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      The synthetic cannabinoid WIN55,212-2 mesylate decreases the production of inflammatory mediators in rheumatoid arthritis synovial fibroblasts by activating CB 2, TRPV1, TRPA1 and yet unidentified receptor targets

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          Abstract

          Background

          In rheumatoid arthritis (RA), synovial fibroblasts (SF) secrete large amounts of IL-6, IL-8 and matrix metalloproteinases (MMPs) which are crucial for cartilage destruction. RASFs are sensitive to the action of cannabinoids and they not only express cannabinoid receptors type I and II (CB 1 and CB 2) but also transient receptor potential channels type vanilloid (TRPV1) and ankyrin (TRPA1). The synthetic cannabinoid WIN55,212-2 mesylate (WIN) demonstrated strong anti-inflammatory effects in monocytes and synovial fibroblasts only in high concentrations in a non-cannabinoid receptor dependent manner. In this study we assessed the ability of WIN to modulate cytokine and MMP-3 production in SFs over a wide concentration range and identified specific receptor targets that mediate the effects of this synthetic cannabinoid.

          Methods

          MMP-3, IL-6 and IL-8 were determined by ELISA. Adhesion was measured by the XCELLigence system. Proliferation was assessed by cell titer blue assays.

          Results

          WIN significantly reduced TNF-induced IL-6, IL-8 and MMP-3 production in concentrations below 2 μM, while higher concentrations completely inhibited production of IL-6 and IL-8 but increased extracellular MMP-3 levels. The inhibitory effect at low concentrations (<2 μM) was independent on activation of either CB 1 or CB 2 but was attenuated by TRPV1 or TRPA1 inhibition in OASFs and RASFs. The effects of high concentrations of WIN on cytokine and MMP-3 production were decreased by the calcium chelating agent BAPTA, the AMPK activator metformin, the TRPA1 antagonist A967079 and the CB 2 antagonist COR170. Furthermore, fetal calf serum content in culture media strongly influenced the efficacy of WIN at high concentrations. In addition, high concentrations of WIN also diminished SF adhesion and proliferation without altering cell viability whereas low concentrations promoted SF adhesion without any influence on proliferation.

          Conclusion

          The synthetic cannabinoid WIN in low concentrations exhibits anti-inflammatory effects in synovial fibroblasts independent of CB 1 and CB 2 while CB 2 and yet unidentified receptor targets are responsible for WIN effects in micromolar concentrations. Our results indicate a TRPV1/TRPA1 dependent mechanism of SF regulation that might be coupled to cellular energy status and calcium content.

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          Most cited references30

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          The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

          The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
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            Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis.

            Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.
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              Macrophages in rheumatoid arthritis

              The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains an efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage.
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                Author and article information

                Contributors
                +49 2118106150 , torsten.lowin@med.uni-duesseldorf.de
                Journal
                J Inflamm (Lond)
                J Inflamm (Lond)
                Journal of Inflammation (London, England)
                BioMed Central (London )
                1476-9255
                5 May 2016
                5 May 2016
                2016
                : 13
                : 15
                Affiliations
                [ ]Funktionsbereich & Hiller Forschungszentrum für Rheumatologie, Life Science Center, University Hospital Duesseldorf, Merowingerplatz1A, 1. Etage, D-40225 Duesseldorf, Germany
                [ ]Laboratory of Experimental Rheumatology and Neuroendocrine Immunology, University Hospital of Regensburg, D-93053 Regensburg, Germany
                Article
                114
                10.1186/s12950-016-0114-7
                4858820
                27158245
                56d48389-85c8-4a5d-9e70-e26ffc8133de
                © Lowin et al. 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 August 2015
                : 11 February 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (DE);
                Award ID: LO 1686/2-1
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Immunology
                cannabinoid,synovial fibroblasts,cytokines,mmp,proliferation,arthritis
                Immunology
                cannabinoid, synovial fibroblasts, cytokines, mmp, proliferation, arthritis

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