Cell stress proteins in extracellular fluids: friend or foe?

For many years the perception has been that mammalian stress proteins are intracellular molecules that are only present in the extracellular environment as a consequence of pathological situations such as necrotic cell death. However, many investigators have now shown that these proteins can be released from a variety of viable (non-necrotic) cell types in vitro, by a mechanism which has yet to be fully established. Moreover, we and a number of others have reported Hsp60 and/or Hsp70 to be present in the peripheral circulation of normal individuals. These observations have profound implications for the perceived role of these proteins as universal pro-inflammatory intercellular 'danger' signalling molecules, and the functional significance and role(s) of these ubiquitously expressed and highly conserved families of molecules must therefore be critically re-evaluated. This paper reviews the evolving evidence which indicates that stress proteins such as Hsp60 and Hsp70 are present in, and can be released into the extracellular compartment under normal physiological conditions, and puts into context their pro- and anti-inflammatory potential.