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Rheumatology (Oxford). 2014 May;53(5):802-9. doi: 10.1093/rheumatology/ket447. Epub 2014 Jan 17.

Expression of cannabinoid receptor 2 and its inhibitory effects on synovial fibroblasts in rheumatoid arthritis.

Author information

1
Department of Rheumatology and Immunology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai 200433, China. dsm@medmail.com.cn.

Abstract

OBJECTIVE:

Recent studies have suggested immunomodulatory and anti-inflammatory effects of cannabinoid receptor 2 (CB2R) activation, which shows no psychoactivity. However, it is still unclear whether CB2R is expressed in fibroblast-like synoviocytes (FLS) of RA. In this study we investigated whether CB2R is expressed in FLS of RA, and whether CB2R activation modulates the function of RA-FLS.

METHODS:

Expression of CB2R in synovial tissue and FLS was studied by immunohistochemistry, western blotting and RT-PCR. mRNA expression levels of CB2R, IL-6 and MMPs were analysed by quantitative real-time RT-PCR. The protein concentrations of IL-6 and MMPs in culture supernatants were determined by ELISA. The protein levels of signal transducing molecules were assayed by western blotting.

RESULTS:

Both mRNA and protein expression of CB2R were found in synovial tissue and cultured FLS with slightly higher levels in RA patients than in OA patients. In cultured RA-FLS, the expression level of CB2R was up-regulated by stimulation with IL-1β, TNF-α or lipopolysaccharide. In vitro, HU-308, a selective CB2R agonist, inhibited IL-1β-induced proliferation of RA-FLS as well as IL-1β-induced production of MMP-3, MMP-13 and IL-6 in RA-FLS in a dose-dependent manner. HU-308 also suppressed IL-1β-induced activation of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase in FLS.

CONCLUSION:

In RA-FLS, proinflammatory mediators up-regulate the expression of CB2R, which negatively regulates the production of proinflammatory cytokines and MMPs. These data suggest that CB2R may be a potential therapeutic target of RA.

KEYWORDS:

cannabinoid receptor 2; fibroblast-like synoviocytes; interleukin 6; matrix metalloproteinases; rheumatoid arthritis

PMID:
24440992
DOI:
10.1093/rheumatology/ket447
[Indexed for MEDLINE]

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