The Heat Shock Response Inhibits Inducible Nitric Oxide Synthase Gene Expression by Blocking Iκ-B Degradation and NF-κB Nuclear Translocation

Abstract

We investigated the mechanisms by which the heat shock response inhibits inducible nitric oxide synthase (iNOS) gene expression. Incubation of cultured murine lung epithelium (MLE-15) at temperatures ranging from 39 to 43° C, for 1 h, demonstrated that only severe thermal stress (41 to 43° C) was sufficient to induce the heat shock response. Thermal stress inhibited cytokine-mediated iNOS gene expression only when associated with induction of the heat shock response. Transient transfection assays with an iNOS promoter-reporter gene construct demonstrated that the heat shock response inhibited cytokine-mediated iNOS promoter activity. Electromobility gel shift assays demonstrated that the heat shock response inhibited cytokine-mediated NF-κB nuclear translocation. The heat shock response also inhibited cytokine-mediated Iκ-B degradation. These data suggest that the heat shock response inhibits iNOS gene expression by transcriptional mechanisms involving the NF-κB/Iκ-B pathway.