18. Anandamide attenuates the inflammatory phenotype of rheumatoid arthritis synovial fibroblasts by activating multiple receptor pathways

• Published in: Brain, behavior, and immunity Vol. 26; pp. S5 - S6
• Main Authors: Lowin, T, Gräber, A, Neumann, E, Straub, R.H
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.09.2012
• Subjects: Allergy and Immunology; Psychiatry
• ISSN: 0889-1591; 1090-2139
• DOI: 10.1016/j.bbi.2012.07.042

Background In rheumatoid arthritis (RA), synovial fibroblasts (SF) secrete large amounts of IL-6, IL-8 and several matrixmetalloproteinases which are crucial for cartilage destruction. RASF are sensitive to the action of cannabinoids and they express cannabinoid receptors type I and II as well as endocannabinoid degrading enzymes. Cannabinoids are regarded as antiinflammatory and since anandamide is found in RA synovial fluid we investigated how this endocannabinoid affects adhesion, proliferation and the production of inflammatory mediators of RASF. Methods Adhesion was assessed by Roches xcelligence system. Proliferation was quantified by the amount of incorporated fluorescent dye into cellular DNA. MMP-3 and cytokines were detected by ELISA. Cannabinoid receptors were visualized by immunofluorescence. Results Anandamide dose-dependently decreased the production of IL-6, IL-8 and MMP-3 by activating classical cannabinoid receptors. Adhesion was increased in a cannabinoid receptor-dependent manner. Proliferation was inhibited by anandamide and this was reverted by blocking cyclooxygenase-2. Furthermore, proliferation was negatively correlated with CB1 receptor expression. Furthermore, the expression of GPR18 and GPR55 was verified in SFs. Conclusion Anandamide promotes an antiinflammatory phenotype in RASFs by activating classical cannabinoid receptors. Additionally, cyclooxygenase-2 metabolites of anandamide exert their anti-proliferative effects independent of cannabinoid receptors 1 and 2. The identification of GPR18 and GPR55 in RASFs present novel sites of action for anandamide and its metabolites and provide attractive targets for future therapeuticals in RA.