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Leptin stimulates interleukin-6 production via janus kinase 2/signal transducer and activator of transcription 3 in rheumatoid synovial fibroblasts
S. Muraoka, N. Kusunoki, H. Takahashi, K. Tsuchiya, S. Kawai
CER6158
2013 Vol.31, N°4
PI 0589, PF 0595
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PMID: 23622344 [PubMed]
Received: 22/11/2012
Accepted : 05/02/2013
In Press: 22/04/2013
Published: 30/07/2013
Abstract
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.
