Elkington Paul T G, Emerson Jenny E, Lopez-Pascua Laura D C, O'Kane Cecilia M, Horncastle Donna E, Boyle Joseph J, Friedland Jon S
Department of Infectious Diseases, Imperial College, London, United Kingdom.
J Immunol. 2005 Oct 15;175(8):5333-40. doi: 10.4049/jimmunol.175.8.5333.
Pulmonary cavitation is vital to the persistence and spread of Mycobacterium tuberculosis (MTb), but mechanisms underlying this lung destruction are poorly understood. Fibrillar type I collagen provides the lung's tensile strength, and only matrix metalloproteinases (MMPs) can degrade it at neutral pH. We investigated MTb-infected lung tissue and found that airway epithelial cells adjacent to tuberculosis (Tb) granulomas expressed a high level of MMP-1 (interstitial collagenase). Conditioned media from MTb-infected monocytes (CoMTb) up-regulated epithelial cell MMP-1 promoter activity, gene expression, and secretion, whereas direct MTb infection did not. CoMTb concurrently suppressed tissue inhibitor of metalloprotease-1 (TIMP-1) secretion, further promoting matrix degradation, and in Tb patients very low TIMP-1 expression was detected. MMP-1 up-regulation required synergy between TNF-alpha and G protein-coupled receptor signaling pathways. CoMTb stimulated p38 MAPK phosphorylation, and this is the point of TNF-alpha synergy with G protein-coupled receptor activation. Furthermore, p38 phosphorylation was the switch up-regulating MMP-1 activity and decreasing TIMP-1 secretion. Activated p38 localized to MMP-1-secreting airway epithelial cells in Tb patients. These data reveal a monocyte-epithelial cell network whereby MTb may drive tissue destruction, and they demonstrate that p38 phosphorylation is a key regulatory point in the generation of a matrix-degrading phenotype.
肺空洞形成对于结核分枝杆菌（MTb）的持续存在和传播至关重要，但这种肺组织破坏的潜在机制尚不清楚。纤维状I型胶原蛋白赋予肺组织抗张强度，而只有基质金属蛋白酶（MMPs）能在中性pH值下将其降解。我们研究了MTb感染的肺组织，发现结核（Tb）肉芽肿附近的气道上皮细胞表达高水平的MMP-1（间质胶原酶）。MTb感染的单核细胞的条件培养基（CoMTb）上调了上皮细胞MMP-1启动子活性、基因表达和分泌，而MTb直接感染则无此作用。CoMTb同时抑制金属蛋白酶组织抑制剂-1（TIMP-1）的分泌，进一步促进基质降解，并且在Tb患者中检测到极低的TIMP-1表达。MMP-1的上调需要肿瘤坏死因子-α（TNF-α）和G蛋白偶联受体信号通路之间的协同作用。CoMTb刺激p38丝裂原活化蛋白激酶（p38 MAPK）磷酸化，这是TNF-α与G蛋白偶联受体激活协同作用的关键点。此外，p38磷酸化是上调MMP-1活性和降低TIMP-1分泌的开关。在Tb患者中，活化的p38定位于分泌MMP-1的气道上皮细胞。这些数据揭示了一个单核细胞-上皮细胞网络，MTb可能借此驱动组织破坏，并且表明p38磷酸化是产生基质降解表型的关键调控点。
