Seminal Plasma Induces Prostaglandin-Endoperoxide Synthase (PTGS) 2 Expression in Immortalized Human Vaginal Cells: Involvement of Semen Prostaglandin E2 in PTGS2 Upregulation1

Abstract

Inflammation of the cervicovaginal mucosa is considered a risk factor for HIV infection in heterosexual transmission. In this context, seminal plasma (SP) may play an important role that is not limited to being the main carrier for the virions. It is known that SP induces an inflammatory reaction in the cervix called postcoital leukocytic reaction, which has been associated with promotion of fertility. The mechanisms by which SP triggers this reaction, however, have not been clearly established. Previously we reported the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase 2 (COX-2), in human vaginal cells in response to toll-like receptor (TLR) ligands and other proinflammatory stimuli. In this study, we demonstrate that SP induces transcriptional and translational increase of COX-2 expression in human vaginal cells and cervicovaginal tissue explants. Furthermore, SP potentiates vaginal PTGS2 expression induced by other proinflammatory stimulants, such as TLR ligands and a vaginal mucosal irritant (nonoxynol-9) in a synergistic manner. SP-induced PTGS2 expression is mediated by intracellular signaling pathways involving MAPKs and NF-κB. Using fractionation and functional analysis, seminal prostaglandin (PG)-E(2) was identified as a one of the major factors in PTGS2 induction. Given the critical role of this PG-producing enzyme in mucosal inflammatory processes, the finding that SP induces and potentiates the expression of PTGS2 in cervicovaginal cells and tissues has mechanistic implications for the role of SP in fertility-associated mucosal leukocytic reaction and its potential HIV infection-enhancing effect.

Role of Semen in Modulating the Female Genital Tract Microenvironment – Implications for HIV Transmission

“…16,84 We also demonstrated that semen strongly potentiates vaginal epithelial TLR activation induced by their ligands. 16 Considering that physiological levels of pro-inflammatory cytokines enhance susceptibility to HIV-1 infection fivefold to eightfold in cervical explant tissues, 85 this heightened inflammatory response could have important ramifications for viral transmission.…”

“…15 In addition, this mucosal reaction also encompasses local cellular changes that may impact susceptibility to HIV-1 infection. 16,17 The exact nature of seminal modulation of viral transmission across the genital mucosa remains controversial, and semen-mediated effects both promote and inhibit infection. 17 Biologic factors of the FRT that condition acquisition of HIV infection in women include the following: alterations in epithelial integrity, immune cell recruitment and activation, inflammation, innate antimicrobial activity, adaptive immunity, mucus barrier, and microbiota.…”

“…83 The concentration of semen PGE is several orders of magnitude higher than that of serum, although there is a high interindividual variability in the semen PGE content, 124 In our laboratory, we found that SP stimulates expression of PTGS2 (COX-2) gene in vaginal epithelial cells and identified PGE 2 as the seminal factor responsible for mediating this induction. 16 Seminal plasma has been shown to upregulate COX-2 expression in cervical adenocarcinoma cells. 125 Importantly, COX-2 is also known to be induced in human vaginal epithelial cells in response to TLR ligands and pro-inflammatory compounds, 126 an effect that is potentiated in the presence of SP.…”

“…125 Importantly, COX-2 is also known to be induced in human vaginal epithelial cells in response to TLR ligands and pro-inflammatory compounds, 126 an effect that is potentiated in the presence of SP. 16 Enhanced mucosal expression of COX-2, induced by pro-inflammatory stimuli and further increased by semen PGE 2 , may have implications for HIV-1 transmission in the FRT and explain, in part, the costimulatory effect of cervicovaginal infections.…”

Influence of Common Mucosal Co‐Factors on HIV Infection in the Female Genital Tract

“…When semen from HIV-uninfected men is deposited into the FGT, it elicits a transient inflammatory response characterized by proinflammatory cytokine and chemokine production and immune cell recruitment, which serves to prime the FGT for the conceptus. 26,[130][131][132][133] However, this response may also create an environment favorable for HIV infection as SP has also been shown to induce the overexpression of COX-2 in mare and porcine endometrium 134,135 and enhance COX-2 expression in human vaginal ECs, 136 thus promoting an inflammatory environment. Additionally, vaginal GECs have been shown to upregulate the chemokine CCL20 in response to SP, which promoted the migration of LCs into the vaginal mucosa.…”