Steroidal regulation of uterine immune defenses

Progesterone suppresses uterine immune defenses and predisposes postpartum animals to nonspecific uterine infections. Progesterone can also suppress uterine eicosanoid synthesis. This effect of progesterone seems to be an important factor in the onset of uterine infections because eicosanoids can enhance uterine immune defenses. In fact, exogenous prostaglandin F(2alpha) (PGF(2alpha)), an eicosanoid that stimulates uterine PGF(2alpha) production, enhances uterine immune defenses and promotes the ability of ewes and sows to resolve uterine infections, even when progesterone is maintained at luteal phase concentrations. Prostaglandin F(2alpha) is also a proinflammatory molecule that stimulates the production of proinflammatory cytokines and may enhance uterine production of leukotriene B(4) (LTB(4)), which stimulates various neutrophil functions. Neutrophils seem to mount the initial response to bacteria that enter the uterus, and proinflammatory cytokines and LTB(4) enhance phagocytic activity of neutrophils. Even though there are clear associations among PGF(2alpha), LTB(4), proinflammatory cytokines, phagocytosis, and the ability of the uterus to resist or resolve infections, the mechanisms of action of exogenous PGF(2alpha) in mitigating the immunosuppressive effects of progesterone have not yet been defined. However, defining the PGF(2alpha) mechanisms should yield important new information that can be used to develop novel prevention and treatment strategies that do not rely on antibiotic and antimicrobial compounds for managing uterine infections.