Tumor necrosis factor alfa and interleukin 1 alfa induced phosphorylation and degradation of inhibitory kappa B alpha are regulated by estradiol in endometrial cells

Objective: When bound to the inhibitory kappa B (IкB) protein, the transcription factor nuclear factor kappa B (NF-кB) remains inactively in the cytoplasm. Activated NF-кB upregulates the gene expression of many chemokines including monocyte chemoattractant protein-1 and interleukin (IL)-8. We hypothesized that estrogen may regulate IкB phosphorylation and degradation thus influencing NF-кB-dependent gene expression. Regulation of chemokines by estrogen is different in uterine endometrial cells when compared to ectopic endometrial cells of endometriosis. Materials and Methods: We investigated the in vivo expression of IкB in normal endometrium and in eutopic and ectopic endometrium of women with endometriosis. We then studied in cultured endometrial cells to assess the effects of estradiol on IкB and NF-кB function. Results: Normal endometrium from mid-late proliferative phase revealed the strongest IкB immunoreactivity throughout the cycle (p<0.05). When compared to paired homologous eutopic endometrium, ectopic endometrium revealed significantly less immunoreactivity for IкB (p<0.05). Moreover, estradiol induced a decrease in tumor necrosis factor-and IL-1-induced IкB phosphorylation, and also decreased the levels of active-NF-кB (p<0.05). Conclusion: Our results support the conclusion that one pathway for estradiol-mediated NF-кB inhibition occurs through the down-regulation of IкB phosphorylation. We propose that the estradiol-induced regulation of IкB and consequent reduction in active-NF-кB may affect inflammatory responses in human endometrial cells.

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