Human recombinant heat shock protein 70 affects the maturation pathways of dendritic cells in vitro and has an in vivo adjuvant activity.
Heat shock proteins (HSPs) are potent inducers of an antigen-specific immunological response. A role of chaperon of immunogenic peptides and a direct effect on APC activation and function have been described. However, the signal transduction events involved in the activation of human APCs are poorly characterized. We investigated, using human monocyte-derived dendritic cells (DCs), the signal transduction pathways activated by a human recombinant HSP70 (r)HSP70 purified from eukaryotic cells. rHSP70 effectively induced a partial maturation of DCs in vitro and a significant increase in the titers of antigen-specific IgG when used as a vaccine adjuvant in vivo. rHSP70 did not desensitize human DCs to LPS stimulation and retained its adjuvant properties in C3H/HeJ mice, which are LPS-resistant as a result of a mutation in TLR-4, ruling out the potential interference of LPS contamination. Effects on DC maturation and in vivo functions correlate to the ability of rHSP70 to activate IkappaB-alpha/NF-kappaB and ERK1/2 pathways in human DCs. No activation of p38 was induced in the same experimental conditions. Our data suggest that the IkappaB-alpha/NF-kappaB pathway has a critical role in the partial maturation of DCs induced by rHSP70.
Valentinis
Barbara
B
Molmed S.p.A., via Olgettina 58, 20132 Milan, Italy. barbara.valentinis@molmed.com
Capobianco
Annalisa
A
Esposito
Francesca
F
Bianchi
Alessandro
A
Rovere-Querini
Patrizia
P
Manfredi
Angelo A
AA
Traversari
Catia
C
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000941:Antigens; D002454:Cell Differentiation / Q000187:drug effects*; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility / Q000187:drug effects
D000276:Adjuvants, Immunologic; D000941:Antigens; D018840:HSP70 Heat-Shock Proteins; D011994:Recombinant Proteins