Background Classical adipokines, leptin and adiponectin, are thought to originate principally from white adipose tissue. Although both of them have been suggested to participate in pathogenesis of rheumatoid arthritis (RA), their role is still controversial . Data concerning leptin contribution are inconsistent. Adiponectin was reported to exert mostly proinflammatory and prodestructive effects, but little is known about biological activities of its low (LMW) and high molecular (HMW) complexes. We have recently reported that not only rheumatoid synovial membrane (SM), but also articular adipose tissue (AAT) releases biologically active factors, including leptin and adiponectin . However, it is not known whether periarticular subcutaneous adipose tissue (ScAT) shows similar secretory activity.
Objectives (1) To compare the production of leptin and adiponectin by rheumatoid ScAT, AAT, and SM explants. (2) To investigate the effects of leptin and adiponectin on rheumatoid fibroblast-like synoviocytes (FLS) function.
Methods Tissue specimens were obtained from the knee joints of 60 patients with established rheumatoid arthritis (RA) who were undergoing total joint replacement surgery. Tissue explants (100 mg/ml/well) were cultured in medium (DMEM) alone or treated for 18 h with recombinant human cytokines relevant to RA pathogenesis: IL-1β, TNF, interferon γ or IL-15, applied at 1, 10 or 40 ng/ml concentrations, respectively. After the treatment leptin and adiponectin concentrations were measured in tissue explants culture supernatants by ELISA. Moreover, RA FLS isolated from SM specimens were stimulated for 18 h with recombinant human leptin, HMW or LMW adiponectin (0.1-10 ng/ml), then the culture supernatants were collected and concentrations of proinflammatory cytokines (IL-6, IL-8) and connective tissue degrading enzyme, matrix metalloproteinase-3 (MMP-3), were measured using specific ELISA.
Results Spontaneous leptin secretion by AAT, ScAT and SM explants was similar ($≈ $200 pg/100 mg), while SM secreted twice as much adiponectin as AAT and ScAT (mean ± SEM equal 7966±1016, 4649±340 and 4962±585 pg/100 mg, respectively). The release of both adipokines from SM did not change upon stimulation, while all applied stimuli raised their secretion from AAT and ScAT. In these conditions AAT and ScAT produced twice as much leptin but still less adiponectin than SM. Exogenously added adipokines exerted little (leptin), moderate (HMW adiponectin) or strong (LMW adiponectin) stimulatory effects on IL-6, IL-8 and MMP-3 secretion by RA FLS. Interestingly, the effect of LMW adiponectin (10 ng/ml) was comparable to that exerted by TNF.
Conclusions Joint-associated adipose tissues (AAT and ScAT) are highly reactive to proinflammatory cytokines and upon stimulation their contribution to local adipokine pool is substantial. In RA joints adiponectin, especially of LMW, may contribute to synovitis and tissue destruction owing to potent up-regulation of IL-6, IL-8 and MMP-3 secretion by FLS.
Acknowledgements This work was sponsored by grant No N N402 369938 from the Polish Ministry of Science and Higher Education.
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Disclosure of Interest None Declared