The Immunological Pregnancy Protective Effect of Progesterone Is Manifested via Controlling Cytokine Production

PROBLEM: This study was aimed at investigating the involvement of an altered cytokine pattern in the immunomodulatory and anti-abortive effects of a progesterone-induced immunomodulatory protein (PIBF). METHOD: PIBF expression on lymphocytes of healthy pregnant women and from women at risk for premature pregnancy termination was determined. In sera of the same women TNFα was quantified by a bioassay using L929 cells. NK activity was determined by a single cell cytotoxicity assay. Cytokine production of the lymphocytes or murine spleen cells was measured by ELISA or detected by immunocytochemistry. In pregnant mice endogenous PIBF activity was neutralized by anti-PIBF IgG. RESULTS: Sera of women at risk for premature pregnancy termination contained significantly higher concentrations of TNFα than those from healthy pregnant women and PIBF expression on the lymphocytes was inversely related to serum concentration of TNFα. Increased NK activity of lymphocytes after neutralization of endogenous PIBF activity is corrected by anti-IL2 treatment and PIBF inhibits IL12 expression on activated lymphocytes. PIBF increases IL-10 production by activated spleen cells. In pregnant mice, neutralization of endogenous PIBF activity by specific antibody results in increased resorption rate and reduced splenic IL-10 production. CONCLUSIONS: Our data allow the assumption that via blocking IL-12 production PIBF inhibits NK activation with a concomitant reduction of TNFα levels. Disturbances in this system might lead to the expression of the known synergistic effect of IL-12 and TNFα, resulting in a Th1 type cytokine dominance and pregnancy termination.