Novel Signal Transduction Pathway Utilized by Extracellular HSP70

By A. Asea, M. Rehli, E. Kabingu, J. A. Boch, Olivia Baré, P. Auron, M. Stevenson, Stuart K. Calderwood. Journal of Biological Chemistry, 2002

1,645 citations recorded by the source corpus.

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).

Subfields: Immunology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/80c3b1b0fb6a915f8ab191c87f52a2a1cb229e2b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Infectious Diseases

In Molecular Biology

Citations in the corpus

Pattern recognition receptors and inflammation. (2010, background): “Furthermore, heat shock proteins (HSPs) such as HSP60, HSP70, gp96, and HSP22 are also reported to be recognized by TLR2 and TLR4 (Asea et al., 2002; Ohashi et al., 2000; Roelofs et al., 2006; Warger et al., 2006).”
Endogenous ligands of Toll‐like receptors (2004, background): “Since then, using TLR4 mutant mice (C3H/HeJ with point mutation or C57BL/10ScCr with gene deletion), TLR2 KO mice, and/or fibroblasts transfected with TLR2, TLR3, or TLR4 cDNA, it has been shown that fibrinogen [8], surfactant protein-A [9], fibronectin extra domain A [10], heparan sulfate [11, 58],”
Toll-like receptors. (2003, background): “CD91 (α-macroglobulin receptor) has been identified as a receptor for several heat shock proteins, including HSP70 (65).”
Heat shock protein 70 surface-positive tumor exosomes stimulate migratory and cytolytic activity of natural killer cells. (2005, background): “Monocytes secreted proinflammatory cytokines in response to soluble Hsp70 protein through a CD14-dependent signaling pathway (8, 9), and membrane-bound Hsp70 was identified as a target structure for the cytolytic attack mediated by natural killer (NK) cells.”
The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. (2006, background): “Factors that induce innate immune responses similar to microbial pathogens include heat shock proteins (Asea et al., 2002; Ohashi et al., 2000; Srivastava, 2002), hyaluronic acid (Termeer et al.”
Receptors, Mediators, and Mechanisms Involved in Bacterial Sepsis and Septic Shock (2003, background): “pneumoniae Cell wall (611) Group B streptococci Soluble factor (GBS-F) (211) Neisseria meningitidis Porins (344) Yeast (zymosan) Complete cells (537) Human protein Heat shock protein 70 (14, 541)”
DAMPening Inflammation by Modulating TLR Signalling (2010, background): “This includes both TLR2 and 4 agonists, such as HSP60, HSP70, and biglycan, as well as TLR4 activators such as oxidized LDL and S100 proteins [15, 23, 69, 76, 77].”