Age-dependent regulation of antioxidant genes by p38α MAPK in the liver

p38 alpha is a redox sensitive MAPK activated by pro-inflammatory cytokines and environmental, genotoxic and endoplasmic reticulum stresses. The aim of this work was to assess whether p38 alpha controls the antioxidant defense in the liver, and if so, to elucidate the mechanism(s) involved and the age-related changes. For this purpose, we used liver-specific p38 alpha-deficient mice at two different ages: young-mice (4 months-old) and old-mice (24 months-old). The liver of young p38 alpha knock-out mice exhibited a decrease in GSH levels and an increase in GSSG/GSH ratio and malondialdehyde levels. However, old mice deficient in p38 alpha had higher hepatic GSH levels and lower GSSG/GSH ratio than young p38 alpha knock-out mice. Liver-specific p38 alpha deficiency triggered a dramatic down-regulation of the mRNAs of the key antioxidant enzymes glutamate cysteine ligase, superoxide dismutase 1, superoxide dismutase 2, and catalase in young mice, which seems mediated by the lack of p65 recruitment to their promoters. Nrf-2 nuclear levels did not change significantly in the liver of young mice upon p38 alpha deficiency, but nuclear levels of phospho-p65 and PGC-1 alpha decreased in these mice. p38 alpha-dependent activation of NF-kappa B seems to occur through classical I kappa B Kinase and via ribosomal S6 kinasel and AKT in young mice. However, unexpectedly the long-term deficiency in p38 alpha triggers a compensatory up-regulation of antioxidant enzymes via NF-kappa B activation and recruitment of p65 to their promoters. In conclusion, p38 alpha MAPK maintains the expression of antioxidant genes in liver of young animals via NF-kappa B under basal conditions, whereas its long-term deficiency triggers compensatory up-regulation of antioxidant enzymes through NF-kappa B.