title: Despite inhibition of nuclear localization of NF-kappa B p65, c-Rel, and RelB, 17-beta estradiol up-regulates NF-kappa B signaling in mouse splenocytes: the potential role of Bcl-3.
abstract: NF-kappaB plays a major role in regulating the immune system. Therefore, alterations in NF-kappaB activity have profound effects on many immunopathologies, including inflammation, autoimmunity, and lymphoid neoplasia. We investigated the effects of estrogen (17beta-estradiol) on NF-kappaB in C57BL/6 mice since estrogen is a natural immunomodulator and we have recently reported that estrogen up-regulates several NF-kappaB-regulated proteins (inducible NO synthase, IFN-gamma, and MCP-1). We found that in vivo estrogen treatment had differential effects on NF-kappaB 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-kappaB activation pathways, estrogen induced constitutive NF-kappaB activity and increased the levels of cytokines regulated by NF-kappaB (IL-1 alpha, IL-1 beta, IL-10, and IFN-gamma). Studies involving a NF-kappaB inhibitor confirmed a positive regulatory role of NF-kappaB 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-kappaB transcriptional activity. Chromatin immunoprecipitation assays confirmed that Bcl-3 bound to the promoter of the NF-kappaB-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-kappaB proteins by estrogen provide fresh insight into potential mechanisms by which estrogen can regulate NF-kappaB-dependent immunological events.
authors.affiliation: Department of Biomedical Sciences and Pathology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
authors.forename: Rujuan
authors.initials: R
authors.lastname: Dai
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Phillips
authors.forename: S Ansar
authors.initials: SA
authors.lastname: Ahmed
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D019281:Dimerization; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020569:Proto-Oncogene Proteins c-rel / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051841:Transcription Factor RelB / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology*
chemical_list: D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; C498144:Rela protein, mouse; C497594:Relb protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D051841:Transcription Factor RelB; D004958:Estradiol