Misoprostol impairs female reproductive tract innate immunity against Clostridium sordellii.

Aronoff DM, Hao Y, Chung J, Coleman N, Lewis C, Peres CM, Serezani CH, Chen GH, Flamand N, Brock TG, Peters-Golden M
J Immunol. 2008 180 (12): 8222-30

PMID: 18523288 · PMCID: PMC2667109 · DOI:10.4049/jimmunol.180.12.8222

Fatal cases of acute shock complicating Clostridium sordellii endometritis following medical abortion with mifepristone (also known as RU-486) used with misoprostol were reported. The pathogenesis of this unexpected complication remains enigmatic. Misoprostol is a pharmacomimetic of PGE(2), an endogenous suppressor of innate immunity. Clinical C. sordellii infections were associated with intravaginal misoprostol administration, suggesting that high misoprostol concentrations within the uterus impair immune responses against C. sordellii. We modeled C. sordellii endometritis in rats to test this hypothesis. The intrauterine but not the intragastric delivery of misoprostol significantly worsened mortality from C. sordellii uterine infection, and impaired bacterial clearance in vivo. Misoprostol also reduced TNF-alpha production within the uterus during infection. The intrauterine injection of misoprostol did not enhance mortality from infection by the vaginal commensal bacterium Lactobacillus crispatus. In vitro, misoprostol suppressed macrophage TNF-alpha and chemokine generation following C. sordellii or peptidoglycan challenge, impaired leukocyte phagocytosis of C. sordellii, and inhibited uterine epithelial cell human beta-defensin expression. These immunosuppressive effects of misoprostol, which were not shared by mifepristone, correlated with the activation of the G(s) protein-coupled E prostanoid (EP) receptors EP2 and EP4 (macrophages) or EP4 alone (uterine epithelial cells). Our data provide a novel explanation for postabortion sepsis leading to death and also suggest that PGE(2), in which production is exaggerated within the reproductive tract during pregnancy, might be an important causal determinant in the pathogenesis of more common infections of the gravid uterus.

MeSH Terms (18)

Animals Cell Line Clostridium Infections Clostridium sordellii Disease Models, Animal Endometritis Female Humans Immunity, Innate Immunosuppressive Agents Inflammation Mediators Macrophages, Peritoneal Mice Mice, Inbred CBA Misoprostol Rats Rats, Wistar Virulence

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