Synergistic and differential modulation of immune responses by Hsp60 and lipopolysaccharide.

2.50
Hdl Handle:
http://hdl.handle.net/10033/19775
Title:
Synergistic and differential modulation of immune responses by Hsp60 and lipopolysaccharide.
Authors:
Osterloh, Anke; Kalinke, Ulrich; Weiss, Siegfried; Fleischer, Bernhard; Breloer, Minka
Abstract:
Activation of professional antigen-presenting cells (APC) is a crucial step in the initiation of an efficient immune response. In this study we show that Hsp60 mediates immune stimulation by different mechanisms, dependent and independent of lipopolysaccharide (LPS). We have demonstrated earlier that both, Hsp60 and LPS, increase antigen-specific interferon (IFN) gamma release in T cells. Here we show that in contrast to LPS Hsp60 induces IFNalpha production in professional APC. Neutralization of IFNalpha as well as the absence of functional IFNalphabeta receptor on APC and T cells interfered with Hsp60-mediated IFNgamma secretion in antigen-dependent T cell activation, strongly suggesting that IFNalpha represents one factor contributing to Hsp60-specific immune stimulation. On the other hand, we show that Hsp60 bound to the cell surface of APC colocalizes with the LPS co-receptor CD14 and LPS binding sites. Hsp60 specifically binds bacterial LPS and both molecules synergistically enhanced IL-12p40 production in APC and IFNgamma release in antigen-dependent T cell activation. This effect was Hsp60-specific and dependent on LPS-binding by Hsp60. Furthermore, we show that Hsp60 exclusively binds to macrophages and DC but not to T or B lymphocytes and that both, T cell stimulation by Hsp60 as well as Hsp60/LPS complexes, strictly depends on the presence of professional APC and is not mediated by B cells. Taken together, our data support an extension of the concept of Hsp60 as an endogenous danger signal: besides its function as a classical danger signal indicating unplanned tissue destruction to the innate immune system, in the incident of bacterial infection extracellular Hsp60 may bind LPS and facilitate microbe recognition by lowering the threshold of pathogen-associated molecular pattern (PAMP) detection and enhancing Toll-like receptor (TLR) signaling.
Affiliation:
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany. osterloh@bni.uni-hamburg.de
Citation:
Synergistic and differential modulation of immune responses by Hsp60 and lipopolysaccharide. 2007, 282 (7):4669-80 J. Biol. Chem.
Journal:
The Journal of biological chemistry
Issue Date:
16-Feb-2007
URI:
http://hdl.handle.net/10033/19775
DOI:
10.1074/jbc.M608666200
PubMed ID:
17164250
Type:
Article
Language:
en
ISSN:
0021-9258
Appears in Collections:
publications of the research group molecular Immunology (MOLI)

Full metadata record

DC FieldValue Language
dc.contributor.authorOsterloh, Anke-
dc.contributor.authorKalinke, Ulrich-
dc.contributor.authorWeiss, Siegfried-
dc.contributor.authorFleischer, Bernhard-
dc.contributor.authorBreloer, Minka-
dc.date.accessioned2008-03-05T10:41:01Z-
dc.date.available2008-03-05T10:41:01Z-
dc.date.issued2007-02-16-
dc.identifier.citationSynergistic and differential modulation of immune responses by Hsp60 and lipopolysaccharide. 2007, 282 (7):4669-80 J. Biol. Chem.en
dc.identifier.issn0021-9258-
dc.identifier.pmid17164250-
dc.identifier.doi10.1074/jbc.M608666200-
dc.identifier.urihttp://hdl.handle.net/10033/19775-
dc.description.abstractActivation of professional antigen-presenting cells (APC) is a crucial step in the initiation of an efficient immune response. In this study we show that Hsp60 mediates immune stimulation by different mechanisms, dependent and independent of lipopolysaccharide (LPS). We have demonstrated earlier that both, Hsp60 and LPS, increase antigen-specific interferon (IFN) gamma release in T cells. Here we show that in contrast to LPS Hsp60 induces IFNalpha production in professional APC. Neutralization of IFNalpha as well as the absence of functional IFNalphabeta receptor on APC and T cells interfered with Hsp60-mediated IFNgamma secretion in antigen-dependent T cell activation, strongly suggesting that IFNalpha represents one factor contributing to Hsp60-specific immune stimulation. On the other hand, we show that Hsp60 bound to the cell surface of APC colocalizes with the LPS co-receptor CD14 and LPS binding sites. Hsp60 specifically binds bacterial LPS and both molecules synergistically enhanced IL-12p40 production in APC and IFNgamma release in antigen-dependent T cell activation. This effect was Hsp60-specific and dependent on LPS-binding by Hsp60. Furthermore, we show that Hsp60 exclusively binds to macrophages and DC but not to T or B lymphocytes and that both, T cell stimulation by Hsp60 as well as Hsp60/LPS complexes, strictly depends on the presence of professional APC and is not mediated by B cells. Taken together, our data support an extension of the concept of Hsp60 as an endogenous danger signal: besides its function as a classical danger signal indicating unplanned tissue destruction to the innate immune system, in the incident of bacterial infection extracellular Hsp60 may bind LPS and facilitate microbe recognition by lowering the threshold of pathogen-associated molecular pattern (PAMP) detection and enhancing Toll-like receptor (TLR) signaling.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshAntigen Presentationen
dc.subject.meshAntigens, CD14en
dc.subject.meshCOS Cellsen
dc.subject.meshCercopithecus aethiopsen
dc.subject.meshChaperonin 60en
dc.subject.meshCytokinesen
dc.subject.meshDendritic Cellsen
dc.subject.meshImmunity, Naturalen
dc.subject.meshLeukocytesen
dc.subject.meshLipopolysaccharidesen
dc.subject.meshLymphocyte Activationen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred BALB Cen
dc.subject.meshMice, Knockouten
dc.subject.meshProtein Bindingen
dc.subject.meshReceptor, Interferon alpha-betaen
dc.subject.meshSignal Transductionen
dc.subject.meshToll-Like Receptorsen
dc.titleSynergistic and differential modulation of immune responses by Hsp60 and lipopolysaccharide.en
dc.typeArticleen
dc.contributor.departmentDepartment of Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany. osterloh@bni.uni-hamburg.deen
dc.identifier.journalThe Journal of biological chemistryen

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