Abstract
IntroductionThe endocannabinoid system modulates function of immune cells and mesenchymal cells such as fibroblasts, which contribute to cartilage destruction in rheumatoid arthritis (RA). The aim of the study was to determine the influence of N-acylethanolamines anandamide (AEA), palmitoylethanolamine (PEA) and oleylethanolamine (OEA) on several features of arthritic inflammation in vitro (human material) and in vivo (a mouse model).MethodsImmunofluorescence and western blotting were used to detect cannabinoid receptors and related enzymes. Cytokines and MMP-3 were measured by ELISA. Intracellular signaling proteins were detected by proteome profiling. Proliferation was quantified by CTB reagent. Adhesion was assessed by the xCELLigence system. After onset of collagen type II arthritis, mice were treated daily with the FAAH inhibitor JNJ1661010 (20 mg/kg) or vehicle.ResultsIL-6, IL-8 and MMP-3 (determined only in synovial fibroblasts (SFs)) were downregulated in primary synoviocytes and SFs of RA and OA after AEA, PEA and OEA treatment. In SFs, this was due to activation of TRPV1 and TRPA1 in a COX-2-dependent fashion. FAAH inhibition increased the efficacy of AEA in primary synoviocytes but not in SFs. The effects of OEA and PEA on SFs were diminished by FAAH inhibition. Adhesion to fibronectin was increased in a CB1-dependent manner by AEA in OASFs. Furthermore, elevation of endocannabinoids ameliorated collagen-induced arthritis in mice.ConclusionsN-acylethanolamines exert anti-inflammatory effects in SFs. A dual FAAH/COX-2 inhibitor, increasing N-acylethanolamine levels with concomitant TRP channel desensitization, might be a good candidate to inhibit the production of proinflammatory mediators of synovial cells and to reduce erosions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0845-5) contains supplementary material, which is available to authorized users.
Highlights
The endocannabinoid system modulates function of immune cells and mesenchymal cells such as fibroblasts, which contribute to cartilage destruction in rheumatoid arthritis (RA)
Anandamide reduces IL-6, IL-8 and tumor necrosis factor (TNF) production by primary mixed synoviocytes In the first experiments, the effects of acylethanolamines anandamide (AEA) with or without Fatty acid amide hydrolase (FAAH) inhibition on cytokine production by primary mixed synovial cells containing fibroblasts, macrophages, T and B lymphocytes and dendritic cells under normoxic (20 % O2) serum-free conditions were determined
Synovial fibroblasts express several receptors and enzymes involved in endocannabinoid action In subsequent experiments, RASF generated from primary synovial cells were investigated, since effects of AEA were only augmented in mixed RA synoviocytes
Summary
The endocannabinoid system modulates function of immune cells and mesenchymal cells such as fibroblasts, which contribute to cartilage destruction in rheumatoid arthritis (RA). Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by cartilage and bone destruction [1]. Additional targets for EC and related Nacylethanolamines were identified These include the transient receptor potential vanilloid channel TRPV1, peroxisome proliferator-activated receptors α and γ and G protein-coupled receptors GPR18 and GPR55 >8–10>. Pharmacological inhibition of FAAH or MAGL increases systemic levels of the respective EC [12]. Besides their well-characterized central effects, EC reduce the production of proinflammatory cytokines in various cell types, decrease T cell proliferation and inhibit migration of immune cells [13]
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