HSP70 as Endogenous Stimulus of the Toll/Interleukin-1 Receptor Signal Pathway*

By R. Vabulas, P. Ahmad-Nejad, S. Ghose, C. Kirschning, R. Issels, H. Wagner. Journal of Biological Chemistry, 2002

1,038 citations recorded by the source corpus.

Human heat-shock protein (HSP)70 activates innate immune cells and hence requires no additional adjuvants to render bound peptides immunogenic. Here we tested the assumption that endogenous HSP70 activates the Toll/IL-1 receptor signal pathway similar to HSP60 and pathogen-derived molecular patterns. We show that HSP70 induces interleukin-12 (IL-12) and endothelial cell-leukocyte adhesion molecule-1 (ELAM-1) promoters in macrophages and that this is controlled by MyD88 and TRAF6. Furthermore, HSP70 causes MyD88 relocalization and MyD88-deficient dendritic cells do not respond to HSP70 with proinflammatory cytokine production. Using the system of genetic complementation with Toll-like receptors (TLR) we found that TLR2 and TLR4 confer responsiveness to HSP70 in 293T fibroblasts. The expanding list of endogenous ligands able to activate the ancient Toll/IL-1 receptor signal pathway is in line with the “danger hypothesis” proposing that the innate immune system senses danger signals even if they originate from self.

Subfields: Immunology, Infectious Diseases, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/114fb4534a17e55d44aad3a565286d0fbaa20658

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In Immunology

1. Shizuo Akira
2. M. Karin
3. K. Takeda
4. R. Medzhitov
5. T. Kaisho
6. T. Lawrence
7. Baochong Gao
8. M. Tsan

In Infectious Diseases

1. Baochong Gao
2. M. Tsan
3. Shizuo Akira

In Molecular Biology

1. M. Karin
2. T. Lawrence
3. Shizuo Akira
4. DM Mosser
5. X. Zhang
6. Baochong Gao
7. K. Takeda
8. M. Tsan

Citations in the corpus

• Regulatory T Cells Selectively Express Toll-like Receptors and Are Activated by Lipopolysaccharide (2003, background): “Thus, this is the case for HSP, HSP-60 (10), HSP70 (12), and GP96 (11), heparan sulfate (33), surfactant protein A (34), and the product of degradation of the extracellular matrix hyaluronic acid (14).”
• 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)”
• Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. (2006, background): “Heat-shock protein 70 (HSP70), described as a TLR4 agonist (Vabulas et al., 2002), and chromatin component HMG-B1, which appears to activate macrophages through the receptor for advanced glycation products (RAGE; Scaffidi et al.”
• Macrophage activation by endogenous danger signals (2008, background): “TLR4 is also critical for HSP70 induction of IL-12 production [54].”
• 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],”