THE HEAT-SHOCK RESPONSE INHIBITS INDUCIBLE NITRIC-OXIDE SYNTHASE GENE-EXPRESSION BY BLOCKING I-KAPPA-B DEGRADATION AND NF-KAPPA-B NUCLEAR TRANSLOCATION

We investigated the mechanisms by which the heat shock response inhibi ts inducible nitric oxide synthase (iNOS) gene expression. Incubation of cultured murine lung epithelium (MLE-15) at temperatures ranging fr om 39 to 43 degrees C, for 1 h, demonstrated that only severe thermal stress (41 to 43 degrees C) was sufficient to induce the heat shock re sponse. Thermal stress inhibited cytokine-mediated iNOS gene expressio n only when associated with induction of the heat shock response. Tran sient transfection assays with an iNOS promoter-reporter gene construc t demonstrated that the heat shock response inhibited cytokine-mediate d iNOS promoter activity. Electromobility gel shift assays demonstrate d that the heat shock response inhibited cytokine-mediated NF-kappa B nuclear translocation. The heat shock response also inhibited cytokine -mediated I kappa-B degradation. These data suggest that the heat shoc k response inhibits iNOS gene expression by transcriptional mechanisms involving the NF-kappa B/I kappa-B pathway. (C) 1997 Academic Press.