Inflammatory cytokines differentially up-regulate human endometrial haptoglobin production in women with endometriosis†

Evidence suggests that eutopic endometrium from women with endometriosis (US-E) has intrinsic functional anomalies compared with women without endometriosis (US-C). We hypothesized that differences in endometrial haptoglobin (eHp) mRNA and protein levels exist between eutopic endometrium from US-E and US-C and that inflammatory mediators may be involved. Endometrial stromal cells and tissue explants from US-E (n = 18) and US-C (n = 18) were cultured (24 h/48 h for cells/explants) with interleukin (IL)-1 alpha, -1 beta, -6, -8 or tumor necrosis factor-alpha (TNF-alpha) at 0-100 ng/ml. eHp protein in media and mRNA levels were quantified by enzyme-linked immunosorbent assay and quantitative PCR. In eutopic endometrial stromal cells from US-E, IL-1 beta, IL-6 and TNF-alpha (10 ng/ml) increased eHp mRNA levels (P = 0.002, P < 0.001 and P < 0.001, respectively) and eHp protein (P = 0.023, 0.031 and 0.006, respectively) versus control. In endometrial tissues from US-E, IL-1 beta, IL-6 and TNF-alpha increased eHp mRNA (P < 0.001, P = 0.017 and P < 0.001, respectively) and eHp protein (P < 0.001, P = 0.007 and 0.039, respectively) versus control. IL-1 alpha and IL-8 had small or no effects on isolated endometrial cells or tissues. In US-C, IL-1 beta, IL-8 and TNF-alpha each reduced eHp mRNA in endometrial stromal cells (all P < 0.001) versus control; IL-1 alpha and IL-6 had no effect. eHp mRNA increased in endometrial tissues from US-C in response to IL-1 beta (P = 0.008), IL-6 (P = 0.015) and TNF-alpha (P = 0.031) versus control; IL-1 alpha or IL-8 had no effect. Endometrium from US-E differentially responds to specific inflammatory cytokines by production of eHp. We propose that up-regulation of endometrial eHp by inflammatory mediators disrupts normal endometrial function and may facilitate the pathogenesis of endometriosis.