Regulation of MMP-9 by a WIN-binding site in the monocyte-macrophage system independent from cannabinoid receptors

PLoS One. 2012;7(11):e48272. doi: 10.1371/journal.pone.0048272. Epub 2012 Nov 6.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzoxazines / metabolism*
  • Binding Sites
  • Bone Resorption / pathology
  • Bronchoalveolar Lavage Fluid
  • Capsaicin / analogs & derivatives
  • Capsaicin / pharmacology
  • Cell Differentiation / drug effects
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glycosylation / drug effects
  • Humans
  • Macrophages / drug effects
  • Macrophages / enzymology*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Mice
  • Microglia / drug effects
  • Microglia / enzymology
  • Monocytes / drug effects
  • Monocytes / enzymology*
  • Monocytes / pathology
  • Morpholines / metabolism*
  • Naphthalenes / metabolism*
  • Osteoclasts / drug effects
  • Osteoclasts / enzymology
  • Osteoclasts / pathology
  • PPAR gamma / metabolism
  • Phosphorylation / drug effects
  • Pneumonia / enzymology
  • Pneumonia / pathology
  • Receptors, Cannabinoid / metabolism*
  • Signal Transduction / drug effects
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / antagonists & inhibitors
  • TRPV Cation Channels / metabolism
  • rho GTP-Binding Proteins / metabolism

Substances

  • Benzoxazines
  • Morpholines
  • Naphthalenes
  • PPAR gamma
  • Receptors, Cannabinoid
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • (3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone
  • Extracellular Signal-Regulated MAP Kinases
  • Matrix Metalloproteinase 9
  • rho GTP-Binding Proteins
  • capsazepine
  • 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.