Hum. Reprod. Advance Access originally published online on August 4, 2006
Human Reproduction 2006 21(10):2555-2563; doi:10.1093/humrep/del206
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Doxycycline alters the expression of inflammatory and immune-related cytokines and chemokines in human endometrial cells: implication in irregular uterine bleeding*
1 Department of Obstetrics & Gynecology 2 Department of Pharmacy Practice, University of Florida, Gainesville, FL and 3 Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA
4 To whom correspondence should be addressed at: Department of Obstetrics & Gynecology, University of Florida, Box 100294, Gainesville, FL 32610-0294, USA. E-mail: cheginin{at}obgyn.ufl.edu
* This study was presented in part at the 51st Annual Meeting of the Society for Gynecological Investigation, Houston, TX, USA, March 2004.
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-
(TNF-). 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
-estradiol (E2), medroxyprogesterone acetate (MPA) and E2 + MPA (10–8 M) as well as TNF- (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--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.
Key words: chemokines/cytokines/doxycycline/endometrium/uterine bleeding
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