Abstract
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.
Highlights
Immunologic-endocrine interactions mediate and participate in complex physiologic processes that occur within the uterus throughout the menstrual cycle and pregnancy, and are important to the pathophysiology of endometriosis[1,2,3]
When the eutopic endometrium from women with endometriosis was compared with the endometrium of women without endometriosis, no significant difference was observed in staining intensity, eutopic endometrial cells of women with endometriosis showed a trend towards decreased immunoreactivity for IkBa (p=0.1) (Figure 1, Table 2)
To determine whether the effect of E2 on IkBa phosphorylation was specific to the Tumor necrosis factor-alpha (TNF-a) signaling cascade, we explored the effect of estrogen on IL-1a-mediated activation of nuclear factor kappa B (NF-kB)
Summary
Immunologic-endocrine interactions mediate and participate in complex physiologic processes that occur within the uterus throughout the menstrual cycle and pregnancy, and are important to the pathophysiology of endometriosis[1,2,3]. Tumor necrosis factor-alpha (TNF-a) and interleukin (IL)-1 induce the phosphorylation and subsequent degradation of IkBa. This, in turn, results in the activation and relocation of NF-kB to the nucleus, leading to NF-kB-mediated transcription of responsive genes[16,17]. Previous studies have shown that estrogen down-regulates the expression of many cytokines such as IL1, TNF-a, IL-6 and regulated-upon activation, normal T-cellexpressed and secreted (RANTES), which are regulated by NFkB in various cell types[25,26,27]. There may be differential regulation of NFkB signaling by estrogen and by cytokines such as TNF-a and IL-l in endometriotic cells as compared with normal endometrial cells. We hypothesized that estrogen might regulate IkBa phosphorylation and degradation in vivo and in vitro in normal endometrium and in eutopic and ectopic endometrium of women with endometriosis, influencing NFkB-dependent gene expression. We investigated the modulation of IkBa by E2 in TNF-a- and IL-1a-treated endometrial stromal and glandular cells, in vitro, using Western blot analysis and immunocytochemistry
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