Endocytosed HSP60s Use Toll-like Receptor 2 (TLR2) and TLR4 to Activate the Toll/Interleukin-1 Receptor Signaling Pathway in Innate Immune Cells*

By R. Vabulas, P. Ahmad-Nejad, C. D. da Costa, T. Miethke, C. Kirschning, Hans Häcker, H. Wagner. Journal of Biological Chemistry, 2001

869 citations recorded by the source corpus.

Heat shock proteins (HSPs) require no adjuvant to confer immunogenicity to bound peptides, as if they possessed an intrinsic “danger” signature. To understand the proinflammatory nature of HSP, we analyzed signaling induced by human and chlamydial HSP60. We show that both HSP60s activate the stress-activated protein kinases p38 and JNK1/2, the mitogen-activated protein kinases ERK1/2, and the I-κB kinase (IKK). Activation of JNK and IKK proceeds via the Toll/IL-1 receptor signaling pathway involving MyD88 and TRAF6. Human fibroblasts transfected with TLR2 or TLR4 plus MD-2 gain responsiveness to HSP60, while TLR2- or TLR4-defective cells display impaired responses. Initiation of signaling requires endocytosis of HSP60 that is effectively inhibited by serum component(s). The results revealed that adjuvanticity of HSP60 operates similar to that of classical pathogen-derived ligands.

Subfields: Genetics, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/929f1c65b5d68a43a8c005cc1f3582cb4e1280cc

How researchers see this paper

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

In Genetics

1. G. Núñez
2. Shizuo Akira

In Immunology

1. Shizuo Akira
2. K. Takeda
3. T. Kaisho
4. H. Kono
5. G. Núñez
6. K. Rock
7. R. Medzhitov
8. Baochong Gao

In Molecular Biology

1. G. Núñez
2. Shizuo Akira
3. Grace Y. Chen
4. H. Kono
5. K. Rock
6. Baochong Gao
7. K. Takeda
8. M. Tsan

Citations in the corpus

• Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury (2011, background): “, heat shock proteins [58], mRNA [59], degraded extracellular matrix (ECM) components [60]).”
• Toll-like receptors. (2003, background): “The immuno-stimulatory activity of HSP60 is mediated by TLR4 (58, 59).”
• A Comparative Review of Toll-Like Receptor 4 Expression and Functionality in Different Animal Species (2014, background): “In addition to exogenous PAMPs, TLR4 also binds endogenous molecules such as heat shock proteins in the mouse (22, 23), in the rat (24), and in the human (25).”
• The inflammatory response to cell death. (2008, background): “Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, Koo GC, Calderwood SK. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine.”
• 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],”
• Sterile inflammation: sensing and reacting to damage (2010, background): “Although several of the purified endogenous molecules, including HSPs, HMGB1 and uric acid, can induce the production of pro-inflammatory cytokines through TLR2 and/or TLR4 in vitro”