Artikel
Activation of the endocannabinoid system provides anti-inflammatory effects in synovial cells via modulation of ion channels TRPA1 and TRPV1 and subsequent changes in intracellular calcium levels
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Autoren
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Torsten Lowin
- Innere Medizin I, Laboratory of Neuroendocrine Immunology and Experimental Rheumatology, Regensburg
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Martin Apitz
- Innere Medizin I, Laboratory of Neuroendocrine Immunology and Experimental Rheumatology, Regensburg
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Tanja Späth
- Innere Medizin I, Laboratory of Neuroendocrine Immunology and Experimental Rheumatology, Regensburg
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Angelika Gräber
- Universitätsklinikum Regensburg, Klinik und Poliklinik für Innere Medizin I, Regensburg
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Rainer H. Straub
- University Hospital Regensburg, Lab. of Exp. Neuroendocrine Immunology and Rheumatology, Dept. of Internal Medicine, Regensburg
| Veröffentlicht: | 12. September 2014 |
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Gliederung
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Background: In collagen-induced arthritis, elevation of endocannabinoid levels improves clinical parameters and decreases synovial inflammation partly by activating the peripheral cannabinoid receptor CB2. However, several studies demonstrated beneficial effects of cannabinoids independent of CB1 or CB2. In rheumatoid arthritis (RA), synovial fibroblasts (SF) secrete IL-6, IL-8 and matrix metalloproteinases (MMPs) which are crucial for cartilage destruction. RASFs are sensitive to the action of cannabinoids and they express cannabinoid receptors type I and II (CB1 and CB2), the vanilloid receptor (TRPV1) as well as endocannabinoid degrading enzymes (FAAH and COX-2). Since anandamide (AEA) is found in RA synovial fluid we investigated how this endocannabinoid affects RASFs and mixed synovial cells' capacity to produce inflammatory mediators.
Methods: MMP-3 and cytokines were detected by ELISA. ERK 1/2, p38, CREB and cjun phosphorylation was assessed by proteome profiler analysis and cell-based ELISA.
Results: AEA did not modulate basal production of IL-6 and IL-8 but dose-dependently decreased TNF induced production of MMP-3, IL-6 and IL-8 in RASFs and OASFs under hypoxic conditions (1% O2). The efficacy of AEA was significantly enhanced by COX-2 inhibiton but not by FAAH inhibiton. The effects of AEA were not inhibited by CB1 or CB2 antagonism but were blocked by TRPV1 and TRPA1 antagonists in RASFs and OASFs. Furthermore, high AEA concentrations (>1µM) induced cell death which was blocked by the intracellular calcium chelating agent BAPTA-AM.
In mixed synovial cell cultures, AEA increased the production of TNF (100%) only in samples from patients with osteoarthritis (OA) but not RA. IL-6 and IL-8 production was reduced in OA and RA, which was enhanced by FAAH inhibition.
Analysis of intracellular signaling pathways revealed inhibitory effects of AEA on p38 and ERK1/2 phosphorylation after TNF stimulation
Conclusion: AEA promotes an antiinflammatory phenotype in RASFs, OASFs and mixed synovial cells by activating/desensitizing TRPV1 and TRPA1 under hypoxic conditions. This might be due to down-regulation of MAP kinase signaling after AEA treatment. Furthermore, COX-2 and FAAH inhibition are necessary to fully exploit the therapeutic potential of AEA. This might be important in RA where low oxygen and abundant cytokine expression up-regulate COX-2 in the joint.
