Modulation of NF-κB–Dependent Gene Expression by H 2 O 2 : A Major Role for a Simple Chemical Process in a Complex Biological Response

Abstract

We recently observed that H₂O₂ regulates inflammation via upexpression of a few NF-κB–dependent genes, while leaving expression of most NF-κB–dependent genes unaltered. Here we test the hypothesis that this differential gene expression depends on the apparent affinity of κB sites in the gene-promoter regions toward NF-κB. Accordingly, cells were transfected with three reporter plasmids containing κB sequences with different affinities for NF-κB. It was observed that the lower the affinity, the higher the range of TNF-α concentrations where H₂O₂ upregulated gene expression. Mathematical models reproduced the key experimental observations indicating that H₂O₂ upregulation ceased when NF-κB fully occupied the κB sites. In vivo, it is predicted that genes with high-affinity sites remain insensitive to H₂O₂, whereas genes with lower-affinity sites are upregulated by H₂O₂. In conclusion, a simple chemical mechanism is at the root of a complex biologic process such as differential gene expression caused by H₂O₂. Antioxid. Redox Signal. 11, 2043–2053.