Opposing roles for heat and heat shock proteins in macrophage functions during inflammation: a function of cell activation state?

Abstract

Macrophages function both under normothermia and during periods of body temperature elevation (fever). Whether macrophages sense and respond to thermal signals in a manner which regulates their function in a specific manner is still not clear. In this brief review, we highlight recent studies which have analyzed the effects of mild heating on macrophage cytokine production, and summarize thermally sensitive molecular mechanisms, such as heat shock protein (HSP) expression, which have been identified. Mild, physiologically achievable, hyperthermia has been shown to have both pro- and anti-inflammatory effects on macrophage inflammatory cytokine production and overall it is not clear how hyperthermia or HSPs can exert opposing roles on macrophage function. We propose here that the stage of activation of macrophages predicts how they respond to mild heating and the specific manner in which HSPs function. Continuing research in this area is needed which will help us to better understand the immunological role of body temperature shifts. Such studies could provide a scientific basis for the use of heat in treatment of inflammatory diseases.

Keywords: arthritis; cytokines; fever; heat shock factor; heat shock protein; hyperthermia; inflammation.

FIGURE 1

Pro- and anti-inflammatory effects of heat and heat shock proteins. Fever range temperature exerts both positive and negative effects on macrophage pro-inflammatory cytokine production. We proposed that these opposing effects may depend on the activation stage of macrophages as well as the cellular location of heat shock proteins. First, in the initiation phase of macrophage activation, fever range temperature enhances the production of LPS-induced pro-inflammatory cytokines TNF-α, IL-6, and NO. (1) This thermally enhanced cytokine production is associated with an induction of HSP70/72 in these cells. (2) HSP70 can then be released into the extracellular environment, and (3) exerts its cytokine effect through the CD14/TLR pathway. (4) This leads to the activation of NF-κB and MAPK pathway and subsequent cytokine gene transcription. On the other hand, fever-range temperature can also suppress LPS-induced TNF-α, IL-6, and IL-1β production and HMGB-1 release. (5) This is due to thermally induced HSF-1 binding directly to the heat shock response element in the cytokine promoter region and functions as a transcriptional repressor. (6) In addition, LPS and heat treatment can also induce HSP70 expression. HSP70 then binds to TRAF6 or IKK and inhibits subsequent NF-κB activation and cytokine production.