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

Vabulas, Ramunas M.; Ahmad-Nejad, Parviz; da Costa, Clarissa; Miethke, Thomas; Kirschning, Carsten J.; Häcker, Hans; Wagner, Hermann

doi:10.1074/jbc.m103217200

Cited by 805Immune Response and InflammationHeat shock proteins researchInflammasome and immune disorders

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

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Vabulas, Ramunas M., Ahmad-Nejad, Parviz, da Costa, Clarissa, Miethke, Thomas, Kirschning, Carsten J., Häcker, Hans, Wagner, Hermann·2001·Journal of Biological Chemistry

DOI 10.1074/jbc.m103217200

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Abstract

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-kappaB 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.

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Several purified endogenous molecules, including HSPs, HMGB1 and uric acid, can induce the production of pro-inflammatory cytokines through TLR2 and/or TLR4 in vitro.
“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 vitro25–27, the relevance of these observations has previously been questioned because of the possibility of microbial contamination: several of these proteins, including HSPs and HMGb1, bind lipopolysaccharide (LPS), making”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [25]

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Authors: Vabulas, R. M., Ahmad-Nejad, P., da Costa, C., Miethke, T., Kirschning, C. J., Häcker, H., & Wagner, H.
Affiliations: Technical University of Munich (DE)
Corresponding author: Wagner, Hermann
ORCID: Vabulas, Ramunas M.
Miethke, Thomas
Kirschning, Carsten J.
Häcker, Hans
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2001-08
Volume: 276
Issue: 33
Pages: 31332-31339
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m103217200
OpenAlex: W1971521446
Cited by: 805
References: 49
Citations by year: 2026: 10 · 2025: 9 · 2024: 6 · 2023: 12 · 2022: 16 · 2021: 15 · 2020: 26 · 2019: 11 · 2018: 18 · 2017: 26 · 2016: 31 · 2015: 21 · 2014: 32 · 2013: 40 · 2012: 34
FWCI: 16.61
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6992 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: HSP60, heat shock proteins, TLR2, TLR4, innate immunity, endocytosis, MyD88, TRAF6, p38 MAPK, JNK, ERK, IκB kinase, MD-2, adjuvant effect, fibroblasts
MeSH terms: Animals, Antigens, Differentiation, Bacterial Proteins, Cell Line, Endocytosis, Humans, Membrane Glycoproteins, Proteins, Receptors, Cell Surface, Receptors, Immunologic, Tumor Necrosis Factor-alpha, Receptors, Interleukin-1, Chaperonins, Chaperonin 60, Drosophila Proteins, TNF Receptor-Associated Factor 6, Adaptor Proteins, Signal Transducing, Toll-Like Receptors, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice, Myeloid Differentiation Factor 88

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

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