title: IL-6 induction of TLR-4 gene expression via STAT3 has an effect on insulin resistance in human skeletal muscle.
abstract: We investigated the cytokines and mechanisms involved in the induction of insulin resistance in human skeletal muscle. Ten subjects with impaired glucose tolerance (IGT) and 10 control subjects were recruited. We performed biopsies on the vastus lateralis muscle and used immunoblotting to determine levels of inflammatory cytokines, Toll-like receptor (TLR) gene expression, and insulin signaling. We also used a human myotube culture system to examine the mechanisms underlying TLR-4 gene expression. To identify inflammatory cytokines associated with insulin resistance, we measured the levels of IL-6, TNF-α, TLR-2, and TLR-4 in skeletal muscle from non-obese patients with IGT and control subjects. Levels of IL-6, TNF-α, and TLR-4, but not TLR-2, were significantly increased in the IGT group. Insulin resistance decreased significantly in HSMMs following long-term IL-6 treatment. TLR-4 gene expression was significantly increased in human skeletal muscle myoblasts (HSMMs) treated with IL-6. To determine the main signaling pathway for IL-6-induced TLR-4 gene expression, we examined several signaling factors associated with IL-6 signaling pathways. We found that the active form of "signal transducer and activator of transcription 3" (STAT3) was increased. "Stattic" (a STAT3 inhibitor) markedly inhibited TLR-4 gene expression. IL-6 induction of TLR-4 gene expression via STAT3 is one of the main mechanisms underlying insulin resistance in human skeletal muscle.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, College of Medicine, Myongji Hospital, Kwandong University, Goyang, South Korea.
authors.forename: Tae Ho
authors.initials: TH
authors.lastname: Kim
authors.forename: Sung E
authors.initials: SE
authors.lastname: Choi
authors.forename: Eun Suk
authors.initials: ES
authors.lastname: Ha
authors.forename: Jong Gab
authors.initials: JG
authors.lastname: Jung
authors.forename: Seung Jin
authors.initials: SJ
authors.lastname: Han
authors.forename: Hae Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Dae Jung
authors.initials: DJ
authors.lastname: Kim
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
authors.forename: Kwan Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000032:analysis / Q000494:pharmacology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D032446:Myoblasts / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000032:analysis; D051197:Toll-Like Receptor 4 / Q000032:analysis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D007328:Insulin; D015850:Interleukin-6; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha