Induction of Cyclooxygenase (COX)-2 in Human Vaginal Epithelial Cells in Response to TLR ligands and TNF-α

• Published in: American journal of reproductive immunology (1989) 2012-06, Vol.67 (6), p.482-490
• Main Authors: Joseph, Theresa, Zalenskaya, Irina A., Yousefieh, Nazita, Schriver, Suzanne D., Cote, Lyn C., Chandra, Neelima, Doncel, Gustavo F.
• Format: Article
• Language: English
• Subjects: Aminoquinolines - pharmacology; Cell Line; COX-2; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - genetics; Dinoprostone - biosynthesis; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Female; genital; HIV; Humans; Imiquimod; inflammation; Ligands; Lipopeptides - pharmacology; Lipopolysaccharides - pharmacology; Polydeoxyribonucleotides - pharmacology; prostaglandin; RNA, Messenger - biosynthesis; Teichoic Acids - pharmacology; TLRs; Toll-Like Receptors - agonists; Toll-Like Receptors - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Up-Regulation; Vagina - cytology; Vagina - metabolism; Zymosan - pharmacology
• ISSN: 1046-7408; 1600-0897
• DOI: 10.1111/j.1600-0897.2011.01099.x

Problem Mucosal inflammation caused by infections of the female lower genital tract is considered to be an important cofactor for HIV transmission. We hypothesize that COX‐2, a key inflammation‐related enzyme, is involved in these responses and is upregulated by microbial ligands and pro‐inflammatory cytokines. Method of study Human vaginal epithelial cells (VK‐2/E6E7) and ectocervical biopsy tissues were stimulated with TLR ligands and the cytokine TNF‐α, used as surrogates of vaginal infections, and assessed for COX‐2 expression and activity by microarray, real‐time RT‐PCR, immunoblotting, immunohistochemistry, and ELISA. Results TLR agonists and TNF‐α induce transcriptional and translational expression of COX‐2 in vaginal cells. TLR ligands, MALP2, Pam3CSK4, LTA, and imiquimod induced high epithelial COX‐2 expression, while zymosan and poly dI:dC induced very low enzyme expression. Induced mRNA and protein expression correlated with increased COX‐2 activity, which led to increased levels of PGE2 in the cell culture supernatant. These cell‐based findings were confirmed in primary cervicovaginal tissue explants. Conclusion Induction of COX‐2 expression and activity and the consequent increased levels of prostaglandins are common inflammatory pathways in human cervicovaginal epithelial cells and tissues in response to diverse TLR ligands and pro‐inflammatory cytokines. These findings are relevant to the understanding of genital mucosal inflammation, its potential treatment, and its possible relationship with increased tissue susceptibility to HIV‐1 infection.