ESTROGEN INHIBITS PHORBOL ESTER-INDUCED I-KAPPA-B-ALPHA TRANSCRIPTIONAND PROTEIN-DEGRADATION

Estrogen (E2) is known to prevent bone loss and the mechanism is, at l east in part, mediated by inhibition of expression of cytokines such a s interleukin-6 (IL-6). Expression of IL-6 is tightly regulated and th e 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 s tate by associating with its cytoplasmic inhibitor I kappa B alpha. Up on mitogenic stimulation, I kappa B alpha becomes phosphorylated, foll owed by a rapid protein degradation. As a result, NF kappa B is releas ed and translocate to the nucleus where DNA binding occurs. It has bee n shown that E2 treatment downregulates mitogen-induced IL-6 expressio n by inhibiting NF kappa B activity. Here, we sought to determine whet her E2 regulates IL-6 gene expression by modulating the levels of I ka ppa B alpha. Our results show that E2 treatment almost completely inhi bits phorbol ester-induced I kappa B alpha protein degradation. In add ition, E2 inhibits phorbol ester-stimulated I kappa B alpha gene expre ssion. Taken together, our results suggest that E2 maintains steadysta te levels of I kappa B alpha upon mitogen stimulation, resulting in in hibition of NF kappa B activation and IL-6 gene expression. This may e xplain the protective effect of E2 on bone loss. (C) 1998 Academic Pre ss.