Noor Shahid, Goldfine Howard, Tucker Dawn E, Suram Saritha, Lenz Laurel L, Akira Shizuo, Uematsu Satoshi, Girotti Milena, Bonventre Joseph V, Breuel Kevin, Williams David L, Leslie Christina C
Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
J Biol Chem. 2008 Feb 22;283(8):4744-55. doi: 10.1074/jbc.M709956200. Epub 2007 Dec 14.
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 (cPLA2alpha). 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 (DeltahlyLM) induce similar levels of cyclooxygenase 2. Arachidonic acid release requires activation of MAPKs by WTLM and DeltahlyLM. The attenuated release of arachidonic acid that is observed in TLR2-/- and MyD88-/- macrophages infected with WTLM and DeltahlyLM correlates with diminished MAPK activation. WTLM but not DeltahlyLM increases intracellular calcium, which is implicated in regulation of cPLA2alpha. Prostaglandin E2, prostaglandin I2, and leukotriene C4 are produced by cPLA2alpha+/+ but not cPLA2alpha-/- macrophages in response to WTLM and DeltahlyLM. Tumor necrosis factor (TNF)-alpha production is significantly lower in cPLA2alpha+/+ than in cPLA2alpha-/- macrophages infected with WTLM and DeltahlyLM. Treatment of infected cPLA2alpha+/+ macrophages with the cyclooxygenase inhibitor indomethacin increases TNFalpha production to the level produced by cPLA2alpha-/- macrophages implicating prostaglandins in TNFalpha down-regulation. Therefore activation of cPLA2alpha in macrophages may impact immune responses to L. monocytogenes.
巨噬细胞产生类花生酸是对微生物感染的早期反应,可促进急性炎症。细胞内病原体单核细胞增生李斯特菌通过激活IVA组胞质磷脂酶A2(cPLA2α),刺激驻留小鼠腹膜巨噬细胞释放花生四烯酸并产生类花生酸。野生型单核细胞增生李斯特菌(WTLM)刺激花生四烯酸释放的能力部分依赖于毒力因子溶血素O;然而,WTLM和缺乏溶血素O的单核细胞增生李斯特菌(DeltahlyLM)诱导的环氧化酶2水平相似。WTLM和DeltahlyLM刺激花生四烯酸释放需要激活丝裂原活化蛋白激酶(MAPK)。在感染WTLM和DeltahlyLM的TLR2-/-和MyD88-/-巨噬细胞中观察到的花生四烯酸释放减弱与MAPK激活减少相关。WTLM而非DeltahlyLM可增加细胞内钙,这与cPLA2α的调节有关。前列腺素E2、前列腺素I2和白三烯C4由cPLA2α+/+而非cPLA2α-/-巨噬细胞响应WTLM和DeltahlyLM产生。在感染WTLM和DeltahlyLM的cPLA2α+/+巨噬细胞中,肿瘤坏死因子(TNF)-α的产生明显低于cPLA2α-/-巨噬细胞。用环氧化酶抑制剂吲哚美辛处理感染的cPLA2α+/+巨噬细胞可使TNFα产生增加至cPLA2α-/-巨噬细胞产生的水平,这表明前列腺素参与TNFα的下调。因此,巨噬细胞中cPLA2α的激活可能影响对单核细胞增生李斯特菌的免疫反应。