title: Estrogen inhibits phorbol ester-induced I kappa B alpha transcription and protein degradation.
abstract: Estrogen (E2) is known to prevent bone loss and the mechanism is, at least in part, mediated by inhibition of expression of cytokines such as interleukin-6 (IL-6). Expression of IL-6 is tightly regulated and the transcription factor NF kappa B can upregulate IL-6 gene expression by binding to its promoter region. NF kappa B is kept in an inactive state by associating with its cytoplasmic inhibitor I kappa B alpha. Upon mitogenic stimulation, I kappa B alpha becomes phosphorylated, followed by a rapid protein degradation. As a result, NF kappa B is released and translocate to the nucleus where DNA binding occurs. It has been shown that E2 treatment downregulates mitogen-induced IL-6 expression by inhibiting NF kappa B activity. Here, we sought to determine whether E2 regulates IL-6 gene expression by modulating the levels of I kappa B alpha. Our results show that E2 treatment almost completely inhibits phorbol ester-induced I kappa B alpha protein degradation. In addition, E2 inhibits phorbol ester-stimulated I kappa B alpha gene expression. Taken together, our results suggest that E2 maintains steady state levels of I kappa B alpha upon mitogen stimulation, resulting in inhibition of NF kappa B activation and IL-6 gene expression. This may explain the protective effect of E2 on bone loss.
authors.affiliation: Department of Pediatrics, Children's Memorial Hospital, Chicago, Illinois, USA. wennsun@nwu.edu
authors.forename: W H
authors.initials: WH
authors.lastname: Sun
authors.forename: E T
authors.initials: ET
authors.lastname: Keller
authors.forename: B S
authors.initials: BS
authors.lastname: Stebler
authors.forename: W B
authors.initials: WB
authors.lastname: Ershler
mesh_terms: D004268:DNA-Binding Proteins / Q000378:metabolism*; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D015850:Interleukin-6 / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015663:Osteoporosis, Postmenopausal; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D015850:Interleukin-6; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D004958:Estradiol; D013755:Tetradecanoylphorbol Acetate