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Despite Inhibition of Nuclear Localization of NF-B p65, c-Rel, and RelB, 17- Estradiol Up-Regulates NF-B Signaling in Mouse Splenocytes: The Potential Role of Bcl-3¹

Department of Biomedical Sciences and Pathology, Center for Molecular Medicine and Infectious Diseases,Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061

NF-B plays a major role in regulating the immune system. Therefore, alterations in NF-B activity have profound effects on many immunopathologies, including inflammation, autoimmunity, and lymphoid neoplasia. We investigated the effects of estrogen (17-estradiol) on NF-B in C57BL/6 mice since estrogen is a natural immunomodulator and we have recently reported that estrogen up-regulates several NF-B-regulated proteins (inducible NO synthase, IFN-, and MCP-1). We found that in vivo estrogen treatment had differential effects on NF-B family members. Estrogen profoundly blocked the nuclear translocation of p65, c-Rel, and Rel-B, partially blocked p52, but permitted translocation of p50. Despite blockade of both the classical (p65/p50) and alternative (RelB/p52) NF-B activation pathways, estrogen induced constitutive NF-B activity and increased the levels of cytokines regulated by NF-B (IL-1, IL-1, IL-10, and IFN-). Studies involving a NF-B inhibitor confirmed a positive regulatory role of NF-B on these cytokines. Remarkably, estrogen selectively induced B cell lymphoma 3 (Bcl-3), which is known to associate with p50 to confer transactivation capabilities, thereby providing a potential link between observed p50 DNA-binding activity and estrogen up-regulation of NF-B transcriptional activity. Chromatin immunoprecipitation assays confirmed that Bcl-3 bound to the promoter of the NF-B-regulated inducible NO synthase gene in cells from estrogen-treated mice. Estrogen appeared to act at the posttranscriptional level to up-regulate Bcl-3 because mRNA levels in splenocytes from placebo- and estrogen-treated mice were comparable. The novel findings of differential regulation of NF-B proteins by estrogen provide fresh insight into potential mechanisms by which estrogen can regulate NF-B-dependent immunological events.

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 the National Institutes of Health (1 R01 AI051880-04A1).

² Address correspondence and reprint requests to Dr. S. Ansar Ahmed, Center for Molecular Medicine and Infectious Diseases, 1410 Prices Fork Road, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061. E-mail address: ansrahmd{at}vt.edu

³ Abbreviations used in this paper; iNOS, inducible NO synthase; Bcl-3, B cell lymphoma 3; ER, estrogen receptor; ChIP, chromatin immunoprecipitation.

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