title: Synergistic up-regulation of epithelial cell matrix metalloproteinase-9 secretion in tuberculosis.
abstract: Mycobacterium tuberculosis (MTb) kills approximately 2 million people each year. MTb must drive host tissue destruction to disseminate and also to cause pulmonary cavitation. Matrix metalloproteinase-9 (MMP-9, gelatinase B) is implicated in this Tb-related immunopathology. We demonstrate that conditioned media from MTb-infected monocytes (CoMTb), but not direct infection with MTb, up-regulates MMP-9 gene expression and secretion from primary human bronchial epithelial cells (NHBE). MMP-9 secretion was increased 8.7-fold by CoMTb (P < 0.05) as assayed by gelatin zymography. A549 and 16HBE14o epithelial cell MMP secretion was significantly less than primary NHBE secretion. MMP-9 secretion was decreased 53.2% by inhibition of the p38 mitogen-activated protein kinase (MAPK) by SB203580 (P < 0.01) and 48.3% by inhibition of extracellular signal-regulated kinase with PD98059 (P < 0.05). MMP-9 secretion was prostaglandin independent. TNF-alpha was necessary but not sufficient for MMP-9 up-regulation by the monocyte-epithelial cell network. Soluble factors derived from Tb culture synergized with TNF-alpha to increase MMP-9 secretion by NHBE 6-fold (P < 0.01 compared with either stimulus alone). Together, these data reveal a new mechanism by which host- and pathogen-derived factors act together in MTb infection to drive MAPK-dependent MMP-9 secretion from respiratory epithelial cells.
authors.affiliation: Department of Infectious Diseases, Imperial College, Hammersmith Hospital, London, UK.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Elkington
authors.forename: Justin A
authors.initials: JA
authors.lastname: Green
authors.forename: Jenny E
authors.initials: JE
authors.lastname: Emerson
authors.forename: Laura D
authors.initials: LD
authors.lastname: Lopez-Pascua
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Boyle
authors.forename: Cecilia M
authors.initials: CM
authors.lastname: O'Kane
authors.forename: Jon S
authors.initials: JS
authors.lastname: Friedland
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism* / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D014376:Tuberculosis / Q000201:enzymology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020780:Matrix Metalloproteinase 9