REGULATION OF EUKARYOTIC INITIATION FACTOR-II EXPRESSION DURING SEPSIS

Protein synthesis is stimulated at the level of peptide chain initiati on 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 liv er and skeletal muscle during sepsis by measuring the cellular content of eukaryotic initiation factor-2 (eIF-2), the extent of phosphorylat ion of the alpha-subunit of eIF-2, and the activity of eIF-2B. In skel etal muscle, neither the eIF-2 content nor the extent of phosphorylati on of eIF-2 alpha was altered during sepsis. However, a significant de crease (P < 0.001) in eIF-2B activity was observed in fast-twitch musc les. In liver, neither the extent of phosphorylation of eIF-2 alpha no r the activity of eIF-2B was different in rats with a sterile or septi c abscess compared with control. However, the amount of eIF-2 in liver was increased in both sterile inflammation and sepsis. The relative a bundance of eIF-2 alpha mRNA was not increased in either condition com pared with control. Analysis of the distribution of eIF-2 alpha mRNA f rom control rats revealed that only similar to 40% of the message was associated with polysomes. Sterile inflammation or sepsis caused a 50% increase in the proportion of eIF-2 alpha mRNA associated with the po lysomes compared with control. The shift of message to polysomes in st erile inflammation or sepsis was not observed with p-actin mRNA, which was predominantly associated with polysomes in all conditions. The re sults suggest that inflammation and sepsis may induce hepatic eIF-2 co ntent by recruiting previously untranslated eIF-2 alpha mRNA into poly somes. Thus synthesis of eIF-2 alpha may be regulated through enhanced translation of eIF-2 alpha mRNA under these conditions.