Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 8, Pages 4744-4755Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M709956200
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Funding
- NHLBI NIH HHS [P01 HL034303, HL34303] Funding Source: Medline
- NIAID NIH HHS [R01 AI065638, R56 AI065638, R01 AI065638-03, AI065638] Funding Source: Medline
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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 A(2) (cPLA(2)alpha). 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 (Delta hlyLM) induce similar levels of cyclooxygenase 2. Arachidonic acid release requires activation of MAPKs by WTLM and Delta hlyLM. The attenuated release of arachidonic acid that is observed in TLR2(-/-) and MyD88(-/-) macrophages infected with WTLM and Delta hlyLM correlates with diminished MAPK activation. WTLM but not Delta hlyLM increases intracellular calcium, which is implicated in regulation of cPLA(2)alpha. Prostaglandin E-2, prostaglandin I-2, and leukotriene C-4 are produced by cPLA(2)alpha(+/+) but not cPLA(2)alpha(-/-) macrophages in response to WTLM and Delta hlyLM. Tumor necrosis factor (TNF)-alpha production is significantly lower in cPLA(2)alpha(+/+) than in cPLA(2)alpha(-/-) macrophages infected with WTLM and Delta hlyLM. Treatment of infected cPLA(2)alpha(+/+) macrophages with the cyclooxygenase inhibitor indomethacin increases TNF alpha production to the level produced by cPLA(2)alpha(-/-) macrophages implicating prostaglandins in TNF alpha down-regulation. Therefore activation of cPLA(2)alpha in macrophages may impact immune responses to L. monocytogenes.
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