Sodium salicylate, an anti-inflammatory agent, was examined for its effects on the heat shock response in cultured human cells. Salicylate activation of DNA binding by the heat shock transcription factor (HSF) was comparable to activation attained during heat shock. However, sodium salicylate did not induce heat shock gene transcription even though the HSF was bound in vivo to the heat shock elements upstream of the heat shock protein 70 (Hsp 70) gene. These results reveal that activation of the heat shock transcriptional response is a multistep process. Modulation of extracellular pH augments sensitivity to salicylate-induced activation of HSF.

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The activation of heat shock genes by diverse forms of environmental and physiological stress has been implicated in a number of human diseases, including ischemic damage, reperfusion injury, infection, neurodegeneration, and inflammation. The enhanced levels of heat shock proteins and molecular chaperones have broad cytoprotective effects against acute lethal exposures to stress. Here, we show that the potent antiinflammatory drug indomethacin activates the DNA-binding activity of human heat shock transcription factor 1 (HSF1). Perhaps relevant to its pharmacological use, indomethacin pretreatment lowers the temperature threshold of HSFI activation, such that a complete heat shock response can be attained at temperatures that are by themselves insuffi'cient. The synergistic effect of indomethacin and elevated temperature is biologically relevant and results in the protection of cells against exposure to cytotoxic conditions. Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used in the treatment of inflammation and associated diseases (1). The primary action of these drugs is thought to occur by inhibiting the cyclic pathway from arachidonate to eicosanoids, a potent family of signaling molecules, through inactivation of prostaglandin endoperoxidase synthase (2,3). In addition to its role as an antiinflammatory drug, salicylic acid affects the transcription of injury-response genes in plants (4), inhibits the activation of NF-KB (5), and induces heat shock transcription factor 1 (HSF1) in human cells (6). Additional support for a potential link between inflammation and the heat shock response is suggested by the ability of arachidonic acid to modulate the DNA-binding and transcriptional activities of HSF1 (7).The elevated expression of genes encoding heat shock (stress) proteins and molecular chaperones has been detected in numerous disease states, including ischemia, reperfusion damage, oxidant injury, cardiac hypertrophy, fever, inflammation, bacterial and parasitic infection, metabolic diseases, neoplasia, and in cell and tissue damage (8-16). The activities of heat shock proteins and the heat shock response in general are likely to exert themselves at multiple levels, by serving to detect the onset of physiological stress, to prevent subsequent damage resulting from the synthesis and accumulation of nonnative proteins, and as a key component of cellular repair processes following injury (reviewed in refs. 8 and 17-25). Heat shock proteins and molecular chaperones, whether induced by prior exposure to nontoxic stress conditions or by overexpression of genes encoding heat shock proteins, have been shown to protect cells against a broad range of toxic conditions, including oxidative stress, tumor necrosis factor a (TNF-a), extreme temperatures of heat shock, ethanol, heavy metals, and cellular damage following ischemia or sepsisinduced injury (26-29).Our rationale to look further into a link between heat shock and inflammation was based on observations that diverse conditions of cell and tissue ...

Cell and tissue injury activate the inflammatory response through the action(s) of arachidonic acid and its metabolites, leading to the expression of acute-phase proteins and inflammatory cytokines. At the molecular level, little is known how arachidonic acid regulates the inflammatory response. As inflammation is also associated with local increase in tiue temperatures, we eamned whether aridonic acid was directly involved in the heat shock response. Transcriptional Run-On Assays. In vitro nuclear run-on analysis was done as described (25 Abbreviations: HSE, heat shock element; HSF, heat shock factor.