevated during stress, we investigated whether PRL protected T cells in vivo from GC-induced apoptosis. Adrenalectomized mice [PRL -/-, undetectable PRL; pituitary grafted PRL-/- (PRL-/-Graft), elevated PRL; and PRL+/-, normal PRL] were treated with dexamethasone (DEX) or PBS. Thymocytes and splenocytes were isolated and annexin V labeling of phosphatidylserine, DNA fragmentation, and caspase-3 activation were assessed as indices of apoptosis. Total thymocytes and CD4+ and CD8+ T cells obtained from DEX-treated PRL-/- mice exhibited significantly increased annexin V binding. In contrast, binding was not altered by DEX in PRL-/-Graft thymocytes. In addition, DEX induced classic DNA fragmentation in PRL-/- thymocytes. Elevated serum PRL reduced this effect. Thymocytes from DEX-treated PRL-/- mice exhibited increased caspase-3 activation, which was inhibited in cells from PRL-/-Graft mice. Finally, elevated expression of X-linked inhibitor of apoptosis, XIAP, was observed in thymi from DEX-treated PRL -/-Graft mice. This is the first demonstration that elevated PRL antagonizes apoptosis in thymocytes exposed to GCs in vivo. These observations suggest that, under conditions of increased GCs, such as during stress, elevated PRL functions physiologically to maintain survival and function of T-lymphocytes.

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