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.
We have previously demonstrated that rat uterine epithelial cells (UEC) produce CCL20/macrophage inflammatory protein 3 alpha (MIP3alpha) and tumor necrosis factor alpha (TNF-alpha) 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/MIP3alpha and TNF-alpha 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-alpha and CCL20/MIP3alpha into culture media. Interestingly, E2 pretreatment enhanced CCL20/MIP3alpha secretion due to LPS and Pam3Cys administration. In contrast, and at the same time, E2 lowered the TNF-alpha 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-alpha and CCL20/MIP3alpha secretion. In contrast, ICI 182,780 reversed the stimulatory effect of E2 on LPS- and/or Pam3Cys-induced CCL20/MIP3alpha secretion as well as partially reversed the inhibitory effect of E2 on TNF-alpha production by epithelial cells. Overall, these results indicate that E2 regulates the production of TNF-alpha and CCL20/MIP3alpha by UEC in the absence as well as presence of PAMP. Since CCL20/MIP3alpha has antimicrobial activity and is chemotactic for immune cells, these studies suggest that regulation of CCL20/MIP3alpha and TNF-alpha by E2 and PAMP may have profound effects on innate and adaptive immune responses to microbial challenge in the female reproductive tract.
Crane-Godreau
Mardi A
MA
Department of Physiology, Dartmouth Medical School, Borwell Building, 1 Medical Center Drive, Lebanon, New Hampshire 03756, USA. Mardi.Crane@Dartmouth.edu
Wira
Charles R
CR
D000818:Animals; D002478:Cells, Cultured; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000096:biosynthesis*; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004847:Epithelial Cells / Q000276:immunology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D005260:Female; D000077267:Fulvestrant; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008074:Lipoproteins / Q000494:pharmacology*; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis*; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014599:Uterus / Q000276:immunology* / Q000378:metabolism
C486997:Ccl20 protein, rat; D054418:Chemokine CCL20; D019742:Chemokines, CC; D008070:Lipopolysaccharides; D008074:Lipoproteins; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D000077267:Fulvestrant; D004958:Estradiol; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D003545:Cysteine