The Endoplasmic Reticulum-resident Heat Shock Protein Gp96 Activates Dendritic Cells via the Toll-like Receptor 2/4 Pathway

Vabulas, R. Martin; Braedel, Sibylla; Hilf, Norbert; Singh‐Jasuja, Harpreet; Herter, Sylvia; Ahmad-Nejad, Parvis; Kirschning, Carsten J.; Costa, Clarissa da; Rammensee, Hans‐Georg; Wagner, Hermann; Schild, Hansjoerg

doi:10.1074/jbc.m200425200

Cited by 442 publications

(317 citation statements)

References 36 publications

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“…The involvement of Hsps in the immune response is evidenced by some findings, including the release and presence of these proteins in the extracellular environment as a danger signal to activate DCs [53,54] and macrophages [55,56], the ability to induce several cytokines including TNF-a, IL-1b, IL-12, nitric oxide and some chemokines [57], and the co-stimulation of the adaptive immune response as potent antigen carriers. After release from damaged cells, Hsp60, Hsp70, Hsp90 and Gp96 have been proposed to interact with immune cells through a variety of cell-surface receptors: CD91 with Hsp70, Hsp90 and Gp96 [58]; CD36 and TLR-2 and -4 with Gp96 [59]; CD40, CD14 and TLR-2 and -4 with Hsp70 [60]. Hsp60 might signal through CD14, TLR-2 and TLR-4 [61,62], probably binding to a different molecule [63].…”

Section: Discussionmentioning

confidence: 99%

Differential expression of three Paralichthys olivaceus Hsp40 genes in responses to virus infection and heat shock☆

Caiwen

Zhang

et al. 2006

Fish & Shellfish Immunology

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Section: Discussionmentioning

confidence: 99%

Differential expression of three Paralichthys olivaceus Hsp40 genes in responses to virus infection and heat shock☆

Caiwen

Zhang

et al. 2006

Fish & Shellfish Immunology

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“…These include HMGB1 76 31, uric acid 77 , some HSPs 78 79, some defensins [G] 80 , hyaluronic acid 81 , heparan sulfate 82 , and some fragments of extracellular matrix proteins 70 . Whereas this data may well be correct, caution is warranted because TLRs can be stimulated by microbial contaminants that are easily introduced during the purification of molecules.…”

Section: Receptors For Dampsmentioning

confidence: 99%

How dying cells alert the immune system to danger

2008

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When a cell dies in vivo the event does not go unnoticed. The host has evolved mechanisms to detect the death of cells and rapidly investigate the nature of their demise. If cell death is a result of natural causes, that is, it is part of normal physiological processes, then there is little threat to the organism. In this situation, little else is done other than removing the corpse. However, if cells have died as the consequence of some violence or disease, then both defence and repair mechanisms are mobilized. The importance of this process to host defence and disease pathogenesis has only been appreciated relatively recently. This article will review our current knowledge of these processes.The immune system was recognized in ancient times and rediscovered by Jenner and Pasteur based on its ability to confer protection upon repeat exposure to a pathogen. Through subsequent studies by Von Behring and others it rapidly became apparent that the immune system had the potential to respond not only to whole microorganisms, but to virtually any molecule that was "foreign" to the host. However, whereas injection of such molecules would often provoke a robust immune response, this did not invariably occur. Immunization protocols improved in the 1920s with the discovery by Ramon and Glenny of immunostimulatory molecules (adjuvants [G]) that could boost immune responses to co-administered antigens. Adjuvants were typically of microbial origin and became widely used to promote the effectiveness of immunizations. In the 1960s, Dresser showed that a foreign protein when highly purified would only elicit an immune response if it was admixed with a microbial adjuvant 1 . Injected by itself, the antigen not only failed to elicit immunity but actually induced a state of tolerance 2 . However, the significance of these observations was not well appreciated and adjuvants remained one of those things that everyone used because they were part of standard operating procedures.In 1989 Janeway put these empirical observations into a conceptual framework 3 (Fig. 1). He proposed that the immune system did not respond to all foreign antigens but only to those that are potentially associated with infection. The underlying idea here was that the immune system evolved to protect organisms against microorganisms and this discrimination between infectious versus noninfectious antigens focused defences on real threats rather than innocuous situations.At this time, it was already recognized that in order to stimulate T cell responses, antigens had to first be acquired and presented on MHC molecules of an antigen presenting cell (APC). Moreover, it was further known that APCs also provided additional costimulatory signals necessary to activate T cells. Janeway incorporated these principles into his model (Fig. 1). He postulated that the discrimination between infectious and noninfectious non-self molecules was made by the APCs of the innate immune system through receptors that would recognize pathogen-associated molecular patterns (PAMP...

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“…Both HSP60 and HSP70 can activate TLR2 and TLR4 in DC cultures (16,17), whereas uric acid is the principal endogenous DC-stimulating signal (18). Heparan sulfate is shed from cell surfaces and basement membranes as a result of tissue injury.…”

Section: Discussionmentioning

confidence: 99%

Cutting Edge: TLR4 Activation Mediates Liver Ischemia/Reperfusion Inflammatory Response via IFN Regulatory Factor 3-Dependent MyD88-Independent Pathway

Zhai¹,

Shen²,

O’Connell³

et al. 2004

The Journal of Immunology

417

387

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The triggering molecular mechanism of ischemia-reperfusion injury (IRI), which in clinical settings results in excessive and detrimental inflammatory responses, remains unclear. This study analyzes the role of the TLR system in an established murine model of liver warm ischemia followed by reperfusion. By contrasting in parallel TLR knockout mice with their wild-type counterparts, we found that TLR4, but not TLR2, was specifically required in initiating the IRI cascade, as manifested by liver function (serum alanine aminotransferase levels), pathology, and local induction of proinflammatory cytokines/chemokines (TNF-α, IL-6, IFN-inducible protein 10). We then investigated the downstream signaling pathway of TLR4 activation. Our results show that IFN regulatory factor 3, but not MyD88, mediated IRI-induced TLR4 activation leading to liver inflammation and hepatocellular damage. This study documents the selective usage of TLR in a clinically relevant noninfectious disease model, and identifies a triggering molecular mechanism in the pathophysiology of liver IRI.

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The Endoplasmic Reticulum-resident Heat Shock Protein Gp96 Activates Dendritic Cells via the Toll-like Receptor 2/4 Pathway

Cited by 442 publications

References 36 publications

Differential expression of three Paralichthys olivaceus Hsp40 genes in responses to virus infection and heat shock☆

Differential expression of three Paralichthys olivaceus Hsp40 genes in responses to virus infection and heat shock☆

How dying cells alert the immune system to danger

Cutting Edge: TLR4 Activation Mediates Liver Ischemia/Reperfusion Inflammatory Response via IFN Regulatory Factor 3-Dependent MyD88-Independent Pathway

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