Seminal plasma differentially regulates inflammatory cytokine gene expression in human cervical and vaginal epithelial cells

Abstract

Exposure to semen elicits an inflammatory response in the female reproductive tract of rodents and other animals. The nature and regulation of any similar response in humans is poorly understood. This study investigated seminal plasma induction of inflammatory cytokine and chemokine gene regulation in human cervical and vaginal epithelial cells in vitro. Affymetrix microarray gene profiling revealed that inflammatory cytokine genes were prevalent among 317 known genes differentially expressed in immortalized ectocervical epithelial (Ect1) cells after incubation with pooled human seminal plasma. A dose- and time-dependent induction by seminal plasma of IL8, IL6, CSF2 and CCL2 mRNA expression in Ect1 cells was verified by quantitative RT-PCR. This was accompanied by increases in Ect1 secretion of immunoactive gene products IL-8, IL-6, GM-CSF and MCP-1. Similar cytokine responses were elicited in primary ectocervical epithelial cells. Endocervical epithelial (End1) and vaginal epithelial (Vk2) cells were less responsive to seminal fluid, with induction of IL-8 and MCP-1, but not GM-CSF or IL-6. In a panel of 10 seminal plasma samples, considerable variation in inflammatory cytokine-inducing activity was evident. These experiments show that seminal plasma can elicit expression of a range of inflammatory cytokines and chemokines in reproductive tract epithelia, and implicate the ectocervix as the primary site of responsiveness, with gene-specific differences in the kinetics and site-restrictedness of the response. Seminal factor regulation of inflammatory cytokines in the cervical epithelium is implicated in controlling the immune response to seminal antigens, and defence against infectious agents introduced at intercourse.

Semen Promotes the Differentiation of Tolerogenic Dendritic Cells

“…Acting at the female genital tract, it induces the activation of both inflammatory responses and regulatory mechanisms mediated by T cells (18). Semen has been shown to induce the expression of inflammatory cytokines and chemokines, and a massive recruitment of macrophages, DCs, and memory T cells to the female genital mucosa after coitus (7,10,43). A similar response has been described in mice, pigs, rabbits, and other mammals (14,15).…”

“…Moreover, the indirect effects of seminal fluid on DCs could also be mediated by cytokines produced by epithelial cells. In fact, Sharkey and coworkers (10,16) have shown that seminal plasma induces the production of a number of cytokines by cervical epithelial cells, among them GM-CSF and G-CSF, two inducers of a tolerogenic phenotype in DCs (40,53).…”

“…It has been shown that semen deposition in the human female reproductive mucosa results in the induction of a strong inflammatory response that includes the production of inflammatory cytokines and chemokines (7,9,10), the upregulation of cyclooxygenase-2 expression (11), the infiltration of the cervix by neutrophils, and the recruitment of dendritic cells (DCs) (9,12,13). This inflammatory response induced by semen has also been described in mice, pigs, rabbits, and other mammals, and appears to induce the adaptation of the female immune response to promote fertility (14,15).…”

Variability in human semen content and its potential effects in the female reproductive tract

“…While the FRT is a large and complex environment, the epithelial lining can essentially be broken down into three main regions: the vagina, which has the largest surface area in the FRT and is characterized by a squamous epithelium that can be up to 25 cell layers thick; the ectocervix, which encompasses the portion of the epithelium that transitions from a multi-layer squamous phenotype into a simple columnar phenotype characterized by low tight junction expression; and the endocervix, which is describedas a single columnar epithelial layer with high levels of tight junction expression [26]. Interestingly, our group and others have observed that each of these regions is not only unique in phenotype or tight junction expression, but in responsiveness to stimuli, such as seminal fluid, revealing that the epithelium is more than just a mechanical barrier -it is also a dynamic tissue [27]. In fact, seminal fluid seems to elicit this response on tight junctions on epithelial cells in a variety of environments [28].…”

Seminal plasma insemination during ovum-pickup—a method to increase pregnancy rate in IVF/ICSI procedure. A pilot randomized trial

“…Johansson demonstrated that activation and expansion of the female lymphocyte populations after mating were triggered by constituents of SP derived from seminal vesicle glands [11]. SP determines an inflammation-like response in the female reproductive tract associated with recruitment of dendritic cells into the endometrium [18]. These cells process the male antigens from SP and activate proliferation and activation of regulatory T cells [11] which promote tolerance of paternal alloantigens at the time of the embryo implantation [17].…”