Regulation of eukaryotic initiation factor-2 expression during sepsis

Protein synthesis is stimulated at the level of peptide chain initiation in livers from rats with a sterile or septic abscess. In contrast, peptide chain initiation is inhibited in fast-twitch skeletal muscles from septic rats. We investigated the possible mechanisms responsible for these differential changes in peptide chain initiation between liver and skeletal muscle during sepsis by measuring the cellular content of eukaryotic initiation factor-2 (eIF-2), the extent of phosphorylation of the α-subunit of eIF-2, and the activity of eIF-2B. In skeletal muscle, neither the eIF-2 content nor the extent of phosphorylation of eIF-2α was altered during sepsis. However, a significant decrease (P < 0.001) in eIF-2B activity was observed in fast-twitch muscles. In liver, neither the extent of phosphorylation of eIF-2α nor the activity of eIF-2B was different in rats with a sterile or septic abscess compared with control. However, the amount of eIF-2 in liver was increased in both sterile inflammation and sepsis. The relative abundance of eIF-2α mRNA was not increased in either condition compared with control. Analysis of the distribution of eIF-2α mRNA from control rats revealed that only ~40% of the message was associated with polysomes. Sterile inflammation or sepsis caused a 50% increase in the proportion of eIF-2α mRNA associated with the polysomes compared with control. The shift of message to polysomes in sterile inflammation or sepsis was not observed with β-actin mRNA, which was predominantly associated with polysomes in all conditions. The results suggest that inflammation and sepsis may induce hepatic eIF-2 content by recruiting previously untranslated eIF- 2α mRNA into polysomes. Thus synthesis of eIF-2α may be regulated through enhanced translation of eIF-2α mRNA under these conditions.