Interactions between the heat shock response and the nuclear factor-kappaB signaling pathway

The heat shock response (HSR) and the nuclear factor (NF)-kappaB signaling pathway are two fundamental cellular responses. Various laboratories have documented in vitro and in vivo interactions between the HSR and NF-kappaB activation when they are activated sequentially. For example, induction of the HSR before a proinflammatory signal inhibits NF-kappaB activation and NF-kappaB-dependent proinflammatory gene expression. The central point of control appears to be at the level of IkappaBalpha phosphorylation as demonstrated by HSR-mediated inhibition of IkappaB kinase activation and HSR-mediated induction of intracellular phosphatase activity. In addition, induction of the HSR can independently increase de novo expression of the IkappaBalpha gene, thereby providing another potential mechanism through which the HSR can modulate cellular proinflammatory signaling. Another level of interaction is illustrated by the observation that various pharmacologic inhibitors of the NF-kappaB pathway are capable of simultaneously inducing the HSR. In direct contrast, induction of the HSR after a proinflammatory signal can lead to programmed cell death. Further understanding of how these two fundamental cellular responses interact at the molecular level holds the potential to elucidate some of the molecular interactions that occur during disease states common to critical care medicine.