Estradiol selectively regulates innate immune function by polarized human uterine epithelial cells in culture

Abstract

The goal of this study was to examine the role of E 2 in regulating innate immune protection by human uterine epithelial cells (UECs). Recognizing that UECs produce cytokines and chemokines to recruit and activate immune cells as well as viral and bacterial antimicrobials, we sought to examine the effect of E 2 on constitutive and Toll-like receptor (TLR) agonist (lipopolysaccharide (LPS) and poly (I:C))-induced immune responses. The secretion by polarized UECs in culture of interleukin (IL)-6, macrophage inhibitory factor (MIF), and secretory leukocyte protease inhibitor (SLPI) was examined as well as the mRNA expression of human β-defensin-2 (HBD2), tumor necrosis factor (TNF)-α, IL-8, and nuclear factor (NF)-kB. When incubated with E 2 for 24-48 h, we found that E 2 stimulated UEC secretion of SLPI (fourfold) and mRNA expression of HBD2 (fivefold). Moreover, when antibacterial activity in UEC secretions was measured using Staphylococcus aureus, E 2 increased the secretion of soluble factor(s) with antibacterial activity. In contrast, E 2 had no effect on constitutive secretion of proinflammatory cytokines and chemokines by UECs but completely inhibited LPS-and poly (I:C)-induced secretion of MIF, IL-6, and IL-8. Estradiol also reversed the stimulatory effects of IL-1β on mRNA expression of TNF-α, IL-8, and NF-kB by 85, 95, and 70%, respectively. As SLPI is known to inhibit NF-kB expression, these findings suggest that E 2 inhibition of proinflammatory cytokines may be mediated through SLPI regulation of NF-kB. Overall, these findings indicate that the production of cytokines, chemokines, and antimicrobials by UECs are differentially regulated by E 2 . Further, it suggests that with E 2 regulation, epithelial cells that line the uterine cavity have evolved immunologically to be sensitive to viral and bacterial infections as well as the constraints of procreation.

Mucosa-Associated Epithelial Chemokine/CCL28 Expression in the Uterus Attracts CCR10+ IgA Plasma Cells following Mucosal Vaccination via Estrogen Control

“…2B). Several recent studies demonstrate that the innate immune responses in female reproductive organs are controlled by hormones and vary with menstrual cycle stage (37,47). For instance, production of proinflammatory cytokines and antimicrobials by human uterine epithelial cells are regulated differently by estradiol (47).…”

“…Several recent studies demonstrate that the innate immune responses in female reproductive organs are controlled by hormones and vary with menstrual cycle stage (37,47). For instance, production of proinflammatory cytokines and antimicrobials by human uterine epithelial cells are regulated differently by estradiol (47). ERa interacts with target gene promoters either directly, through specific estrogen response elements, or indirectly, through contacts with other DNA-bound transcription cofactors (coactivator or corepressor) (48).…”

Polarized Epithelial Cells Secrete Interleukin 6 Apically in the Bovine Endometrium1

“…Similarly, human cells treated with estradiol, but not with progesterone, had reduced IL6 responses to LPS [52].…”

Delayed healing and induction of secretory leukocyte protease inhibitor in polycystic ovary syndrome rat skin wounds

“…In the OVX rat, SLPI was not expressed in the uterine tissues but increased after estrogen treatment (22). When the human uterine epithelial cells (UECs) were incubated with estrogen, the secretion of SLPI was enhanced but the secretion of inflammatory cytokines, such as interleukin-6 (IL-6) and IL-8, and decreased after stimulation with lipopolysaccharide (LPS) (26). These results show that the inhibitory function of estrogen to inflammatory cytokines is mediated by SLPI regulation and suggest that SLPI secretion is controlled by the hormone, estrogen, but not progesterone in human UECs.…”