Abstract

Objective. The cytokine interleukin-6 (IL-6) stimulates AMP activated protein kinase (AMPK) and insulin signaling in skeletal muscle, both which result in the activation of endothelial nitric oxide synthase (eNOS). Accordingly, we hypothesized that IL-6 promotes endothelial cell signaling and capillary recruitment in vivo, contributing to increased glucose uptake.

Research Design and Methods. The effect of IL-6, with and without insulin, on AMPK, insulin and eNOS signaling in, and nitric oxide (NO) release from, human aortic endothelial cells (HAEC) was examined. The physiological significance of these in vitro signaling events was assessed by measuring capillary recruitment in rats during control and euglycemic hyperinsulinemic clamps with and without IL-6 infusion.

Results. IL-6 blunted increases in insulin signaling, eNOS phosphorylation (Ser¹¹⁷⁷) and NO production and reduced phosphorylation of AMPK in HAEC in vitro, and capillary recruitment in vivo. In contrast, IL-6 increased Akt phosphorylation (Ser⁴⁷³) in hindlimb skeletal muscle and enhanced whole body glucose disappearance and glucose uptake during the clamp. The differences in endothelial cell and skeletal muscle signaling was mediated by the cell specific, additive effects of IL-6 and insulin, since this treatment markedly increased TNF-α protein expression in HAEC without any effect on TNF-α in skeletal muscle. Furthermore, when HAEC were incubated with a TNF-α neutralizing antibody, the negative effects of IL-6 on eNOS signaling were abolished.

Conclusions. In the presence of insulin, IL-6 contributes to aberrant endothelial cell signaling, due to increased TNF-α expression.