Identification of stimulating and inhibitory epitopes within the heat shock protein 70 molecule that modulate cytokine production and maturation of dendritic cells.
The 70-kDa microbial heat shock protein (mHSP70) has a profound effect on the immune system, interacting with the CD40 receptor on DC and monocytes to produce cytokines and chemokines. The mHSP70 also induces maturation of dendritic cells (DC) and thus acts as an alternative ligand to CD40L on T cells. In this investigation, we have identified a cytokine-stimulating epitope (peptide 407-426), by activating DC with overlapping synthetic peptides (20-mers) derived from the sequence of mHSP70. This peptide also significantly enhances maturation of DC stimulated by mHSP70 or CD40L. The epitope is located at the base of the peptide-binding groove of HSP70 and has five critical residues. Furthermore, an inhibitory epitope (p457-496) was identified downstream from the peptide-binding groove that inhibits cytokine production and maturation of DC stimulated by HSP70 or CD40L. The p38 MAP kinase phosphorylation is critical in the alternative CD40-HSP70 pathway and is inhibited by p457-496 but enhanced by p407-426.
Wang
Yufei
Y
Mucosal Immunology Unit, Department of Oral Medicine and Pathology, Guy's, King's and St. Thomas' Hospital Medical and Dental Schools, London, United Kingdom.
Whittall
Trevor
T
McGowan
Edward
E
Younson
Justine
J
Kelly
Charles
C
Bergmeier
Lesley A
LA
Singh
Mahavir
M
Lehner
Thomas
T
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites / Q000235:genetics; D023201:CD40 Ligand / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D000939:Epitopes / Q000235:genetics; D029968:Escherichia coli Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D000939:Epitopes; D029968:Escherichia coli Proteins; D018840:HSP70 Heat-Shock Proteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D023201:CD40 Ligand; D048051:p38 Mitogen-Activated Protein Kinases