Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells.
The exercise-induced interleukin (IL)-6 production and secretion within skeletal muscle fibers has raised the question of a putative tissue-specific function of IL-6 in the energy metabolism of the muscle during and after the exercise. In the present study, we followed the hypothesis that IL-6 signaling may directly interact with insulin receptor substrate (IRS)-1, a keystone in the insulin signaling cascade. We showed that IL-6 induces a rapid recruitment of IRS-1 to the IL-6 receptor complex in cultured skeletal muscle cells. Moreover, IL-6 induced a rapid and transient phosphorylation of Ser-318 of IRS-1 in muscle cells and in muscle tissue, but not in the liver of IL-6-treated mice, probably via the IL-6-induced co-recruitment of protein kinase C-delta. This Ser-318 phosphorylation improved insulin-stimulated Akt phosphorylation and glucose uptake in myotubes since transfection with an IRS-1/Glu-318 mutant simulating a permanent phospho-Ser-318 modification increased Akt phosphorylation and glucose uptake. Noteworthily, two inhibitory mechanisms of IL-6 on insulin action, phosphorylation of the inhibitory Ser-307 residue of IRS-1 and induction of SOCS-3 expression, were only found in liver but not in muscle of IL-6-treated mice. Thus, the data provided evidence for a possible molecular mechanism of the physiological metabolic effects of IL-6 in skeletal muscle, thereby exerting short term beneficial effects on insulin action.
Weigert
Cora
C
Department of Internal Medicine, Division of Endocrinology, Metabolism, Pathobiochemistry and Clinical Chemistry, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Germany. caweiger@med.uni-tuebingen.de
Hennige
Anita M
AM
Lehmann
Rainer
R
Brodbeck
Katrin
K
Baumgartner
Frank
F
Schaüble
Myriam
M
Häring
Hans U
HU
Schleicher
Erwin D
ED
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003847:Deoxyglucose / Q000493:pharmacokinetics; D005947:Glucose / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000737:chemistry / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6 / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D015233:Models, Statistical; D018482:Muscle, Skeletal / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D051745:Protein Kinase C-delta / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000737:chemistry; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D015850:Interleukin-6; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014443:Tyrosine; D012694:Serine; D003847:Deoxyglucose; D051057:Proto-Oncogene Proteins c-akt; D051745:Protein Kinase C-delta; D005947:Glucose