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Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii¹

David M. Aronoff^2,*, Yibai Hao^*, Jooho Chung, Nicole Coleman^*, Casey Lewis, Camila M. Peres, Carlos H. Serezani, Gwo-Hsiao Chen, Nicolas Flamand, Thomas G. Brock and Marc Peters-Golden

^* Division of Infectious Diseases and Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109

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 PGE₂, 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- 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- and chemokine generation following C. sordellii or peptidoglycan challenge, impaired leukocyte phagocytosis of C. sordellii, and inhibited uterine epithelial cell human β-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 PGE₂, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants HL058897 and HL078727 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. David M. Aronoff, 4618-C Medical Sciences Building II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-5623. E-mail address: daronoff{at}umich.edu

³ Abbreviations used in this paper: EP, E prostanoid; BMDM, bone marrow-derived macrophage; i.g., intragastric; i.u., intrauterine; UEC, uterine epithelial cell; UM, uterine macrophage; EIA, enzyme immunoassay; PGN, peptidoglycan.

This article has been cited by other articles:

				C. Shannon and B. Winikoff Comment on "Misoprostol Impairs Female Reproductive Tract Innate Immunity against Clostridium sordellii" J. Immunol., August 15, 2008; 181(4): 2263 - 2263. [Full Text] [PDF]