Evidence for a role of heat shock factor 1 in inhibition of NF-kappaB pathway during heat shock response-mediated lung protection.
Heat shock transcription factor (HSF)-1 is recognized as a central component of the heat shock response, which protects against various harmful conditions. However, the mechanisms underlying the protection and the role of HSF-1 in these mechanisms have not yet been clearly elucidated. Using HSF-1 knockout mice (Hsf1(-/-)), we examined whether heat shock response-mediated lung protection involved an inhibition of the proinflammatory pathway via an interaction between HSF-1 and NF-kappaB, in response to cadmium insult. The HSF-1-dependent protective effect against intranasal instillation of cadmium (10 and 100 microg/mouse) was demonstrated by the higher protein content (1.2- and 1.4-fold), macrophage (1.6- and 1.9-fold), and neutrophil (2.6- and 1.8-fold) number in bronchoalveolar fluids, higher lung wet-to-dry weight ratio, and more severe lung damage evaluated by histopathology in Hsf1(-/-) compared with wild-type animals. These responses were associated with higher granulocyte/macrophage colony-stimulating factor (GM-CSF; 1.7-fold) but not TNF-alpha concentrations in bronchoalveolar fluids of Hsf1(-/-) mice compared with those of wild-type animals, indicating that HSF-1 behaved as a repressor of specific cytokine production in our model. To further investigate the mechanism of GM-CSF repression, we analyzed the NF-kappaB activity and IkappaB stability. The DNA binding NF-kappaB activity, in particular p50 homodimer activity, was higher in Hsf1(-/-) mice than in wild-type mice after cadmium exposure. These results provide a first line of evidence that mechanisms of lung protection depending on HSF-1 involve specific cytokine repression via inhibition of NF-kappaB activation in vivo.
Wirth
Delphine
D
Unit of Pharmacology, Pharmacotherapy, and Toxicology, Department of Functional Sciences, Faculty of Veterinary Medicine, University of Liege, Belgium.
Bureau
Fabrice
F
Melotte
Dorothée
D
Christians
Elisabeth
E
Gustin
Pascal
P
D000281:Administration, Intranasal; D000818:Animals; D002104:Cadmium; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D016328:NF-kappa B; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D002104:Cadmium; D016178:Granulocyte-Macrophage Colony-Stimulating Factor