title: Gonadotropin-releasing hormone alters the T helper cytokine balance in the pregnant rat.
abstract: The interactions between immune-endocrine and reproductive systems are heightened during pregnancy as an adaptive mechanism, and are regulated by a complex array of hormones and cytokines that control the survival of a semiallogeneic conceptus. GnRH can exert direct effects on the immune system via its receptor (GnRH-R) on lymphoid cells. In the present study, we employed in vitro, ex vivo, and in vivo approaches to investigate the role of GnRH in the modulation of T helper cytokines in pregnant rats undergoing termination of pregnancy. Day 8 pregnant rats were infused with a GnRH agonist (GnRH-Ag) for 24 h using an osmotic minipump. Sham control rats were infused with the vehicle, saline. Lymphocytes were isolated from sham and treated rats and polyclonally stimulated with immobilized anti-CD3 antibody. The levels of the signature T helper 1 (Th-1) cytokines (interferon-gamma [IFN-gamma] and interleukin-2 [IL-2]) and Th-2 cytokines (IL-4 and IL-10) were measured in culture supernatants. Using immunoflourescence confocal microscopy, we demonstrated for the first time the spatial localization of GnRH-R protein on the surface of lymphocytes. We observed a marked increase in IFN-gamma and inhibition of IL-4 production from lymphocytes of pregnant rats treated in vitro with different doses of GnRH-Ag. Further, the responsiveness of lymphocytes to produce IFN-gamma was markedly increased in cells cultured ex vivo from GnRH-Ag infused rats, whereas the capacity of lymphocytes to produce IL-4 was significantly inhibited. In addition, GnRH-Ag infusion in pregnant rats induced a shift toward Th-1 cytokines in the serum. We did not observe any significant difference in IL-2 and IL-10 production in response to GnRH-Ag. Our results suggest an additional function for GnRH as a Th-1 inducer and Th-2 inhibitor. GnRH can thus skew the cytokine balance to predominantly Th-1 type in pregnancy, leading to the termination of pregnancy in rats.
authors.affiliation: Department of Physiology, Morehouse School of Medicine, Atlanta, Georgia 30310-1495, USA.
authors.forename: Vishwa Deep
authors.initials: VD
authors.lastname: Dixit
authors.forename: Hyunwon
authors.initials: H
authors.lastname: Yang
authors.forename: Venkatachalam
authors.initials: V
authors.lastname: Udhayakumar
authors.forename: Rajagopala
authors.initials: R
authors.lastname: Sridaran
mesh_terms: D000019:Abortifacient Agents; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists / Q000494:pharmacology*; D007111:Immunity, Cellular / Q000187:drug effects; D018613:Microscopy, Confocal; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011966:Receptors, LHRH / Q000187:drug effects / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000019:Abortifacient Agents; D016207:Cytokines; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone