Effects of Estradiol on Lipopolysaccharide and Pam3Cys Stimulation of CCL20/Macrophage Inflammatory Protein 3 Alpha and Tumor Necrosis Factor Alpha Production by Uterine Epithelial Cells in Culture

摘要

We have previously demonstrated that rat uterine epithelial cells (UEC) produce CCL20/macrophage inflammatory protein 3 alpha (MIP3α) and tumor necrosis factor alpha (TNF-α) in response to live and heat-killed Escherichia coli and to the pathogen-associated molecular patterns (PAMP) lipopolysaccharide (LPS) and Pam3Cys. To determine whether estradiol (E2) modulates PAMP-induced CCL20/MIP3α and TNF-α secretion, primary cultures of rat UEC were incubated with E2 for 24 h and then treated with LPS or Pam3Cys or not treated for an additional 12 h. E2 inhibited the constitutive secretion of TNF-α and CCL20/MIP3α into culture media. Interestingly, E2 pretreatment enhanced CCL20/MIP3α secretion due to LPS and Pam3Cys administration. In contrast, and at the same time, E2 lowered the TNF-α response to both PAMP. To determine whether estrogen receptors (ER) mediated the effects of E2, epithelial cells were incubated with E2 and/or ICI 182,780, a known ER antagonist. ICI 182,780 had no effect on E2 inhibition of constitutive TNF-α and CCL20/MIP3α secretion. In contrast, ICI 182,780 reversed the stimulatory effect of E2 on LPS- and/or Pam3Cys-induced CCL20/MIP3α secretion as well as partially reversed the inhibitory effect of E2 on TNF-α production by epithelial cells. Overall, these results indicate that E2 regulates the production of TNF-α and CCL20/MIP3α by UEC in the absence as well as presence of PAMP. Since CCL20/MIP3α has antimicrobial activity and is chemotactic for immune cells, these studies suggest that regulation of CCL20/MIP3α and TNF-α by E2 and PAMP may have profound effects on innate and adaptive immune responses to microbial challenge in the female reproductive tract.