PALMITATE STIMULATES INTERLEUKIN-6 PRODUCTION IN SKELETAL MUSCLE CELLS THROUGH ACTIVATION OF PROTEIN KINASE C AND NUCLEAR FACTOR kappa B

Introduction. The mechanisms by which elevated levels of free fatty acids in skeletal muscle cause insulin resistance are not well understood. In addition, accumulating evidence suggests a link between inflammation and type 2 diabetes, which could be involved in the development of this disorder. Material, methods and results. Exposure of C2C12 skeletal muscle cells to 0.5 mM palmitate increased mRNA levels (3.5-fold induction, p<0.05) and secretion (control 375 +/- 57 vs palmitate 1129 +/- 177 pg/ml, p<0.001) of the proinflammatory cytokine interleukin (IL)-6. Palmitate increased nuclear factor (NF)-kappa B activation and coincubation of the cells with palmitate and the NF-kappa B inhibitor pyrrolidine dithiocarbamate prevented both IL-6 expression and secretion. Furthermore, incubation of palmitate-treated cells with calphostin C, a strong and specific inhibitor of protein kinase C (PKC), and PMA, which down-regulates PKC in long-term incubations, abolished induction of IL-6 production. Finally, exposure of skeletal muscle cells to palmitate decreased mRNA and protein levels of GLUT4. However, in the presence of anti-IL-6 antibody, which neutralizes the biological activity of mouse IL-6 in cell culture, these reductions were prevented. Conclusions. These findings suggest that IL-6 may mediate several of the prodiabetic effects of palmitate.