IL-1β-Mediated Proinflammatory Responses Are Inhibited by Estradiol via Down-Regulation of IL-1 Receptor Type I in Uterine Epithelial Cells

Abstract

The objective of this study was to examine the effects of sex hormones on IL-1β-mediated responses by uterine epithelial cells. The mRNA expression and secretion of human β-defensin-2 and CXCL8 by uterine epithelial cells was examined following stimulation with IL-1β in the presence of estradiol or progesterone. Estradiol inhibited the IL-1β-mediated mRNA expression and secretion of human β-defensin-2 and CXCL8 by uterine epithelial cells while progesterone had no effect. Inhibition of the IL-1β-mediated response by estradiol was dose dependent, with maximal inhibition observed using 10−7 to 10−10 M, and was shown to be mediated through the estrogen receptor because addition of a pure estrogen receptor antagonist abrogated this effect. The mechanism by which estradiol inhibits IL-1β-mediated responses by uterine epithelial cells appears to be the down-modulation of the IL-1R type I, thereby reducing the uterine epithelial cell’s ability to respond to IL-1β. These results suggest that the inhibitory effect of estradiol on IL-1β-mediated inflammatory responses by uterine epithelial cells indicates a link between the endocrine and immune systems and may be crucial for dampening proinflammatory responses during the time of ovulation or pregnancy.

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

“…Using the ECC-1 cell line derived from the uterus, we previously showed that IL-1β stimulates mRNA expression and production of HBD2 and IL-8, and that these increases are suppressed by E 2 . 41 We found that E 2 inhibited the expression of IL-1Receptor type I on the ECC-1 epithelial cells. 41 The present studies extend these findings to primary UECs and suggest that E 2 acts by inhibiting IL-1Receptor type I so that cells respond relatively poorly to the IL-1β ligand.…”

“…41 We found that E 2 inhibited the expression of IL-1Receptor type I on the ECC-1 epithelial cells. 41 The present studies extend these findings to primary UECs and suggest that E 2 acts by inhibiting IL-1Receptor type I so that cells respond relatively poorly to the IL-1β ligand. Studies are under way to determine whether a similar mechanism exists in primary UECs.…”

“…6 We also observed that under a variety of stimuli including TLR agonists (LPS, poly (I:C)) and IL-1β, epithelial cell secretion of cytokines, chemokines, and antimicrobials is enhanced. 5,38,39,41 Recognizing that the functions of E 2 in the FRT are multifaceted, we hypothesized that the E 2 would regulate UEC immune function in a way that would allow them to act as sentinels in the FRT by protecting against potential pathogens while simultaneously providing an environment for successful fertilization, implantation, and pregnancy. To the best of our knowledge, the results presented represent the first comprehensive study that systematically examines the seemingly opposite inductive and suppressive activities of E 2 on epithelial cells from the upper FRT.…”

Estradiol Attenuates Lipopolysaccharide-Induced CXC Chemokine Ligand 8 Production by Human Peripheral Blood Monocytes

“…In this regard, recent studies have demonstrated that physiologic levels of estradiol modulate proinflammatory cytokine production in innate immune effector cells, including epithelial cells and macrophages (12,13). To determine whether estradiol mediates similar effects in primary human monocytes, CD14 ϩ monocytes were preincubated with estradiol at concentrations ranging from 10 Ϫ11 to 10 Ϫ7 M and then stimulated with LPS.…”

Lipopolysaccharide-Induced IL-1β Production by Human Uterine Macrophages Up-Regulates Uterine Epithelial Cell Expression of Human β-Defensin 2

“…Recent work from our group has demonstrated that activation of uterine epithelial cells with rIL-1␤ induces expression of the antimicrobial peptide human ␤-defensin 2 (HBD2) (26). Epithelial cells form a first line of defense in the FRT and are in close contact with macrophages.…”