Lipoteichoic acid-induced nitric oxide synthase expression in RAW 264.7 macrophages is mediated by cyclooxygenase-2, prostaglandin E2, protein kinase A, p38 MAPK, and nuclear factor-κB pathways
Lipoteichoic acid-induced nitric oxide synthase expression in RAW 264.7 macrophages is mediated by cyclooxygenase-2, prostaglandin E2, protein kinase A, p38 MAPK, and nuclear factor-κB pathways
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DOI：
10.1016/j.cellsig.2005.10.005
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发表时间：
2006-08-01
影响因子：
4.8
通讯作者：
Lin, Chien-Huang
中科院分区：
文献类型：
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作者：
Chang, Yau-Chong;Li, Pei-Chih;Lin, Chien-Huang
我们最近报道，脂磷壁酸（LTA），革兰氏阳性菌金黄色葡萄球菌的细胞壁成分，刺激诱导型一氧化氮合酶（iNOS）的表达，一氧化氮（NO）的释放，和环氧化酶-2（考克斯-2）在RAW 264.7巨噬细胞的表达。本研究旨在进一步探讨考克斯-2和前列腺素E-2（PGE（2））在LTA诱导RAW 264.7巨噬细胞iNOS表达和NO释放中的作用。用LTA处理RAW 264.7巨噬细胞引起PGE（2）释放的时间依赖性增加。非选择性考克斯抑制剂（吲哚美辛）、选择性COX 2抑制剂（NS-398）、腺苷酸环化酶（AC）抑制剂（双脱氧腺苷，DDA）和蛋白激酶A（PKA）抑制剂（KT-5720）可抑制LTA诱导的iNOS表达和NO释放。此外，PGE（2）和PKA直接激活剂二丁酰cAMP也以浓度依赖性方式诱导iNOS表达。用LTA、PGE（2）和二丁酰-cAMP刺激RAW 264.7巨噬细胞均能引起p38 MAPK激活，并呈时间依赖性。LTA介导的p38 MAPK活化被吲哚美辛、NS-398和SB 203580抑制，但不被PD 98059抑制。DDA、KT-5720和SB 203580可抑制PGE（2）介导的p38 MAPK活化，但PD 98059不抑制。LTA引起核因子-κ B（NF-κ B）特异性DNA-蛋白质复合物形成的时间依赖性激活。吲哚美辛、NS-398、KT-5720和p38 α MAPK显性负突变体（p38 α MAPK DN）可抑制LTA诱导的κ B-荧光素酶活性增加。这些结果表明，在RAW 264.7巨噬细胞中，LTA诱导的iNOS表达和NO释放涉及考克斯-2产生的PGE产生以及AC、PKA、p38 MAPK和NF-κ B活化。(c)2005年爱思唯尔公司All rights reserved.
We recently reported that lipoteichoic acid (LTA), a cell wall component of the gram-positive bacterium Staphylococcus aureus, stimulated inducible nitric oxide synthase (iNOS) expression, nitric oxide (NO) release, and cyclooxygenase-2 (COX-2) expression in RAW 264.7 macrophages. This study was carried out to further investigate the roles of COX-2 and prostaglandin E-2 (PGE(2)) in LTA-induced iNOS expression and NO release in RAW 264.7 macrophages. Treatment of RAW 264.7 macrophages with LTA caused a time-dependent increase in PGE(2) release. LTA-induced iNOS expression and NO release were inhibited by a non-selective COX inhibitor (indomethacin), a selective COX2 inhibitor (NS-398), an adenylyl cyclase (AC) inhibitor (dideoxyadenosine, DDA), and a protein kinase A (PKA) inhibitor (KT-5720). Furthermore, both PGE(2) and the direct PKA activator, dibutyryl-cAMP, also induced iNOS expression in a concentration-dependent manner. Stimulation of RAW 264.7 macrophages with LTA, PGE(2) and dibutyryl-cAMP all caused p38 MAPK activation in a time-dependent manner. LTA-mediated p38 MAPK activation was inhibited by indomethacin, NS-398, and SB 203580, but not by PD 98059. The PGE(2)-mediated p38 MAPK activation was inhibited by DDA, KT-5720, and SB 203580, but not by PD 98059. LTA caused time-dependent activation of the nuclear factor-kappa B(NF-kappa B)-specific DNA-protein complex formation. The LTA-induced increase in kappa B-luciferase activity was inhibited by indomethacin, NS-398, KT-5720, and a dominant negative mutant of p38 alpha MAPK (p38 alpha MAPK DN). These results suggest that LTA-induced iNOS expression and NO release involve COX-2-generated PGE, production, and AC, PKA, p38 MAPK, and NF-kappa B activation in RAW 264.7 macrophages. (c) 2005 Elsevier Inc. All rights reserved.