ARACHIDONATE IS A POTENT MODULATOR OF HUMAN HEAT-SHOCK GENE-TRANSCRIPTION

Cell and tissue injury activate the inflammatory response through the action(s) of arachidonic acid and its metabolites, leading to the expr ession of acute-phase proteins and inflammatory cytokines. At the mole cular level, little is known how arachidonic acid regulates the inflam matory response. As inflammation is also associated with local increas e in tissue temperatures, we examined whether arachidonic acid was dir ectly involved in the heat shock response. Extracellular exposure to a rachidonic acid induced heat shock gene transcription in a dose-depend ent manner via acquisition of DNA-binding activity and phosphorylation of heat shock factor 1 (HSF1). In addition, exposure of cells to low concentrations of arachidonic acid, which by themselves did not induce HSF1 DNA-binding activity, reduced the temperature threshold for HSF1 activation from elevated temperatures which are not physiologically r elevant (>42 degrees C) to temperatures which can be attained during t he febrile response (39-40 degrees C). These results indicate that ele vated heat shock gene expression is a direct consequence of an arachid onic acid-mediated cellular response.