Role of HNF4alpha in the superinduction of the IL-1beta-activated iNOS gene by oxidative stress.

IL-1beta (interleukin-1beta) treatment of hepatocytes results in an NF-kappaB (nuclear factor-kappaB)-mediated activation of the iNOS (induced nitric oxide synthase) gene, and this increase in gene expression is further augmented by oxidative stress. Oxidative stress alone has no influence on the iNOS promoter, therefore indicating that the promoter needs to be primed by NF-kappaB. In this issue of the Biochemical Journal, Guo et al. extend their earlier work, showing that HNF4alpha (hepatocyte nuclear factor 4alpha) mediates the superinduction of iNOS observed by co-treating cells with IL-1b plus H2O2. A specific phosphorylation by p38 kinase at Ser-158 of HNF4alpha results in increased binding of HNF4alpha to the iNOS promoter, leading to enhanced transcription. The study by Guo et al. is the first to show definitively that HNF4alpha can be modulated to differentially activate specific genes. However, issues remain to determine the functional significance in vivo of the elevated iNOS activity, and the mechanism that governs the specificity of HNF4alpha towards the iNOS promoter element as compared with many other HNF4alpha target genes in the hepatocyte.