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Up-Regulation of Bcl-2 through ERK Phosphorylation Is Associated with Human Macrophage Survival in an Estrogen Microenvironment¹

National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India

Estrogen is a known immunomodulator with pleiotropic effects on macrophage function that partly accounts for the gender bias observed in numerous autoimmune, cardiovascular, and neurodegenerative disorders. The effect of estrogen on the survival of human macrophages is largely unknown, and in this study we demonstrate that 17-estradiol (E2) provokes a death response in human THP-1 macrophages by initiating Bax translocation from cytosol to the mitochondria; however, a concomitant up-regulation of Bcl-2 creates a Bax to Bcl-2 ratio favorable for Bcl-2, thus ensuring cell survival. Both Bcl-2 up-regulation and Bax translocation are estrogen receptor-dependent events; however, Bcl-2 augmentation but not Bax translocation is dependent on Ca²⁺ increase, activation of protein kinase C, and ERK phosphorylation. This estrogen-induced Bcl-2 increase is crucial for the survival of THP-1 macrophages as well as that of human peripheral blood monocyte-derived macrophages, which is evident from E2-induced cell death under small interfering RNA-mediated Bcl-2 knockdown conditions. Hence, this study demonstrates that E2-induced Bcl-2 up-regulation is a homeostatic survival mechanism necessary for the manifestation of immunomodulatory effect of estrogen on human macrophages.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Department of Biotechnology, New Delhi, India.

² Address correspondence and reprint requests to Dr. Chandrima Shaha, National Institute of Immunology, Aruna Asaf Ali Marg, 110067 New Delhi, India. E-mail address: cshaha{at}nii.res.in

³ Abbreviations used in this paper: E2, 17-estradiol; siRNA, small interfering RNA; MFI, mean fluorescence intensity; fluo-3-AM, fluo-3 acetoxymethyl ester; BIM, bisindoleylmaleimide; MDM, monocyte-derived macrophage; PKC, protein kinase C.

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