title: Regulation of MMP-9 by a WIN-binding site in the monocyte-macrophage system independent from cannabinoid receptors.
abstract: The cannabinoid system is known to be involved in the regulation of inflammatory processes. Therefore, drugs targeting cannabinoid receptors are considered as candidates for anti-inflammatory and tissue protective therapy. We demonstrated that the prototypical cannabinoid agonist R(+)WIN55,212-2 (WIN) reduced the secretion of matrix metalloproteinase-9 (MMP-9) in a murine model of cigarette-smoke induced lung inflammation. In experiments using primary cells and cell lines of the monocyte-macrophage-system we found that binding of the cannabinoid-receptor agonist WIN to a stereo-selective, specific binding site in cells of the monocyte-macrophage-system induced a significant down-regulation of MMP-9 secretion and disturbance of intracellular processing, which subsequently down-regulated MMP-9 mRNA expression via a ERK1/2-phosphorylation-dependent pathway. Surprisingly, the anti-inflammatory effect was independent from classical cannabinoid receptors. Our experiments supposed an involvement of TRPV1, but other yet unidentified sites are also possible. We conclude that cannabinoid-induced control of MMP-9 in the monocyte-macrophage system via a cannabinoid-receptor independent pathway represents a general option for tissue protection during inflammation, such as during lung inflammation and other diseases associated with inflammatory tissue damage.
authors.affiliation: Institute of Anatomy, Faculty of Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Svantje
authors.initials: S
authors.lastname: Tauber
authors.forename: Katrin
authors.initials: K
authors.lastname: Paulsen
authors.forename: Susanne
authors.initials: S
authors.lastname: Wolf
authors.forename: Peggy
authors.initials: P
authors.lastname: Synwoldt
authors.forename: Andreas
authors.initials: A
authors.lastname: Pahl
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Oliver
authors.initials: O
authors.lastname: Ullrich
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000378:metabolism*; D001665:Binding Sites; D001862:Bone Resorption / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009025:Morpholines / Q000378:metabolism*; D009281:Naphthalenes / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011014:Pneumonia / Q000201:enzymology / Q000473:pathology; D043882:Receptors, Cannabinoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D048588:Benzoxazines; D009025:Morpholines; D009281:Naphthalenes; D047495:PPAR gamma; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D048049:Extracellular Signal-Regulated MAP Kinases; D020780:Matrix Metalloproteinase 9; D020741:rho GTP-Binding Proteins; C071423:capsazepine; D002211:Capsaicin