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¹ Department of Medicine and Division of Rheumatology, Immunology, and Allergy and ² Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115

CORRESPONDENCE Heinz G. Remold: hremold{at}rics.bwh.harvard.edu

Virulent Mycobacterium tuberculosis (Mtb) induces a maladaptive cytolytic death modality, necrosis, which is advantageous for the pathogen. We report that necrosis of macrophages infected with the virulent Mtb strains H37Rv and Erdmann depends on predominant LXA₄ production that is part of the antiinflammatory and inflammation-resolving action induced by Mtb. Infection of macrophages with the avirulent H37Ra triggers production of high levels of the prostanoid PGE₂, which promotes protection against mitochondrial inner membrane perturbation and necrosis. In contrast to H37Ra infection, PGE₂ production is significantly reduced in H37Rv-infected macrophages. PGE₂ acts by engaging the PGE₂ receptor EP2, which induces cyclic AMP production and protein kinase A activation. To verify a role for PGE₂ in control of bacterial growth, we show that infection of prostaglandin E synthase (PGES)^–/– macrophages in vitro with H37Rv resulted in significantly higher bacterial burden compared with wild-type macrophages. More importantly, PGES^–/– mice harbor significantly higher Mtb lung burden 5 wk after low-dose aerosol infection with virulent Mtb. These in vitro and in vivo data indicate that PGE₂ plays a critical role in inhibition of Mtb replication.

M. Divangahi and H. Gan contributed equally to this study.

M. Chen's present address is Clinical Research Center, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China.

S. Hong's present address is Louisiana State University Neuroscience Center, New Orleans, LA 70112.

© 2008 Chen et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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