Pharmacological modulation of heat shock factor 1 by antiinflammatory drugs results in protection against stress-induced cellular damage.

Abstract

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 ...

Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model

“…19). Moreover, in mammalian cells nonsteroidal antiinflammatory drugs such as salicylate and indomethalcin enhance HSF1 DNA binding, but not HSP70 transcriptional activation without heat shock stress (22,23). Their results and ours suggest that drug-induced transcription and translation of HSP are multistep processes, highly regulated, and can be insult dependent.…”

Interaction of intracellular β amyloid peptide with chaperone proteins

“…It is of particular interest whether this proposed intracellular A␤ metabolism also occurs to some degree in human neurons. We speculate that the ability of some nonsteroidal anti-inflammatory drugs to inhibit A␤1-42 secretion from cultured cells (48) and to reduce plaque load in transgenic A␤ mice (49) may result from the previously demonstrated ability of these drugs to modulate cellular chaperone functions (50)(51)(52).…”

Herpes simplex virus 2 causes apoptotic infection in monocytoid cells

“…This excludes the possibility that indomethacin inhibitory action could be due to a protective effect against virus infection and/or replication. Interestingly, indomethacin has recently been shown to protect against stress-induced cellular damage through the modulation of heat shock factor 1 (Lee et al, 1995). Considering that HSV infection could result in elevated expression of heat shock proteins (La Thangue et al, 1984), protection by indomethacin against virusinduced apoptosis could be referred to a similar action.…”