59 ISG15

is expressed in the pregnant endometrium in primates,58 rodents,60 and ruminants.61 However, the conceptus signal(s) inducing these changes in humans has not been defined, but it does not appear to be as a direct effect of hCG production. In addition, ISG15 is increased in PBL in cattle during early pregnancy.62,63 Ixazomib Whether similar increases in ISG15 in peripheral immune cells are induced during human pregnancy is not known. Nonetheless, hCG clearly alters circulating immune cell function in ways expected to result in immunosuppression. Komorowski et al.64 showed that hCG reduced IL-2 and increased sIL-2 receptor secretion by human PBMC. These two together would result in reduced peripheral T-cell activation in response to paternal alloantigens. In rodents treated with hCG peptides, there was evidence of reduced neutrophil migration to sites of Listeria monocytogenes replication associated with reduced chemokine production.65 These results are consistent with the observations that pregnant humans exhibit

increased susceptibility to this pathogen.66 T cells treated with recombinant hCG showed reduced proliferation, decreased IFN-γ secretion and increased IL-10 production.30 Furthermore, hCG reduced the ability of in vitro-matured dendritic cells to stimulate T cells, potentially contributing to peripheral tolerance during pregnancy.67,68 In addition, hCG stimulated PBMC to increase IL-8 production which would support embryo implantation.43 GSI-IX cost Taken together these studies provide strong support for a systemic, non-luteal

action for hCG targeting specific components of the circulating immune system. With the discovery and characterization of the systemic role for CG from the primate conceptus,1 numerous investigations were launched to determine if similar systemic actions were involved in pregnancy recognition in ruminants.69 These studies identified an early conceptus protein that, when introduced into the uterus in purified eltoprazine form, rescued the CL. This protein, first called ovine trophoblast protein-1 or trophoblastin, and later IFN-τ, blocked development of the uterine luteolytic mechanism through paracrine actions on the uterine endometrium.6 These studies all led to the conclusion that there was little evidence for a systemic effect of the ruminant conceptus on the CL. For example, Godkin et al.7 injected iodinated IFN-τ into the uterus and assayed various tissues, including blood, for radioactivity and found that only very small amounts of label escaped the uterus (<1%). There was no evidence of significant accumulation of labeled IFN-τ in the ovary, nor were they able to demonstrate that IFN-τ could enhance progesterone production by luteal cells in vitro even though luteal membrane preparations specifically bound labeled IFN-τ. Numerous attempts to detect IFN-τ in uterine venous blood by radioimmunoassay were unsuccessful.