OBJECTIVE: The
cytokine interleukin-6 (IL-6) stimulates
AMP-activated protein kinase (
AMPK) and
insulin signaling in
skeletal muscle, both of which result in the
activation of
endothelial nitric oxide synthase (eNOS). 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 (HAECs) 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 or 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 were mediated by the cell-specific, additive effects of IL-6 and
insulin because this treatment markedly increased
tumor necrosis factor (
TNF)-alpha
protein expression in HAECs without any effect on
TNF-alpha in
skeletal muscle. When HAECs were incubated with a TNF-alpha-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 because of increased
TNF-alpha expression.
