Effects of age on the posttranscriptional regulation of CCAAT/enhancer binding protein alpha and CCAAT/enhancer binding protein beta isoform synthesis in control and LPS-treated livers.

The CCAAT/enhancer binding protein alpha (C/EBPalpha) and CCAAT/enhancer binding protein beta (C/EBPbeta) mRNAs are templates for the differential translation of several isoforms. Immunoblotting detects C/EBPalphas with molecular masses of 42, 38, 30, and 20 kDa and C/EBPbetas of 35, 20, and approximately 8.5 kDa. The DNA-binding activities and pool levels of p42(C/EBPalpha) and p30(C/EBPalpha) in control nuclear extracts decrease significantly whereas the binding activity and protein levels of the 20-kDa isoforms increase dramatically with LPS treatment. Our studies suggest that the LPS response involves alternative translational initiation at specific in-frame AUGs, producing specific C/EBPalpha and C/EBPbeta isoform patterns. We propose that alternative translational initiation occurs by a leaky ribosomal scanning mechanism. We find that nuclear extracts from normal aged mouse livers have decreased p42(C/EBPalpha) levels and binding activity, whereas those of p20(C/EBPalpha) and p20(C/EBPbeta) are increased. However, translation of 42-kDa C/EBPalpha is not down-regulated on polysomes, suggesting that aging may affect its nuclear translocation. Furthermore, recovery of the C/EBPalpha- and C/EBPbeta-binding activities and pool levels from an LPS challenge is delayed significantly in aged mouse livers. Thus, aged livers have altered steady-state levels of C/EBPalpha and C/EBPbeta isoforms. This result suggests that normal aging liver exhibits characteristics of chronic stress and a severe inability to recover from an inflammatory challenge.