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.
OBJECTIVE
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.


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 E(2) (PGE(2) ) increased subsequently to COX-2 elevation. This upregulation was in part because of NF-kB activation.


CONCLUSIONS
Expression of COX-2, a potent inflammation-related enzyme, as well as increased secretion of PGE(2) , 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.
CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA. ZalensIA@EVMS.edu
Irina A
IA
Zalenskaya
Orlando G
OG
Cerocchi
Theresa
T
Joseph
Melissa A
MA
Donaghay
Suzanne D
SD
Schriver
Gustavo F
GF
Doncel
D000890:Anti-Infective Agents / Q000008:administration & dosage; D002461:Cell Line, Transformed; D003271:Contraceptive Agents, Female / Q000008:administration & dosage; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D015658:HIV Infections / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control; D015497:HIV-1 / Q000276:immunology* / Q000472:pathogenicity; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects; D007249:Inflammation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D017137:Nonoxynol / Q000008:administration & dosage / Q000009:adverse effects*; D020411:Oligonucleotide Array Sequence Analysis; D014621:Vagina / Q000473:pathology; D014774:Virulence / Q000187:drug effects
D000890:Anti-Infective Agents; D003271:Contraceptive Agents, Female; D016328:NF-kappa B; D017137:Nonoxynol; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone