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 inhibits inducible nitric oxide synthase (iNOS) gene expression. Incubation of cultured murine lung epithelium (MLE-15) at temperatures ranging from 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 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-kappa B nuclear translocation. The heat shock response also inhibited cytokine-mediated I kappa-B degradation. These data suggest that the heat shock response inhibits iNOS gene expression by transcriptional mechanisms involving the NF-kappa B/ I kappa-B pathway.
Wong
H R
HR
Division of Critical Care Medicine, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Ryan
M
M
Wispé
J R
JR
D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D016207:Cytokines / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000096:biosynthesis*; D006358:Hot Temperature; D006868:Hydrolysis; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051841:Transcription Factor RelB; D014157:Transcription Factors
D016207:Cytokines; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497594:Relb protein, mouse; D014157:Transcription Factors; D051841:Transcription Factor RelB; D019001:Nitric Oxide Synthase