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Keywords:

  • cyclooxygenase-2;
  • inflammation biomarkers;
  • microbicides;
  • nonoxynol-9;
  • PGE2;
  • vaginal epithelium

Citation Zalenskaya IA, Cerocchi OG, Joseph T, Donaghay MA, Schriver SD, Doncel GF. Increased COX-2 expression in human vaginal epithelial cells exposed to nonoxynol-9, a vaginal contraceptive microbicide that failed to protect women from HIV-1 infection. Am J Reprod Immunol 2011; 65: 569–577

Problem  Despite displaying virucidal activity in vitro, nonoxynol-9 (N-9), a vaginal contraceptive microbicide candidate, failed to reduce the rate of human immunodeficiency virus (HIV) transmission in clinical trials. With frequent use, it even increased the risk of HIV acquisition. Such outcome was postulated to be because of N-9-induced mucosal inflammation, which resulted in recruitment of HIV-target immune cells to the sites of virus entry. Understanding the mechanism underlying the response of the vaginal epithelium to N-9 is critical to properly evaluate the safety of prospective vaginal microbicides and contraceptives.

Methods and results  Using DNA microarray and quantitative RT-PCR techniques, we observed that N-9 initiated a strong transcriptional upregulation of cyclooxygenase-2 (COX-2) in immortalized human vaginal epithelial cells (VK2/E6E7 cell line). Increased COX-2 protein expression evaluated by immunoblotting was dose- and time-dependent. The level of prostaglandin E2 (PGE2) increased subsequently to COX-2 elevation. This upregulation was in part because of NF-kB activation.

Conclusion  Expression of COX-2, a potent inflammation-related enzyme, as well as increased secretion of PGE2, an important local mediator of mucosal immunoinflammatory responses, by human vaginal epithelial cells exposed to vaginal microbicide and contraceptive candidates may be used as a biomarker of undesirable compound properties.