Estrogen Inhibits Phorbol Ester-Induced IκBα Transcription and Protein Degradation

• Published in: Biochemical and biophysical research communications Vol. 244; no. 3; pp. 691 - 695
• Main Authors: Sun, Wenn H., Keller, Evan T., Stebler, Barbara S., Ershler, William B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27-03-1998
• Subjects: DNA-Binding Proteins - metabolism; Drug Interactions; Estradiol - pharmacology; Female; HeLa Cells; Humans; I-kappa B Proteins; Interleukin-6 - metabolism; NF-kappa B - antagonists & inhibitors; NF-KappaB Inhibitor alpha; Osteoporosis, Postmenopausal; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology; Transcription, Genetic - drug effects; Up-Regulation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1998.8324

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 NFκB can upregulate IL-6 gene expression by binding to its promoter region. NFκB is kept in an inactive state by associating with its cytoplasmic inhibitor IκBα. Upon mitogenic stimulation, IκBα becomes phosphorylated, followed by a rapid protein degradation. As a result, NFκB 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 NFκB activity. Here, we sought to determine whether E2 regulates IL-6 gene expression by modulating the levels of IκBα. Our results show that E2 treatment almost completely inhibits phorbol ester-induced IκBα protein degradation. In addition, E2 inhibits phorbol ester-stimulated IκBα gene expression. Taken together, our results suggest that E2 maintains steadystate levels of IκBα upon mitogen stimulation, resulting in inhibition of NFκB activation and IL-6 gene expression. This may explain the protective effect of E2 on bone loss.