Novel Signal Transduction Pathway Utilized by Extracellular HSP70

TLDR

Heat shock proteins (HSPs) can exit mammalian cells, interact with immune cells, and exert immunoregulatory effects, marking a paradigm shift in their understood functions. These studies pave the way for developing pharmacological or molecular tools to modulate HSP70‑induced functions in diseases where its effects are desirable (cancer) or undesirable (arthritis, arteriosclerosis). Exogenous HSP70 binds the plasma membrane, triggers a rapid Ca²⁺ flux, activates NF‑κB, and upregulates pro‑inflammatory cytokines in monocytes through a MyD88/IRAK/NF‑κB pathway that requires TLR2, TLR4, and CD14.

Abstract

Recent studies have initiated a paradigm shift in the understanding of the function of heat shock proteins (HSP). It is now clear that HSP can and do exit mammalian cells, interact with cells of the immune system, and exert immunoregulatory effects. We recently demonstrated that exogenously added HSP70 possesses potent cytokine activity, with the ability to bind with high affinity to the plasma membrane, elicit a rapid intracellular Ca²⁺ flux, activate NF-κB, and up-regulate the expression of pro-inflammatory cytokines in human monocytes. Here for the first time, we report that HSP70-induced proinflammatory cytokine production is mediated via the MyD88/IRAK/NF-κB signal transduction pathway and that HSP70 utilizes both TLR2 (receptor for Gram-positive bacteria) and TLR4 (receptor for Gram-negative bacteria) to transduce its proinflammatory signal in a CD14-dependent fashion. These studies now pave the way for the development of highly effective pharmacological or molecular tools that will either up-regulate or suppress HSP70-induced functions in conditions where HSP70 effects are desirable (cancer) or disorders where HSP70 effects are undesirable (arthritis and arteriosclerosis).