Stimulation of Th1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat shock protein 70.
The peptide binding C-terminal portion of heat shock protein (HSP)70 (aa 359-610) stimulates human monocytes to produce IL-12, TNF-alpha, NO, and C-C chemokines. The N-terminal, ATPase portion (HSP70(1-358)) failed to stimulate any of these cytokines or chemokines. Both native and the truncated HSP70(359-610) stimulation of chemokine production is mediated by the CD40 costimulatory molecule. Maturation of dendritic cells was induced by stimulation with native HSP70, was not seen with the N-terminal HSP70(1-358), but was enhanced with HSP70(359-610), as demonstrated by up-regulation of CD83, CCR7, CD86, CD80, and HLA class II. In vivo studies in macaques showed that immunization with HSP70(359-610) enhances the production of IL-12 and RANTES. Immunization with peptide-bound HSP70(359-610) in mice induced higher serum IgG2a and IgG3 Abs than the native HSP70-bound peptide. This study suggests that the C-terminal, peptide-binding portion of HSP70 is responsible for stimulating Th1-polarizing cytokines, C-C chemokines, and an adjuvant function.
Peter Gorer Department of Immunobiology, Guy's, King's, & St. Thomas' Hospital Medical and Dental Schools, London, United Kingdom.
Yufei
Y
Wang
Charles G
CG
Kelly
Mahavir
M
Singh
Edward G
EG
McGowan
Anne-Sophie
AS
Carrara
Lesley A
LA
Bergmeier
Thomas
T
Lehner
D000251:Adenosine Triphosphatases / Q000494:pharmacology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis; D001426:Bacterial Proteins; D002454:Cell Differentiation / Q000276:immunology; D002460:Cell Line; D018946:Chemokine CCL5 / Q000096:biosynthesis; D019742:Chemokines, CC / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000096:biosynthesis; D008253:Macaca mulatta; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding / Q000276:immunology; D019713:Receptors, CCR5 / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014611:Vaccination
D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D018946:Chemokine CCL5; D019742:Chemokines, CC; D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; C444642:HSP70 protein, Mycobacterium tuberculosis; D007074:Immunoglobulin G; D010446:Peptide Fragments; D019713:Receptors, CCR5; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D009569:Nitric Oxide; D000251:Adenosine Triphosphatases