Novel Signal Transduction Pathway Utilized by Extracellular HSP70
Open accessAbstract
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 Ca(2+) flux, activate NF-kappaB, 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-kappaB 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).
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Several candidate receptors capable of binding DAMPs and MAMPs include TLRs, RAGE, and CD91.
“there are several candidate receptors capable of binding DAMPs and MAMPs, including TLRs, RAGE, and CD91 (Asea et al, 2002;Calderwood et al, 2007a, b).”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Asea et al, 2002
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- Authors
- Asea, A., Rehli, M., Kabingu, E., Boch, J. A., Baré, O., Auron, P. E., Stevenson, M. A., & Calderwood, S. K.
- Affiliations
- Harvard University (US)
- University Hospital Regensburg (DE)
- Beth Israel Deaconess Medical Center (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-04
- Volume
- 277
- Issue
- 17
- Pages
- 15028-15034
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2094605832
- Cited by
- 1,510
- References
- 43
- Citations by year
- 2026: 26 · 2025: 31 · 2024: 31 · 2023: 32 · 2022: 26 · 2021: 51 · 2020: 63 · 2019: 61 · 2018: 61 · 2017: 58 · 2016: 52 · 2015: 56 · 2014: 74 · 2013: 75 · 2012: 84
- FWCI
- 27.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5r01ca047404-06, 5r01ca050642-05, HEK293)
- National Cancer Institute (CA31303, CA 68544, P01CA031303, CA 47404, R01CA077465, CA77465, R01CA068544, CA50642)
- National Institute of Allergy and Infectious Diseases (R01AI044122, AI44122)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Keywords
- extracellular Hsp70, heat shock proteins, signal transduction, TLR2, TLR4, CD14, inflammatory cytokines, monocytes, calcium flux, immune regulation, Gram-positive bacteria, Gram-negative bacteria
- MeSH terms
- Cell Line, Humans, Membrane Glycoproteins, Promoter Regions, Genetic, Receptors, Cell Surface, Signal Transduction, NF-kappa B, HSP70 Heat-Shock Proteins, Drosophila Proteins, Toll-Like Receptors, Toll-Like Receptor 2, Toll-Like Receptor 4
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