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J. Biol. Chem., Vol. 283, Issue 8, 4744-4755, February 22, 2008

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Activation of Cytosolic Phospholipase A₂ in Resident Peritoneal Macrophages by Listeria monocytogenes Involves Listeriolysin O and TLR2^*

Shahid Noor, Howard Goldfine, Dawn E. Tucker, Saritha Suram, Laurel L. Lenz^¶, Shizuo Akira^||, Satoshi Uematsu^||, Milena Girotti^**, Joseph V. Bonventre, Kevin Breuel, David L. Williams^¶¶, and Christina C. Leslie^||||1

From the Departments of Pediatrics and ^¶Immunology, National Jewish Medical and Research Center, Denver, Colorado 80206, the Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, the ^||Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan, the ^**Department of Psychology, University of Colorado, Boulder, Colorado 80309, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, ETSU Clinical Labs, ETSU Physicians and Associates, Johnson City, Tennessee 37604, the ^¶¶Department of Surgery, James H. Quillen College of Medicine, Johnson City, Tennessee 37614, and the ^||||Departments of Pathology and Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045

Eicosanoid production by macrophages is an early response to microbial infection that promotes acute inflammation. The intracellular pathogen Listeria monocytogenes stimulates arachidonic acid release and eicosanoid production from resident mouse peritoneal macrophages through activation of group IVA cytosolic phospholipase A₂ (cPLA₂). The ability of wild type L. monocytogenes (WTLM) to stimulate arachidonic acid release is partially dependent on the virulence factor listeriolysin O; however, WTLM and L. monocytogenes lacking listeriolysin O (hlyLM) induce similar levels of cyclooxygenase 2. Arachidonic acid release requires activation of MAPKs by WTLM and hlyLM. The attenuated release of arachidonic acid that is observed in TLR2^-/- and MyD88^-/- macrophages infected with WTLM and hlyLM correlates with diminished MAPK activation. WTLM but not hlyLM increases intracellular calcium, which is implicated in regulation of cPLA₂. Prostaglandin E₂, prostaglandin I₂, and leukotriene C₄ are produced by cPLA₂^+/+ but not cPLA₂^-/- macrophages in response to WTLM and hlyLM. Tumor necrosis factor (TNF)- production is significantly lower in cPLA₂^+/+ than in cPLA₂^-/- macrophages infected with WTLM and hlyLM. Treatment of infected cPLA₂^+/+ macrophages with the cyclooxygenase inhibitor indomethacin increases TNF production to the level produced by cPLA₂^-/- macrophages implicating prostaglandins in TNF down-regulation. Therefore activation of cPLA₂ in macrophages may impact immune responses to L. monocytogenes.

Received for publication, December 6, 2007 , and in revised form, December 13, 2007.

^* This work was supported by National Institutes of Health Grants HL34303 (to C. C. L.) and AI065638 (to L. L. L.). 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 To whom correspondence should be addressed: Dept. of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206. Tel.: 303-398-1214; Fax: 303-270-2155; E-mail: lesliec{at}njc.org.

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