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Hum. Reprod. Advance Access published online on August 4, 2006
Human Reproduction, doi:10.1093/humrep/del206
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received December 21, 2005
Revised May 2, 2006
Accepted May 9, 2006

Article

Doxycycline alters the expression of inflammatory and immune-related cytokines and chemokines in human endometrial cells: implication in irregular uterine bleeding

Rongxiu Li 1, Xiaoping Luo 1, Qun Pan 1, Issam Zineh 2, David F. Archer 3, R. Stan Williams 1, and Nasser Chegini 1

1 Department of Obstetrics & Gynecology, Norfolk, VA, USA
2 Department of Pharmacy Practice, University of Florida, Gainesville, FL, Norfolk, VA, USA
3 Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA


  Abstract

BACKGROUND: Increased production of pro-inflammatory mediators is considered central in the manifestation of events leading to irregular uterine bleeding in progestin-only contraceptive users. Evidence suggests that in addition to its antimicrobial property, doxycycline (Dox) acts as an anti-inflammatory agent mainly through the suppression of pro-inflammatory mediators. METHODS: We tested this hypothesis in the endometrial environment using an in vitro model consisting of isolated human endometrial glandular epithelial and stromal cells and a human endometrial surface (HES) epithelial cell line cultured under defined conditions. RESULTS: We found that Dox at doses ranging from 1 to 100 µg/ml had a limited growth-inhibitory effect on these cells, whereas Dox in a dose-dependent manner inhibited the production of tumour necrosis factor-{alpha} (TNF-{alpha}). Using multiplex cytokine/chemokine protein analysis to test a broader range of Dox activity, we found that Dox at 25 µg/ml either alone or in the presence of 17{beta}-estradiol (E2), medroxyprogesterone acetate (MPA) and E2 + MPA (10-8 M) as well as TNF-{alpha} (25 ng/ml), representing the endometrial environment exposed to contraceptives as well as inflammatory conditions, respectively, altered the production of multiple cytokines and chemokines as compared with untreated controls. These actions of Dox occurred in cell-, ovarian steroid- and cytokine/chemokine-dependent manners. Although Dox reduced the regulatory action of steroids on the production of these cytokines/chemokines, it was less effective on TNF-{alpha}-treated cells. CONCLUSIONS: The results support the hypothesis that Dox, by modulating the endometrial expression of multiple inflammatory-related cytokines/chemokines in a cell- and cytokine/chemokine-dependent manner, may have a therapeutic potential in patients experiencing irregular uterine bleeding, in particular in progestin-dominant contraceptive users.

Keywords: chemokines/cytokines/doxycycline/endometrium/uterine bleeding.
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