Mycobacterium tuberculosis up-regulates matrix metalloproteinase-1 secretion from human airway epithelial cells via a p38 MAPK switch.
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.
Elkington
Paul T G
PT
Department of Infectious Diseases, Imperial College, London, United Kingdom.
Emerson
Jenny E
JE
Lopez-Pascua
Laura D C
LD
O'Kane
Cecilia M
CM
Horncastle
Donna E
DE
Boyle
Joseph J
JJ
Friedland
Jon S
JS
D001980:Bronchi / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D004847:Epithelial Cells / Q000201:enzymology* / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D009000:Monocytes / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D020545:Respiratory Mucosa / Q000201:enzymology* / Q000378:metabolism / Q000382:microbiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014397:Tuberculosis, Pulmonary / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
D017077:Culture Media, Conditioned; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D020781:Matrix Metalloproteinase 1