CXC chemokines: a new family of heat-shock proteins?

The heat shock (HS) response is a generalized stress response that is characterized by the induced synthesis of a family of proteins referred to as heat shock proteins (HSPs). These proteins protect cells from a myriad of stressful insults in part by functioning as chaperones for denatured proteins. Increasing evidence suggests that the stress response is not limited to the HSP family of genes, but includes numerous other genes that are regulated by HS through the activation of the stress-activated transcription factor, heat shock factor-1 (HSF-1). Based on observations from our own in vivo hyperthermia models, we hypothesized that the CXC chemokine family of neutrophil activators and chemoattractants might be a previously unrecognized class of HS-responsive genes. Analysis of the promoters of the CXC family of chemokines in both human and mouse showed that they share a common promoter organization in which multiple copies of the HSF-1 binding sequence (heat shock response element, HRE) are present in the 5'-upstream flanking region of each of these genes. We have reviewed previous work from our own laboratory and others demonstrating a strong correlation between activation of HSPs and generation of CXC chemokines. Although rigorous experimental evidence is still required to support this hypothesis, this strong and consistent correlation between expression of HSPs and CXC chemokines in vivo and in vitro model systems suggests that the putative HREs present in the CXC chemokine genes are functionally active. We speculate that the activation of the HS response during febrile range hyperthermia, inflammation, infection and injury directly enhances expression of the CXC chemokines, thereby augmenting neutrophil delivery to sites of infection and injury during febrile illnesses.