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Infection and Immunity, July 2005, p. 4231-4237, Vol. 73, No. 7
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.7.4231-4237.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Department of Physiology, Dartmouth Medical School, Lebanon, New Hampshire 03756-0001

Received 23 September 2004/ Returned for modification 30 November 2004/ Accepted 20 February 2005

We have previously demonstrated that rat uterine epithelial cells (UEC) produce CCL20/macrophage inflammatory protein 3 alpha (MIP3) and tumor necrosis factor alpha (TNF-) 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/MIP3 and TNF- 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- and CCL20/MIP3 into culture media. Interestingly, E₂ pretreatment enhanced CCL20/MIP3 secretion due to LPS and Pam₃Cys administration. In contrast, and at the same time, E₂ lowered the TNF- 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- and CCL20/MIP3 secretion. In contrast, ICI 182,780 reversed the stimulatory effect of E₂ on LPS- and/or Pam₃Cys-induced CCL20/MIP3 secretion as well as partially reversed the inhibitory effect of E₂ on TNF- production by epithelial cells. Overall, these results indicate that E₂ regulates the production of TNF- and CCL20/MIP3 by UEC in the absence as well as presence of PAMP. Since CCL20/MIP3 has antimicrobial activity and is chemotactic for immune cells, these studies suggest that regulation of CCL20/MIP3 and TNF- by E₂ and PAMP may have profound effects on innate and adaptive immune responses to microbial challenge in the female reproductive tract.

Editor: J. D. Clements

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