Leptin stimulates interleukin-6 production via janus kinase 2/signal transducer and activator of transcription 3 in rheumatoid synovial fibroblasts.

Objectives: The aim of this study was to determine the influence of leptin on the production of proinflammatory cytokines by rheumatoid synovial fibroblasts (RSFs).

Methods: Synovial tissue was obtained from patients with rheumatoid arthritis (RA). Leptin receptor mRNAs were detected by reverse transcription-polymerase chain reaction (RT-PCR). Productions of mRNA and protein of interleukin (IL)-1β, tumour necrosis factor-α (TNF-α), and IL-6 in the culture medium were detected by real-time PCR and ELISA kit, respectively. Small interfering RNA (siRNA) was transfected into RSF to down-regulate the expression of leptin receptor. Effects of inhibitors of janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) on IL-6 production were evaluated. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in RSF were determined by Western blot analysis.

Results: We detected leptin receptor mRNAs in RSFs. Expression of IL-1β and IL-6 mRNA was enhanced in a concentration-dependent manner by addition of leptin to RSFs. IL-6 secretion by RSFs showed an increase after leptin stimulation. Leptin-induced production of IL-6 by RSFs was decreased after exposure to siRNA targeting leptin receptor (Ob-Rb). A JAK2 inhibitor, but not PI3K and MAPK inhibitors, decreased leptin-induced IL-6 production. Enhanced phosphorylation of STAT3 was observed in RSFs after stimulation by leptin.

Conclusions: Leptin may be one of the proinflammatory cytokines that up-regulates IL-6 production in RSFs via activation of JAK2/STAT3. Leptin and JAK/STAT pathway may represent a new alternative therapeutic target in the treatment of RA.