Souza Luiz Fernando de, Jardim Fernanda Rafaela, Sauter Ismael Pretto, Souza Marcela Moreira de, Barreto Fabiano, Margis Rogério, Bernard Elena Aida
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mol Immunol. 2009 Feb;46(5):937-42. doi: 10.1016/j.molimm.2008.09.012. Epub 2008 Oct 31.
Peptidoglycan (PEG) and lipoteichoic acid (LTA) are the main constituents of Gram-positive bacteria cell wall and are described to modulate immune functions. Increased levels of matrix metalloproteinases (MMPs) were described in endotoxemia, suggesting that they participate to tecidual damage, multiple organs failure and vascular disfunction. Staphylococcus aureus PEG is described to increase MMPs 2 and 9 levels in plasma from rat and MMP 9 secretion by human neutrophils, however, the effect of LTA on MMPs is unknown. In this work, was evaluated the modulation of MMPs 2 and 9 expression and secretion in RAW 264.7 macrophages by LTA from S. aureus. The role of A2A and A2B adenosine receptors was also investigated. LTA increased MMP 9 expression and secretion at 12h of treatment. The modulation of MMP 9 secretion was dose dependent, with maximal effect above 1microg/ml. The inhibitor of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway (U0126, 10microM) prevented LTA stimulation of MMP 9 secretion; however, the inhibitors of p38 (SB203580, 10microM) and Jun N-terminal kinase (JNK; SP600125, 10microM) presented any effect. A2A and A2B adenosine receptors pharmacological blockade or gene knockdown resulted in exacerbated MMP 9 secretion, while an adenosine receptors agonist inhibited LTA-stimulated MMP 9 secretion. These results suggest that LTA increased MMP 9 secretion in macrophages could be involved in complications associated to S. aureus infections. Moreover, LTA modulation of MMP 9 is dependent on MEK/ERK pathway and is regulated by A2A and A2B adenosine receptors.
肽聚糖（PEG）和脂磷壁酸（LTA）是革兰氏阳性菌细胞壁的主要成分，据描述可调节免疫功能。内毒素血症中基质金属蛋白酶（MMPs）水平升高，表明它们参与组织损伤、多器官功能衰竭和血管功能障碍。据描述，金黄色葡萄球菌的PEG可提高大鼠血浆中MMPs 2和9的水平以及人中性粒细胞分泌MMP 9的水平，然而，LTA对MMPs的影响尚不清楚。在本研究中，评估了金黄色葡萄球菌的LTA对RAW 264.7巨噬细胞中MMPs 2和9表达及分泌的调节作用。还研究了A2A和A2B腺苷受体的作用。LTA在处理12小时时增加了MMP 9的表达和分泌。MMP 9分泌的调节呈剂量依赖性，在1μg/ml以上有最大效应。丝裂原活化蛋白激酶（MEK）/细胞外信号调节激酶（ERK）途径抑制剂（U0126，10μM）可阻止LTA对MMP 9分泌的刺激；然而，p38抑制剂（SB203580，10μM）和Jun N末端激酶（JNK；SP600125，10μM）没有任何作用。A2A和A2B腺苷受体的药理学阻断或基因敲低导致MMP 9分泌加剧，而腺苷受体激动剂抑制LTA刺激的MMP 9分泌。这些结果表明，LTA增加巨噬细胞中MMP 9的分泌可能与金黄色葡萄球菌感染相关的并发症有关。此外，LTA对MMP 9的调节依赖于MEK/ERK途径，并受A2A和A2B腺苷受体调节。
