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This Article Full Text Full Text (PDF) All Versions of this Article: 287/5/L953    most recent 00184.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Wirth, D. Articles by Gustin, P. Search for Related Content PubMed PubMed Citation Articles by Wirth, D. Articles by Gustin, P.

Evidence for a role of heat shock factor 1 in inhibition of NF-B pathway during heat shock response-mediated lung protection

¹Unit of Pharmacology, Pharmacotherapy, and Toxicology, ²Unit of Physiology, Department of Functional Sciences, Faculty of Veterinary Medicine, University of Liege, 4000 Liege, Belgium; and ³Center of Development Biology, University Paul Sabatier-Toulouse 3, 31062 Toulouse, France

Submitted 11 June 2003 ; accepted in final form 23 June 2004

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-B, in response to cadmium insult. The HSF-1-dependent protective effect against intranasal instillation of cadmium (10 and 100 µg/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- 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-B activity and IB stability. The DNA binding NF-B 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-B activation in vivo.

knockout mice; cadmium; heat shock proteins; granulocyte/macrophage colony-stimulating factor; nuclear factor-B

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