Cytokine‐Leukocyte Networks and the Establishment of Pregnancy

Abstract

Our studies suggest that semen may play a critical role in providing the antigenic and environmental signals necessary to initiate an appropriate maternal immune response to the conceptus during pregnancy.

Seminal fluid and reproduction: much more than previously thought

“…Various signalling molecules including many originally described for their immunological activities have been shown to be present in seminal plasma of both humans and rodents, including TGFβ, interferon-gamma (IFNγ), prostaglandin E 2 (PGE 2 ), tumour necrosis factor-alpha (TNFα) and members of the interleukin (IL) family of cytokines, including IL-1b, IL-6, IL-8, IL-10 and IL-12. TGFβ is produced predominately by the seminal vesicles and is present in ejaculated seminal plasma at concentration of approximately 200 ng/ml, substantially higher concentrations than that of blood plasma [9]. The seminal vesicles of men are also known to produce vast quantities of PGE 2 resulting in seminal plasma levels 100 000 times greater than those seen in tissues during an acute inflammatory responses [53].…”

“…Seminal fluids target the epithelial cell layer of the cervix and uterus, inducing the expression of pro-inflammatory cytokines such as GM-CSF, CSF-1 (colony stimulating factor 1), IL-1α, IL-6, IL-8, LIF, RANTES and MIP-1α [9]. The up-regulation of these cytokines by the epithelium has multiple consequences.…”

“…Females inseminated after uterine ligation become transiently tolerant to male transplantation antigens as measured by survival of paternal tumour challenge, suggesting that semen, as opposed to the embryo itself is a key requirement for inducing tolerance [9]. The cytokine environment at the site of antigen exposure is also a critical factor for the future development of tolerance, and seminal plasma elicits a cascade of events leading to the induction of a unique cytokine microenvironment with the uterine epithelium.…”

“…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]. More recently these studies have been recapitulated in the human, particularly the cervix following intercourse [10][11][12].…”

“…The events leading to these immune changes in pregnancy are unknown, but are hypothesised to be initiated at insemination, when the maternal immune system is first exposed to paternal transplantation antigens, some of which are shared by the conceptus. Thus, insemination may comprise a 'priming' event leading to the maternal immune tolerance required for the survival of the semi-allogeneic conceptus [14,9].…”