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The effect of multimeric adiponectin isoforms and leptin on the function of rheumatoid fibroblast-like synoviocytes

Objectives: To evaluate the effects of physiologically relevant concentrations of multimeric adiponectin isoforms and leptin on the function of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Method: FLS, isolated from the synovial tissue of 21 RA patients, were stimulated for 24 h with interleukin (IL)-1β (1 ng/mL) and adiponectin isoforms [fraction enriched with high-molecular-weight (HMW) oligomers and middle-molecular-weight (MMW) hexamers or low-molecular-weight (LMW) trimers, 10 μg/mL each], or leptin (10 ng/mL), either separately or in a combination of IL-1β and the respective adipokine. Moreover, cells were pre-treated for 24 h with adipokines, then stimulated for 8 h with IL-1β. The concentrations of IL-6, IL-8, matrix metalloproteinase (MMP)-3, and dickkopf (DKK)-1, an inhibitor of osteoblastogenesis, in culture supernatants, as well as the concentrations of leptin, HMW, MMW, and LMW adiponectin in sera and synovial fluid (SF) samples, were measured by specific enzyme-linked immunosorbent assays (ELISAs). Results: In comparison with sera, SF samples contained similar amounts of leptin, lower amounts of total adiponectin but a higher proportion of the LMW isoform. Separately added IL-1β and HMW/MMW adiponectin, but not LMW adiponectin or leptin, up-regulated the release of IL-6, IL-8, and MMP-3 from FLS but no synergy was observed in co-stimulation experiments. However, pre-treatment of FLS with HMW/MMW or LMW significantly raised the IL-1β-triggered secretion of MMP-3 and IL-6 or MMP-3, respectively. Conclusions: Adiponectin not only triggers pro-inflammatory and pro-destructive activities of rheumatoid FLS but also pre-disposes these cells to a stronger response to IL-1β. Thus, it is likely that adiponectin is more important in the initiation phase than in the chronic phase of RA.