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-α, IL-12, and IL-1β. 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-γ 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 IκB 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.

Enhanced T-cell immunity induced by dendritic cells with phagocytosis of heat shock protein 70 gene-transfected tumor cells in early phase of apoptosis

“…In this study, we also demonstrated that apoptotic tumor cells (in late phase of apoptosis) expressing HSP70 stimulate DC maturation after DC phagocytosis of these apoptotic tumor cells, which is consistent with some previous reports. [53][54][55] DCs, with phagocytosis of apoptotic tumor cells (in late phase of apoptosis) expressing HSP70 induced stronger antitumor immunity than DC with phagocytosis of tumor cells in early phase of apoptosis, which is consistent with a recent report from our group. 28 More interestingly, we demonstrated that apoptotic tumor cells expressing HSP70 in early phase of apoptosis more efficiently induce tumor-specific CTL responses and vaccine efficiency than those in late phase of apoptosis in two MCA/HSP and EG7 tumor models.…”

BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas‐mediated cell death

“…However, the ability of BAFF to promote Fas killing is not common to B cells activated through all TLR, since B cells activated with CpG (TLR9 ligand) show no increased susceptibility to Fas-induced death in the presence of BAFF. Additionally, we could not extend our results obtained with LPS to some other proteins (heparan sulfate and HSP60) reported as endogenous ligands of TLR-4 [35][36][37], since endotoxin-free preparations of these proteins systematically failed to activate murine B cells.…”

Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors

“…A further defect in IL2 signaling in hsf1 À/À p53 À/À mice would further amplify this defect. Furthermore, upregulation of Hsp60 expression in p53 À/À lymphomas, known to induce, at least in macrophages, secretion of cytokines such as TNFa, IL6, IL12 and nitric oxide (Flohe et al, 2003), may play a role in tumor progression providing precancerous cells with growth promoting stimuli. A greater dependence of hematological tumors (lymphomas), compared to other tumor types, on survival factors can also explain the selective suppression of lymphomas observed in our study.…”