title: Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype.
abstract: Heat shock protein (HSP) 60 nonspecifically activates cells of the innate immune system. In the present study, we characterized the effects of human HSP60 maturation, cytokine release, and T cell-activating capacity of bone marrow-derived dendritic cells (DC). Furthermore, we analyzed HSP60-induced signal transduction in DC. HSP60 strongly stimulated DC for maturation and release of TNF-alpha, IL-12, and IL-1 beta. However, HSP60 elicited only a weak IL-10 response in DC suggesting a Th1 bias. HSP60-treated DC induced proliferation of allogeneic T cells. Again, a Th1 bias was noted in that cocultures of allogeneic T cells and HSP60-treated DC released IFN-gamma but only small amounts of IL-10 and no detectable IL-4. Signaling via Toll-like receptor 4 was involved in HSP60-induced cytokine release and maturation because DC of C3H/HeJ mice with a mutant Toll-like receptor 4 showed deficient response to HSP60. HSP60 was found to rapidly activate the mitogen-activated protein kinases p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase as well as I kappa B in DC. Phosphorylation of these signaling molecules was also mediated by LPS, but with much slower kinetics. Thus, HSP60 stimulates DC more rapidly than LPS and elicits a Th1-promoting phenotype. These results suggest that DC play a pivotal role in priming for destructive Th1-type responses at sites of local HSP60 release.
authors.affiliation: German Diabetes Research Institute, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Stefanie B
authors.initials: SB
authors.lastname: Flohé
authors.forename: Jutta
authors.initials: J
authors.lastname: Brüggemann
authors.forename: Sven
authors.initials: S
authors.lastname: Lendemans
authors.forename: Marina
authors.initials: M
authors.lastname: Nikulina
authors.forename: Guido
authors.initials: G
authors.lastname: Meierhoff
authors.forename: Sascha
authors.initials: S
authors.lastname: Flohé
authors.forename: Hubert
authors.initials: H
authors.lastname: Kolb
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D018834:Chaperonin 60 / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D029721:Drosophila Proteins; D004340:Drug Contamination; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007519:Isoantigens / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D018834:Chaperonin 60; D016207:Cytokines; D029721:Drosophila Proteins; D007519:Isoantigens; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors