ACTIVATION OF THE HEAT-SHOCK FACTOR-1 BY SERINE-PROTEASE INHIBITORS -AN EFFECT ASSOCIATED WITH NUCLEAR FACTOR-KAPPA-B INHIBITION

Heat shock proteins (HSPs) have a cytoprotective role in several human diseases, including ischemia and viral infection. Nuclear factor-kapp a B (NF-kappa B) is a critical regulator of inflammation and virus rep lication. Here we report that a class of serine protease inhibitors wi th NF-kappa B-inhibitory activity are potent HSP inducers via activati on of heat shock transcription factor 1 (HSF1) in human cells. 3,4-Dic hloroisocoumarin, the most effective compound, rapidly induces HSF1 DN A binding activity and phosphorylation, leading to transcription and t ranslation of heat shock genes for a period of several hours. HSF1 act ivation is independent of de novo protein synthesis and is correlated in a concentration- and time-dependent manner with NF-kappa B inhibiti on. Cysteine protease inhibitors E64 and calpain inhibitor II, which d o not block NF-kappa B activation, do not induce HSF DNA binding activ ity. HSP induction by 3,4-dichloroisocoumarin is associated with antiv iral activity during rhabdovirus infection. These results identify a n ew class of HSP inducers and indicate a link between the regulatory pa thways of HSF and NF-kappa B, suggesting novel strategies to simultane ously switch on cytoprotective genes and down-regulate inflammatory an d viral genes.