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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Benzoxazines / metabolism*
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Binding Sites
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Bone Resorption / pathology
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Bronchoalveolar Lavage Fluid
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Capsaicin / analogs & derivatives
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Capsaicin / pharmacology
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Cell Differentiation / drug effects
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Disease Models, Animal
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Gene Expression Regulation, Enzymologic / drug effects
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Glycosylation / drug effects
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Humans
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Macrophages / drug effects
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Macrophages / enzymology*
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Macrophages / metabolism
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Macrophages / pathology
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Matrix Metalloproteinase 9 / genetics
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Matrix Metalloproteinase 9 / metabolism*
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Mice
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Microglia / drug effects
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Microglia / enzymology
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Monocytes / drug effects
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Monocytes / enzymology*
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Monocytes / pathology
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Morpholines / metabolism*
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Naphthalenes / metabolism*
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Osteoclasts / drug effects
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Osteoclasts / enzymology
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Osteoclasts / pathology
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PPAR gamma / metabolism
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Phosphorylation / drug effects
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Pneumonia / enzymology
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Pneumonia / pathology
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Receptors, Cannabinoid / metabolism*
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Signal Transduction / drug effects
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TRPV Cation Channels / agonists
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TRPV Cation Channels / antagonists & inhibitors
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TRPV Cation Channels / metabolism
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rho GTP-Binding Proteins / metabolism
Substances
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Benzoxazines
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Morpholines
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Naphthalenes
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PPAR gamma
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Receptors, Cannabinoid
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TRPV Cation Channels
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TRPV1 protein, mouse
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(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
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Extracellular Signal-Regulated MAP Kinases
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Matrix Metalloproteinase 9
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rho GTP-Binding Proteins
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capsazepine
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Capsaicin
Grants and funding
This study was supported by a grant from the DFG (DFG Graduate School 1167 and FOR521 grant UL 177/6-1). ST was member of the DFG graduate school 1167 and member of the International Research Training Group “Cell-based Characterization of Disease Mechanisms in Tissue Destruction and Repair” Konstanz/Zurich (IRTG 1331). URL:
www.dfg.de. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.