Chemokine stimulation of monocyte matrix metalloproteinase-9 requires endogenous TNF-alpha.
Leukocyte extravasation into tissues is a multi-step process culminating in the migration of cells through the basement membrane. This requires the production of matrix-degrading enzymes, in particular matrix metalloproteinases (MMP). We investigated the role of chemokines in regulating MMP production in the monocytic cell line THP-1 and in peripheral blood monocytes (PBM). The CC chemokines CCL2 (MCP-1), CCL3 (MIP-1alpha), and CCL5 (RANTES) stimulated the release of monocyte MMP-9 protein in a bell-shaped dose-dependent manner. The increase in MMP-9 protein detected at 24 h was due to de novo synthesis, confirmed by Northern blotting, with MMP-9 mRNA detectable at 6-8 h. Autocrine TNF-alpha was necessary for chemokine stimulation of MMP-9. Chemokines increased TNF-alpha mRNA levels and protein release in monocytes and THP-1 cells, and neutralizing anti-TNF-alpha antibodies inhibited CCL2-induced MMP-9 release. Furthermore, the broad spectrum MMP inhibitor BB 2516, which inhibits TNF-alpha release, abrogated CCL2- and CCL5-induced MMP-9 release in both THP-1 cells and freshly isolated monocytes. Monocyte production of MMP is of major importance in the pathology of cancer, asthma, and rheumatoid arthritis. An understanding of the mechanisms by which these MMP are produced may lead to novel therapies to modulate extravasation of leukocytes in disease.
Robinson
Stephen C
SC
ICRF Translational Oncology Laboratory, Bart's and the London Queen Mary School of Dentistry, Charterhouse Square, London, EC1M 6BQ, GB. s.c.robinson@icrf.icnet.uk
Scott
Kate A
KA
Balkwill
Frances R
FR
D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D018932:Chemokine CCL2 / Q000494:pharmacology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000494:pharmacology; D019742:Chemokines, CC / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D007962:Leukocytes / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D009500:Neutralization Tests; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019742:Chemokines, CC; D006877:Hydroxamic Acids; D019402:Macrophage Inflammatory Proteins; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C100342:marimastat; D020780:Matrix Metalloproteinase 9