Reiling N, Blumenthal A, Flad H D, Ernst M, Ehlers S
Department of Immunochemistry and Biochemical Microbiology and Immunology and Cell Biology, Research Center Borstel, Borstel, Germany.
J Immunol. 2001 Sep 15;167(6):3339-45. doi: 10.4049/jimmunol.167.6.3339.
The clinical course of mycobacterial infections is linked to the capacity of pathogenic strains to modulate the initial antimycobacterial response of the macrophage. To elucidate some of the mechanisms involved, we studied early signal transduction events leading to cytokine formation by human monocyte-derived macrophages (MDM) in response to clinical isolates of Mycobacterium avium. TNF-alpha production induced by M. avium was inhibited by anti-CD14 mAbs, but not by Abs against the macrophage mannose receptor. Analysis of mitogen-activated protein (MAP) kinase activation (extracellular signal-regulated kinase 1/2, p38, and c-Jun NH(2)-terminal kinase) showed a rapid phosphorylation of all three subfamilies in response to M. avium, which was inhibited by anti-CD14 Abs. Using highly specific inhibitors of p38 (SB203580) and MAP kinase kinase-1 (PD98059), we found that activation of the extracellular signal-regulated kinase pathway, but not of p38, was essential for the M. avium-induced TNF-alpha formation. In contrast, IL-10 production was abrogated by the p38 inhibitor, but not by the MAP kinase kinase-1 inhibitor. In conclusion, M. avium-induced secretion of TNF-alpha and IL-10 by human macrophages is differentially regulated at the level of MAP kinase activity.
分枝杆菌感染的临床病程与致病菌株调节巨噬细胞初始抗分枝杆菌反应的能力有关。为了阐明其中一些机制，我们研究了人单核细胞衍生巨噬细胞（MDM）对鸟分枝杆菌临床分离株产生细胞因子的早期信号转导事件。抗CD14单克隆抗体可抑制鸟分枝杆菌诱导的TNF-α产生，但抗巨噬细胞甘露糖受体抗体则无此作用。对丝裂原活化蛋白（MAP）激酶激活（细胞外信号调节激酶1/2、p38和c-Jun氨基末端激酶）的分析表明，鸟分枝杆菌刺激后，所有三个亚家族均迅速磷酸化，抗CD14抗体可抑制这一过程。使用p38（SB203580）和MAP激酶激酶-1（PD98059）的高度特异性抑制剂，我们发现细胞外信号调节激酶途径的激活而非p38的激活对于鸟分枝杆菌诱导的TNF-α形成至关重要。相反，p38抑制剂可消除IL-10的产生，但MAP激酶激酶-1抑制剂则无此作用。总之，鸟分枝杆菌诱导人巨噬细胞分泌TNF-α和IL-10在MAP激酶活性水平上受到不同调节。
