Effects of age on the posttranscriptional regulation of CCAAT/Enhancer binding protein α and CCAAT/Enhancer binding protein β isoform synthesis in control and LPS-Treated livers

The CCAAT/enhancer binding protein alpha (C/EBP alpha) and CCAAT/enhancer binding protein beta (C/EBP beta) mRNAs are templates for the differential translation of several isoforms. Immunoblotting detects C/EBP alpha s with molecular masses of 42, 38, 30, and 20 kDa and C/EBP beta s of 35, 20, and similar to 8.5 kDa. The DNA-binding activities and pool levels of p42(C/EBP alpha) and p30(C/EBP alpha) 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/EBP alpha and C/EBP beta 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/EBP alpha) levels and binding activity, whereas those of p20(C/EBP alpha) and p20(C/EBP beta) are increased. However, translation of 42-kDa C/EBP alpha is not down-regulated on polysomes, suggesting that aging may affect its nuclear translocation. Furthermore, recovery of the C/EBP alpha- and C/EBP beta-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/EBP alpha and C/EBP beta isoforms. This result suggests that normal aging liver exhibits characteristics of chronic stress and a severe inability to recover from an inflammatory challenge.