title: Leptin stimulates interleukin-6 production via janus kinase 2/signal transducer and activator of transcription 3 in rheumatoid synovial fibroblasts.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Muraoka
authors.forename: Natsuko
authors.initials: N
authors.lastname: Kusunoki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kawai
mesh_terms: D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D061251:Primary Cell Culture; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013583:Synovial Membrane / Q000166:cytology
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D020738:Leptin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054411:Receptors, Leptin; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019869:Phosphatidylinositol 3-Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases