Fever, hyperthermia and the heat shock response

The heat shock response is a highly conserved primitive response that is essential for survival against a wide range of stresses, including extremes of temperature. Fever is a more recently evolved response, during which organisms raise their core body temperature and temporarily subject themselves to thermal stress in the face of infections. The present review documents studies showing the potential overlap between the febrile response and the heat shock response and how both activate the same common transcriptional programme (although with different magnitudes) including the stress-activated transcription factor, heat shock factor-1, to modify host defences in the context of infection, inflammation and injury. The review focuses primarily on how hyperthermia within the febrile range that often accompanies infections and inflammation acts as a biological response modifier and modifies innate immune responses. The characteristic 2-3 degrees C increase in core body temperature during fever activates and utilises elements of the heat shock response pathway to modify cytokine and chemokine gene expression, cellular signalling and immune cell mobilisation to sites of inflammation, infection and injury. Interestingly, typical proinflammatory agonists such as Toll-like receptor agonists modify the heat shock-induced transcriptional programme and expression of HSP genes following co-exposure to febrile range hyperthermia or heat shock, suggesting a complex reciprocal regulation between the inflammatory pathway and the heat shock response pathway.