Role of high molecular weight seminal vesicle proteins in eliciting the uterine inflammatory response to semen in mice

Abstract

Mating evokes a characteristic pattern of molecular and cellular events in the rodent reproductive tract, including an infiltration of the endometrial stroma and uterine lumen with activated macrophages and granulocytes, which closely resembles a classic inflammatory response. Previous studies in mice indicate that these cellular changes are associated with, and are largely a consequence of, an upregulated synthesis and release of granulocyte-macrophage colony-stimulating factor (GM-CSF) from the uterine epithelium in response to seminal fluid. The aim of this study was to investigate further the origin and nature of the factors present in seminal fluid that trigger the GM-CSF response. It was found that the characteristic increase in uterine expression of mRNA encoding GM-CSF and release of GM-CSF bioactivity from uterine epithelial cells into the luminal cavity seen after mating with intact or vasectomized males was no longer evident in matings with male mice from whom the seminal vesicles had been surgically removed. The extent of inflammatory leucocyte infiltration into the endometrium was also reduced; the most notable effect was a complete absence of the exocytosis of neutrophils into the luminal cavity normally seen after matings with intact or vasectomized males. Bioassay of the GM-CSF output of oestrous endometrial cells after culture with crude or Sephacryl S-400 chromatographed fractions of seminal vesicle fluid showed that the GM-CSF stimulating activity was predominantly associated with protein moieties in seminal vesicle fluid of approximately 650,000 M(r) and 100,000-400,000 M(r). These data confirm the presence in seminal vesicle fluid of specific factors that initiate an inflammatory response in the uterus after mating through upregulating GM-CSF synthesis in the uterine epithelium. The significance of the cytokine release and cellular changes induced by seminal plasma for implantation of the conceptus and pregnancy outcome remain to be determined.

Seminal fluid and reproduction: much more than previously thought

“…The inflammatory response occurring at insemination can be attributed to factors within seminal plasma, as opposed to sperm. This conclusion is based in findings that show the lack of a uterine inflammatory response after mating mice with seminal vesicle deficient stud males [8], suggesting that the factors initiating this inflammatory cascade originate in the seminal vesicle, where the majority of seminal plasma is produced. The upregulation of cytokines within the human cervix and murine uterus and has been specifically linked with the seminal plasma cytokine TGFβ [7,11].…”

“…After uterine epithelial cells are exposed to seminal factors, the surge of pro-inflammatory cytokines and chemokines (as stated above) causes an infiltration of inflammatory leukocytes. In addition to neutrophils a large number of antigen presenting cells (APCs) are recruited into the uterine endometrium, including macrophages and dendritic cells (DCs) expressing high levels of MHC class II [60,8]. This response has now been well characterised in other species including rabbit, horse, pig, and human [61][62][63][64]12].…”

“…In particular, seminal transforming growth factor-beta (TGFβ) [7] has been described to interact with uterine epithelial cells to induce the expression of an array of pro-inflammatory cytokines, resulting in a classic inflammatory response that culminates in an influx of leukocytes into the endometrial tissues [8]. This inflammatory response to semen and the associated change in the cytokine environment has been hypothesised to mediate several downstream effects in the female reproductive tract [9].…”

Effect of seminal plasma application to the vaginal vault in in vitro fertilization or intracytoplasmic sperm injection treatment cycles—a double-blind, placebo-controlled, randomized study

“…Specifically studies in mice [1,2] and pigs [3] found SP to be essential for implantation, interacts with uterine epithelial cells and induces a postmating inflammatory cascade. Several inflammation-inducing proteins present in SP are transforming growth factor b, [1,4], prostaglandin E and interleukin-8 [7].…”

“…A variety of studies first in animal models such as mice, [1,2] and pigs [3], and then in human in vitro cell culture models [4][5][6] indicate that seminal plasma (SP) reaching the endometrial cavity after intercourse may have an important role in affecting the uterine receptivity. SP contains a variety of factors such as Transforming Growth Factor b, [1,4], prostaglandin E and interleukin-8 [7], that may trigger a cascade of events through pro-inflammatory cytokines synthesis leading to maternal endometrial immunomodulation increasing uterine receptivity.…”