title: Differential regulation of MMP-1/9 and TIMP-1 secretion in human monocytic cells in response to Mycobacterium tuberculosis.
abstract: In tuberculosis, matrix metalloproteinase (MMP) secretion is involved in leukocyte migration to sites of infection but in excess may contribute to tissue destruction. We demonstrate that human monocytic THP-1 cells and primary monocytes secrete MMP-1 (52 kD collagenase) when phagocytosing live, virulent M. tuberculosis but not inert latex. The magnitude of MMP-1 secretion was approximately 10-fold less when compared to MMP-9 (92 kD gelatinase) secretion. MMP-1 secretion was also relatively delayed (detected at 24 h vs. 4 h). M. tuberculosis, zymosan or latex stimulate similar TIMP-1 secretion within 8 h and increasing over 24 h. MMP-1/9 secretion was decreased by inhibitors of protein kinase (PK) C, PKA or tyrosine kinases (PTK) in a concentration-dependent manner. In contrast, TIMP-1 secretion was not affected by PKC or PTK blockade and only somewhat reduced by high level PKA inhibition. In summary, M. tuberculosis-infected monocytes secrete MMP-1 at lower concentrations than MMP-9 and such MMP secretion is regulated by multiple upstream signalling pathways which do not control TIMP-1 secretion. Divergent effects of i on MMP and TIMP secretion from monocytes may be important in influencing matrix degradation in vivo.
authors.affiliation: Department of Infectious Diseases, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. j.friedland@ic.ac.uk
authors.forename: J S
authors.initials: JS
authors.lastname: Friedland
authors.forename: T C
authors.initials: TC
authors.lastname: Shaw
authors.forename: N M
authors.initials: NM
authors.lastname: Price
authors.forename: J-M
authors.initials: JM
authors.lastname: Dayer
mesh_terms: D002227:Carbazoles; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009281:Naphthalenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D015054:Zymosan / Q000494:pharmacology
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D009281:Naphthalenes; D011758:Pyrroles; D019715:Tissue Inhibitor of Metalloproteinase-1; C057416:KT 5720; D015054:Zymosan; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; C058819:calphostin C