Heat shock transcription factor HSF1 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 HSF1 in these mechanisms have not yet been clearly elucidated. Using HSF1 knockout mice (Hsf1^-/-), this study examined whether HS responsemediated lung protection involved an inhibition of the pro-inflammatory pathway via an interaction between HSF1 and NF-B, in response to cadmium insult. The HSF1-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 wildtype animals. These responses were associated with higher granulocyte-macrophage colonystimulating factor (GM-CSF) (1.7-fold), but not TNF- concentrations in bronchoalveolar fluids of Hsf1^-/- mice, compared with those of WT animals, indicating that HSF1 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 HSF1 involve specific cytokine repression via inhibition of NF-B activation, in vivo.