title: The proinflammatory cytokine tumor necrosis factor-alpha increases the amount of glucose transporter-4 at the surface of muscle cells independently of changes in interleukin-6.
abstract: TNFalpha is a proinflammatory cytokine secreted by macrophages in response to bacterial infection. Recently new evidence has emerged suggesting that stressed or injured myocytes produce TNFalpha that then acts as an autocrine and/or paracrine mediator. TNFalpha receptors types 1 and 2 are present in skeletal muscle cells, and muscle cells can secrete, in addition to TNFalpha, other cytokines such as IL-1beta or IL-6. Furthermore, the plasma concentration of TNFalpha is elevated in insulin-resistant states associated with obesity and type 2 diabetes. Here we show that TNFalpha increased the amount of glucose transporter (GLUT)-4 at the plasma membrane and also glucose uptake in the L6 muscle cell line stably expressing GLUT4 tagged with the c-myc epitope. Regardless of the state of differentiation of the L6 cells, TNFalpha did not affect the rate of proliferation or of apoptosis. The stimulatory effects of TNFalpha on cell surface GLUT4 and glucose uptake were blocked by nuclear factor-kappaB and p38MAPK pathway specific inhibitors (Bay 11-7082 and SB220025), and these two pathways were stimulated by TNFalpha. Furthermore, although TNFalpha increased IL-6 mRNA and protein expression, IL-6 did not mediate the effects of TNFalpha on cell surface GLUT4 levels, which also did not require de novo protein synthesis. The results indicate that TNFalpha can stimulate glucose uptake in L6 muscle cells by inducing GLUT4 translocation to the plasma membrane, possibly through activation of the nuclear factor-kappaB and p38MAPK signaling pathways and independently of the production of IL-6.
authors.affiliation: Departament de Fisiologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Roher
authors.forename: Victor
authors.initials: V
authors.lastname: Samokhvalov
authors.forename: Mònica
authors.initials: M
authors.lastname: Díaz
authors.forename: Simon
authors.initials: S
authors.lastname: MacKenzie
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
authors.forename: Josep V
authors.initials: JV
authors.lastname: Planas
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D032448:Myoblasts, Skeletal / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D015850:Interleukin-6; D016328:NF-kappa B; D012333:RNA, Messenger; C495694:Slc2a4 protein, rat; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D005947:Glucose