Abstract
Heat shock proteins (HSPs) have a cytoprotective role in several human diseases, including ischemia and viral infection. Nuclear factor-kappaB (NF-kappaB) is a critical regulator of inflammation and virus replication. Here we report that a class of serine protease inhibitors with NF-kappaB-inhibitory activity are potent HSP inducers via activation of heat shock transcription factor 1 (HSF1) in human cells. 3,4-Dichloroisocoumarin, the most effective compound, rapidly induces HSF1 DNA binding activity and phosphorylation, leading to transcription and translation of heat shock genes for a period of several hours. HSF1 activation is independent of de novo protein synthesis and is correlated in a concentration- and time-dependent manner with NF-kappaB inhibition. Cysteine protease inhibitors E64 and calpain inhibitor II, which do not block NF-kappaB activation, do not induce HSF DNA binding activity. HSP induction by 3,4-dichloroisocoumarin is associated with antiviral activity during rhabdovirus infection. These results identify a new class of HSP inducers and indicate a link between the regulatory pathways of HSF and NF-kappaB, suggesting novel strategies to simultaneously switch on cytoprotective genes and down-regulate inflammatory and viral genes.
Highlights
Heat shock proteins (HSPs) have a cytoprotective role in several human diseases, including ischemia and viral infection
These results identify a new class of HSP inducers and indicate a link between the regulatory pathways of heat shock transcription factor (HSF) and Nuclear factor-B (NF-B), suggesting novel strategies to simultaneously switch on cytoprotective genes and down-regulate inflammatory and viral genes
We reported that cyclooxygenase cyclopentenone metabolites, such as prostaglandins of the A and J type induce the synthesis of the 70-kDa HSP via cycloheximide-dependent activation of heat shock transcription factor 1 (HSF1) [5], and we have shown that induction of hsp70 is associated with a cytoprotective effect of prostaglandins during hyperthermia and virus infection in mammalian cells [6, 7]
Summary
Heat shock proteins (HSPs) have a cytoprotective role in several human diseases, including ischemia and viral infection. We report that a class of serine protease inhibitors with NFB-inhibitory activity are potent HSP inducers via activation of heat shock transcription factor 1 (HSF1) in human cells.
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