Cytokine-triggered decreases in levels of phosphorylated eukaryotic initiation factor 4G in skeletal muscle during sepsis

Chronic septic abscess formation causes an inhibition of protein synthesis in gastrocnemius that is not observed in rats with a sterile abscess. The inhibition is associated with an impaired translation initiation. The present study was designed to investigate the effects of sepsis on the level of phosphorylated eukaryotic initiation factor (elF) 4G in gastrocnemius after induction of a chronic intra-abdominal sterile or septic abscess as a possible mechanism to account for the impairment of translation initiation during sepsis. The extent of phosphorylated elF4G was reduced by more than 50% (P < 0.05) and 68% (P < 0.01) in gastrocnemius after 3 and 5 days, respectively, and returned to control values after 14 days of abscess formation in septic rats compared with sterile inflammatory animals. To examine the mediators of the septic process contributing to the decreased levels of phosphorylated elF4G, the cytokine response to sepsis was pharmacologically modulated. First, treatment of septic rats with tumor necrosis factor (TNF) binding protein or interleukin (IL) 1 receptor antagonist increased the level of phosphorylated elF4G. Second, infusion of TNF-alpha for 24 h in control rats resulted in a 70% decrease in phosphorylated elF4G. Third, infusion of IL-1ra. led to an increase in the level of phosphorylation of elF4G in rats infused with TNF-alpha. Taken together, the data indicate that a cytokine-dependent decrease in the steady state phosphorylation of elF4G is a possible mechanism accounting for the inhibition of skeletal muscle protein synthesis during sepsis. Furthermore, the findings support a role of IL-1 as the proinflammatory mediator responsible for the reduced level of phosphorylated elF4G.