Downregulation of cilia-localized Il-6Rα by 17β-estradiol in mouse and human fallopian tubes

Abstract

The action of interleukin-6 (IL-6) impacts female reproduction. Although IL-6 was recently shown to inhibit cilia activity in human fallopian tubes in vitro, the molecular mechanisms underlying IL-6 signaling to tubal function remain elusive. Here, we investigate the cellular localization, regulation, and possible function of two IL-6 receptors (IL-6Rα and gp130) in mouse and human fallopian tubes in vivo. We show that IL-6Rα is restricted to the cilia of epithelial cells in both mouse and human fallopian tubes. Exogenous 17β-estradiol (E2), but not progesterone (P4), causes a time-dependent decrease in IL-6Rα expression, which is blocked by the estrogen receptor (ER) antagonist ICI-182,780. Exposure of different ER-selective agonists propyl-(1H)-pyrazole-1,3,5-triyl-trisphenol or 2,3-bis-(4-hydroxyphenyl)-propionitrile demonstrated an ER subtype-specific regulation of IL-6Rα in mouse fallopian tubes. In contrast to IL-6Rα, gp130 was detected in tubal epithelial cells in mice but not in humans. In humans, gp130 was found in the muscle cells and was decreased in the periovulatory and luteal phases during the reproductive cycles, indicating a species-specific expression and regulation of gp130 in the fallopian tube. Expression of tubal IL-6Rα and gp130 in IL-6 knockout mice was found to be normal; however, E2 treatment increased IL-6Rα, but not gp130, in IL-6 knockout mice when compared with wild-type mice. Furthermore, expression levels of IL-6Rα, but not gp130, decreased in parallel with estrogenic accelerated oocyte-cumulus complex (OCC) transport in mouse fallopian tubes. Our findings open the posibility that cilia-specific IL-6Rα may play a role in the regulation of OCC transport and suggest an estrogen-regulatory pathway of IL-6Rα in the fallopian tube.