Regulation of innate immunity of mouse uterine epithelial cells by keratinocyte growth factor and estradiol.

摘要

The mucosal immune system of the female reproductive tract (FRT) balances the dual functions of protection against invading pathogens and adaptation of the endometrial environment for successful fertilization and implantation. Growth factors are important in normal endometrial physiology and can act as mediators of some indirect effects of E2. This thesis was undertaken to test the overall hypothesis that E2 and keratinocyte growth factor (KGF) regulate the secretion of macrophage inflammatory protein 3α (MIP3α) and keratinocyte-derived chemokine (KC) by mouse uterine epithelial cells. Culture of polarized uterine epithelial cells with KGF increased both apical and basolateral secretion of MIP3α as well as basolateral secretion of KC. E2 added to the culture media inhibited both constitutive and KGF-induced secretion of MIP3α, yet further increased KGF-induced basolateral KC secretion. The inhibition of constitutive MIP3α secretion by E2 was mediated via the estrogen receptor. Other steroid hormones (progesterone, cortisol, DHT, aldosterone) had no effect on MIP3α and KC secretion, suggesting that these effects were specific to E2. Studies with freshly isolated uterine epithelial cells treated with KGF and E2 showed similar findings to those with polarized cells. One exception was that E2 enhanced both the constitutive and KGF-induced KC secretion. In other studies, it was found that KGF binds to its receptor on the basolateral surface of uterine epithelial cells, signals through the MAPK and PI3K pathways, as well as activates NFκB to induce secretion of MIP3α and KC. It was also found that KGF increased intracellular MIP3α, but had no effect on intracellular KC. In contrast, E2 did not use either MEK1/MAPK or PI3K pathways to regulate MIP3α or KC secretion. Taken together, these findings offer insight into the mechanisms of KGF and E 2 in the FRT by demonstrating that uterine epithelial cells are responsive to KGF, which in turn regulates MIP3α and KC secretion, and that this regulation is differentially mediated by E2. Recognizing that KGF and E2 regulate MIP3α and KC within the uterus suggests that KGF may play a previously unrecognized role in sexually transmitted infections, reproductive cancers, endometriosis, and infertility, all of which threaten reproductive health.