Abstract
Exogenous adenosine and its metabolite inosine exert anti-inflammatory effects in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We analyzed whether these cells are able to synthesize adenosine/inosine and which adenosine receptors (ARs) contribute to anti-inflammatory effects. The functionality of synthesizing enzymes and ARs was tested using agonists/antagonists. Both OA and RA cells expressed CD39 (converts ATP to AMP), CD73 (converts AMP to adenosine), ADA (converts adenosine to inosine), ENT1/2 (adenosine transporters), all AR subtypes (A1, A2A, A2B and A3) and synthesized predominantly adenosine. The CD73 inhibitor AMPCP significantly increased IL-6 and decreased IL-10 in both cell types, while TNF only increased in RA cells. The ADA inhibitor DAA significantly reduced IL-6 and induced IL-10 in both OA and RA cells. The A2AAR agonist CGS 21680 significantly inhibited IL-6 and induced TNF and IL-10 only in RA, while the A2BAR agonist BAY 60-6583 had the same effect in both OA and RA. Taken together, OA and RA synoviocytes express the complete enzymatic machinery to synthesize adenosine/inosine; however, mainly adenosine is responsible for the anti- (IL-6 and IL-10) or pro-inflammatory (TNF) effects mediated by A2A- and A2BAR. Stimulating CD39/CD73 with simultaneous ADA blockage in addition to TNF inhibition might represent a promising therapeutic strategy.
Highlights
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune disorder affecting around 1% of the population worldwide [1]
In order to analyze whether synoviocytes are capable of synthesizing adenosine and inosine, cells were examined for the presence of CD39 and CD73
After cultivation for 24 h under hypoxia, synovial cells spontaneously released physiologically relevant amounts of adenosine and inosine; OA synoviocytes synthesized significantly higher nucleoside concentrations compared to rheumatoid arthritis (RA) cells (Figure 1C)
Summary
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory autoimmune disorder affecting around 1% of the population worldwide [1]. Uncontrolled active synovial inflammation in RA results in joint damage and causes chronic pain, disabilities, decreased quality of life, as well as different comorbidities such as cardiovascular, gastrointestinal, renal and pulmonary diseases or fatigue [3]. After RA induction by an initiating factor such as infection or environmental exposure (e.g., smoking or chronic stress) [5], synovial lining cells become activated and start to release matrix-degrading enzymes, pro-inflammatory cytokines and chemokines, which in turn recruit immune cells [6]. Synovial cells in inflamed synovium contain fibroblasts, macrophages, B- and T lymphocytes and dendritic cells, which release different cytokines [8,9]. The more anti-inflammatory IL-10 is synthesized mainly by B cells and antiinflammatory M2 macrophages, while highly pro-inflammatory cytokine TNF is released by T cells, monocytes, and M1 macrophages [10,11]
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