Regulation of MMP-9 by a WIN-Binding Site in the Monocyte-Macrophage System Independent from Cannabinoid Receptors

Svantje Tauber,Regine Schneider-Stock,Peggy Synwoldt,Katrin Paulsen,Susanne Wolf,Andreas Pahl,Oliver Ullrich,Marco Idzko

doi:10.1371/journal.pone.0048272

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.

Highlights

In the last years, several in vitro, in vivo and clinical studies suggested that the endocannabinoid system (ECS) is a crucial participant in the control and regulation of inflammation, where it interferes at different points and in key mechanisms of the orchestrated immunological network
In contrast to matrix metalloproteinase-9 (MMP-9), the secretion of matrix metalloproteinase (MMP)-12 was not altered by WIN-treatment, which demonstrated that WIN does not generally inhibit MMP secretion
As the amount of MMP-9 protein was decreased, we investigated if this decrease is valid at the level of activity

Summary

Introduction

Several in vitro, in vivo and clinical studies suggested that the endocannabinoid system (ECS) is a crucial participant in the control and regulation of inflammation, where it interferes at different points and in key mechanisms of the orchestrated immunological network. The fact that even plants possess a signal transduction system which exceedingly resembles the endocannabinoid system in animals, underlines the success of this evolutionary achievement [15]. Both cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) are seven-transmembrane Gi/o -protein-coupled receptors, but distinct in distribution and physiological function. Several studies have shown that some effects of cannabinoid ligands cannot be attributed to CB1 or CB2 receptors and several sites distinct from CB receptors, where at least some cannabinoid receptor ligands show activity, have been identified [19] Among these sites are the non-selective cation channel transient receptor potential vanilloid type 1 (TRPV1) [20], the G protein-coupled orphan receptor GPR55 [21,22] and the family of peroxisome proliferator-activated receptors (PPARs) [23]. Today pharmacological modulations of the cannabinoid system offer the opportunity for therapeutic intervention and the possibility to control or limit inflammation and to reduce tissue damage [24,25]

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