The proinflammatory cytokine tumor necrosis factor-α increases the amount of glucose transporter-4 at the surface of muscle cells independently of changes in interleukin-6

TNF alpha is a proinflammatory cytokine secreted by macrophages in response to bacterial infection. Recently new evidence has emerged suggesting that stressed or injured myocytes produce TNF alpha that then acts as an autocrine and/or paracrine mediator. TNF alpha receptors types 1 and 2 are present in skeletal muscle cells, and muscle cells can secrete, in addition to TNF alpha, other cytokines such as IL-1 beta or IL-6. Furthermore, the plasma concentration of TNF alpha is elevated in insulin-resistant states associated with obesity and type 2 diabetes. Here we show that TNF alpha 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, TNF alpha did not affect the rate of proliferation or of apoptosis. The stimulatory effects of TNF alpha on cell surface GLUT4 and glucose uptake were blocked by nuclear factor-kappa B and p38MAPK pathway specific inhibitors (Bay 11-7082 and SB220025), and these two pathways were stimulated by TNF alpha. Furthermore, although TNF alpha increased IL-6 mRNA and protein expression, IL-6 did not mediate the effects of TNF alpha on cell surface GLUT4 levels, which also did not require de novo protein synthesis. The results indicate that TNF alpha can stimulate glucose uptake in L6 muscle cells by inducing GLUT4 translocation to the plasma membrane, possibly through activation of the nuclear factor-kappa B and p38MAPK signaling pathways and independently of the production of IL-6.