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HSP70 as Endogenous Stimulus of the Toll/Interleukin-1 Receptor
Signal Pathway*
Ramunas M.
Vabulas§,
Parviz
Ahmad-Nejad¶,
Sanghamitra
Ghose¶,
Carsten J.
Kirschning,
Rolf D.
Issels**, and
Hermann
Wagner
From the Institute of Medical Microbiology,
Immunology and Hygiene, Technical University of Munich, Trogerstrasse
9, Munich 81675, Germany, the § Institute of Immunology,
Molt pl. 29, Vilnius 2021, Lithuania, the Klinikum
Grosshadern, Medical Clinic III, Ludwig-Maximilians-University, Munich
81377, Germany, and the ** National Research Center
for Environment and Health, KKG Hyperthermie, Institute of Molecular
Immunology, Munich 81377, Germany
Human heat-shock protein (HSP)70 activates innate
immune cells and hence requires no additional adjuvants to render boundpeptides immunogenic. Here we tested the assumption that endogenousHSP70 activates the Toll/IL-1 receptor signal pathway similarto HSP60
and pathogen-derived molecular patterns. We show thatHSP70 induces
interleukin-12 (IL-12) and endothelial cell-leukocyteadhesion
molecule-1 (ELAM-1) promoters in macrophages and thatthis is
controlled by MyD88 and TRAF6. Furthermore, HSP70 causesMyD88
relocalization and MyD88-deficient dendritic cells do notrespond to
HSP70 with proinflammatory cytokine production. Usingthe system of
genetic complementation with Toll-like receptors(TLR) we found that
TLR2 and TLR4 confer responsiveness to HSP70in 293T fibroblasts. The
expanding list of endogenous ligandsable to activate the ancient
Toll/IL-1 receptor signal pathwayis in line with the "danger
hypothesis" proposing that the innateimmune system senses danger
signals even if they originate fromself.
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J. B. Flechtner, K. P. Cohane, S. Mehta, P. Slusarewicz, A. K. Leonard, B. H. Barber, D. L. Levey, and S. Andjelic (2006)
J. Immunol.
177, 1017-1027
|Abstract »|Full Text »|PDF »
Cutting Edge: High-Mobility Group Box 1 Preconditioning Protects against Liver Ischemia-Reperfusion Injury..
K. Izuishi, A. Tsung, G. Jeyabalan, N. D. Critchlow, J. Li, K. J. Tracey, R. A. Demarco, M. T. Lotze, M. P. Fink, D. A. Geller, et al. (2006)
J. Immunol.
176, 7154-7158
|Abstract »|Full Text »|PDF »
Invited review: Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease.
A. E. Medvedev, I. Sabroe, J. D. Hasday, and S. N. Vogel (2006)
Innate Immunity
12, 133-150
|Abstract »|PDF »
CD4+ T Regulatory Cell Induction and Function in Transplant Recipients after CD154 Blockade Is TLR4 Independent.
Y. Zhai, L. Meng, F. Gao, Y. Wang, R. W. Busuttil, and J. W. Kupiec-Weglinski (2006)
J. Immunol.
176, 5988-5994
|Abstract »|Full Text »|PDF »
Releasing signals, secretory pathways, and immune function of endogenous extracellular heat shock protein 72.
B. H. Segal, J. Kwon-Chung, T. J. Walsh, B. S. Klein, M. Battiwalla, N. G. Almyroudis, S. M. Holland, and L. Romani (2006)
Clinical Infectious Diseases
42, 507-515
|Abstract »|Full Text »|PDF »
Activation of Toll-like Receptor 2 on Microglia Promotes Cell Uptake of Alzheimer Disease-associated Amyloid beta Peptide.
K. Chen, P. Iribarren, J. Hu, J. Chen, W. Gong, E. H. Cho, S. Lockett, N. M. Dunlop, and J. M. Wang (2006)
J. Biol. Chem.
281, 3651-3659
|Abstract »|Full Text »|PDF »
Abrupt Expression of TLR4 in TLR4-Deficient Macrophages Imposes a Selective Disadvantage: Genetic Evidence for TLR4-Dependent Responses to Endogenous, Nonmicrobial Stimuli.
E. F. Cohn, C. Nathan, D. Radzioch, H. Yu, Z. Xiang, and A. Ding (2006)
J. Immunol.
176, 1185-1194
|Abstract »|Full Text »|PDF »
Innate Stimuli Accentuate End-Organ Damage by Nephrotoxic Antibodies via Fc Receptor and TLR Stimulation and IL-1/TNF-{alpha} Production.
Y. Fu, C. Xie, J. Chen, J. Zhu, H. Zhou, J. Thomas, X. J. Zhou, and C. Mohan (2006)
J. Immunol.
176, 632-639
|Abstract »|Full Text »|PDF »
Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni- bacterium acnes.
L. Romics Jr, A. Dolganiuc, A. Velayudham, K. Kodys, P. Mandrekar, D. Golenbock, E. Kurt-Jones, and G. Szabo (2005)
J. Leukoc. Biol.
78, 1255-1264
|Abstract »|Full Text »|PDF »
Hepatic Ischemia/Reperfusion Injury Involves Functional TLR4 Signaling in Nonparenchymal Cells.
A. Tsung, R. A. Hoffman, K. Izuishi, N. D. Critchlow, A. Nakao, M. H. Chan, M. T. Lotze, D. A. Geller, and T. R. Billiar (2005)
J. Immunol.
175, 7661-7668
|Abstract »|Full Text »|PDF »
Reduced cardiac hypertrophy in toll-like receptor 4-deficient mice following pressure overload.
T. Ha, Y. Li, F. Hua, J. Ma, X. Gao, J. Kelley, A. Zhao, G. E. Haddad, D. L. Williams, I. William Browder, et al. (2005)
Cardiovasc Res
68, 224-234
|Abstract »|Full Text »|PDF »
Dendritic cells, Fc{gamma} receptors, and Toll-like receptors: potential allies in the battle against rheumatoid arthritis.
T R D J Radstake, A W T van Lieshout, P L C M van Riel, W B van den Berg, and G J Adema (2005)
Ann Rheum Dis
64, 1532-1538
|Abstract »|Full Text »|PDF »
Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages.
M. T. Pritchard, Z. Li, and E. A. Repasky (2005)
J. Leukoc. Biol.
78, 630-638
|Abstract »|Full Text »|PDF »
Heat Shock Proteins as Endogenous Adjuvants in Sterile and Septic Inflammation.
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