Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype

J Immunol. 2003 Mar 1;170(5):2340-8. doi: 10.4049/jimmunol.170.5.2340.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / enzymology
  • Bone Marrow Cells / immunology
  • Bone Marrow Cells / metabolism
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Chaperonin 60 / physiology*
  • Cytokines / biosynthesis
  • Dendritic Cells / cytology*
  • Dendritic Cells / enzymology
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Drosophila Proteins*
  • Drug Contamination
  • Female
  • Humans
  • Immunophenotyping*
  • Isoantigens / immunology
  • Lipopolysaccharides / pharmacology
  • Lymphocyte Activation / immunology
  • MAP Kinase Signaling System / immunology
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • NF-kappa B / physiology
  • Phosphorylation
  • Receptors, Cell Surface / deficiency
  • Receptors, Cell Surface / physiology
  • T-Lymphocytes / immunology
  • Th1 Cells / cytology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism*
  • Toll-Like Receptor 4
  • Toll-Like Receptors

Substances

  • Chaperonin 60
  • Cytokines
  • Drosophila Proteins
  • Isoantigens
  • Lipopolysaccharides
  • Membrane Glycoproteins
  • NF-kappa B
  • Receptors, Cell Surface
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Toll-Like Receptors