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43. Kongress der Deutschen Gesellschaft für Rheumatologie, 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie, 25. Wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie

02.-05. September 2015, Bremen

Pro-inflammatory cytokines up-regulate and sensitize metabotropic and ionotropic cannabinoid receptors in rheumatoid arthritis and osteoarthritis synovial fibroblasts

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  • Torsten Lowin - Innere Med I, Universitätsklinikum Regensburg, Regensburg
  • Tanja Späth - Innere Medizin I, Laboratory of Neuroendocrine Immunology and Experimental Rheumatology, Regensburg
  • Rainer H. Straub - Innere Med I, Universitätsklinikum Regensburg, Regensburg

Deutsche Gesellschaft für Rheumatologie. Deutsche Gesellschaft für Orthopädische Rheumatologie. Gesellschaft für Kinder- und Jugendrheumatologie. 43. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh); 29. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh); 25. wissenschaftliche Jahrestagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR). Bremen, 02.-05.09.2015. Düsseldorf: German Medical Science GMS Publishing House; 2015. DocER.20

doi: 10.3205/15dgrh074, urn:nbn:de:0183-15dgrh0741

Published: September 1, 2015

© 2015 Lowin et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at



Introduction: In collagen-induced arthritis, elevation of endocannabinoid levels improves clinical parameters and decreases synovial inflammation. Joint pain and inflammation are driven by pro-inflammatory cytokines like TNF, which is also involved in sensitizing transient receptor potential channels (TRP). Besides activating cannabinoid receptors type I and II (CB1 and CB2), endocannabinoids also bind several TRPs with TRPV1 and TRPA1 being the most important. In this study we demonstrate the influence of TNF, IL-1β and IFN-γ on the expression and function of metabotropic (CB1 and CB2) and ionotropic (TRPs) cannabinoid receptors.

Methods: Cannabinoid receptor expression was analyzed by western blotting. MMP-3 and cytokines were detected by ELISA. ERK 1/2 and p38 phosphorylation was assessed cell-based ELISA and western blotting. Calcium response was analyzed with Fura-2 staining.

Results: Prolonged incubation with TNF (10ng/ml, 7 days) significantly increased CB1, CB2, TRPV1, TRPA1 and FAAH protein (fatty acid amide hydrolase, important endocannabinoid metabolizing enzyme). Similar results were obtained with IL-1β and IFN-γ (1ng/ml and 10ng/ml, respectively). TNF-induced sensitization and up-regulation of TRPA1 was confirmed by an increase in intracellular calcium in response to TRPA1 agonist polygodial. While synovial fibroblasts only responded to high doses of TRPA1 agonist (50µM) without TNF pretreatment, TNF incubation (72h, 10ng/ml) not only increased Emax, but also lowered the activation threshold of the receptor to 1µM. Furthermore, TNF sensitized synovial fibroblasts to the action of the endocannabinoid anandamide.

Conclusion: The observed up-regulation of metabotropic and ionotropic cannabinoid receptors by TNF might explain lack of effects under healthy/basal conditions. Activation of the cannabinoid receptor system might be an adaptation to the pro-inflammatory environment in rheumatoid arthritis and might help to resolve inflammation.