Progesterone and non-specific immunologic mechanisms in pregnancy

Progesterone-dependent immunomodulation is one of the mechanisms that enables pregnancy to proceed to term. Immunologic effects of progesterone are mediated by a protein named the progesterone-induced blocking factor (PIBF). Among other effects this protein inhibits natural killer (NK) activity and displays an anti-abortive effect in mice. Recently, we have shown that PIBF induces a Th2 shift in vitro. The present study was aimed at investigating the in vivo effect of PIBF on cytokine production, as well as the relationship between cytokine production, NK activity, and pregnancy loss.

Balb-c mice on day 8.5 of pregnancy were injected intraperitoneally with 0.5 mg of rabbit anti-PIBF immunoglobulin G (IgG). Another group of mice was simultaneously treated with anti-NK monoclonal antibodies. Mice treated with the same amount of normal rabbit serum or untreated mice of similar gestational age were used as controls. The animals were sacrificed and their uteri were inspected. The ratio of living and resorbed embryos was determined. NK activity as well as cytokine expression on the spleen cells were determined by immunocytochemistry and enzyme-linked immunoadsorbent assay (ELISA).

Mitogen-activated spleen cells from anti-PIBF-treated mice produced significantly (P < 0.001) less IL-10 than those of pregnant control mice. A significantly higher percentage (P < 0.001) of spleen cells from anti-PIBF-treated mice expressed interferon-gamma (IFN gamma) as determined by immunocytochemistry, than those of untreated pregnant mice. There was a positive relationship between the percentage of IFN gamma-positive spleen cells and resorption rates, and an inverse relationship between the latter and interleukin-10 (IL-10) production. All these effects were corrected by treatment with anti-NK antibodies.

Our data suggest that PIBF contributes to the success of gestation via cytokine-mediated inhibition of NK activity.