Activation by prion peptide PrP106–126 induces a NF-κB-driven proinflammatory response in human monocyte-derived dendritic cells

Abstract

Specific prion peptides have been shown to mimic the pathologic isoform of the prion protein (PrP) and to induce a neurotoxic effect in vitro and in vivo. As monocytic cells are thought to play a role in the transmission and pathogenesis of prion disease, the use of these peptides in regulating monocytic cell function is under intense investigation. In the current study, we characterize the ability of prion peptide PrP(106-126) to activate specific signaling pathways in human monocyte-derived dendritic cells (DCs). Electrophoretic mobility shift assays establish the activation of transcription factor nuclear factor-kappaB within 15 min of exposure, with as little as 25 micro M peptide. This signaling cascade results in the up-regulation of inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha) at the mRNA and protein levels. Phenotypic activation of DCs exposed to PrP(106-126) is partly a result of an autocrine TNF-alpha response and results in an increased ability of these cells to induce lymphocyte proliferation. The effects of PrP(106-126) on DCs were elicited through a receptor complex distinct from that used by human monocytes, demonstrating the ability of this peptide to interact with a multiplicity of receptors on various cell types. Together, these data suggest an involvement of DCs in prion disease pathogenesis.

Accelerated Prion Disease Pathogenesis in Toll-Like Receptor 4 Signaling-Mutant Mice

“…Studies have suggested that the TLR4 ligand LPS and fibrillogenic PrP peptides share a common signaling pathway leading to cytokine generation (3,6,46). Immune cells that express TLR4 such as M⌽s, microglia, and DCs are activated by PrP Sc (3,5,6,38,46,64) and are capable of ingesting and degrading PrP Sc (8,12,35,41).…”

“…Immune cells that express TLR4 such as M⌽s, microglia, and DCs are activated by PrP Sc (3,5,6,38,46,64) and are capable of ingesting and degrading PrP Sc (8,12,35,41). During scrapie pathogenesis, bone marrow-derived M⌽s enter the CNS, where they are likely involved in limiting the accumulation and spread of PrP Sc /scrapie agent throughout the brain (50).…”

Prion Peptide PrP106-126 Induces Inducible Nitric Oxide Synthase and Proinflammatory Cytokine Gene Expression Through the Activation of NF-κB in Macrophage Cells

“…NF-kB pathway and proinflammatory cytokines that are capable of activating it have been previously linked to the pathogenesis of prion diseases (Fabrizi et al, 2001;Bacot et al, 2003;Zhou et al, 2008). In the current study, we characterized the ability of prion peptide PrP106-126 to activate NF-kB signaling pathways in mouse macrophage Ana-1 cells.…”

Clinical Model: Interferons Activate Human Monocytes to An Eradicative Tumor Cell LevelIn Vitro

“…Monocytes were purified from mononuclear cells by Ficoll-Hypaque sedimentation, followed by countercurrent centrifugal elutriation, as reported. 22,23 Elutriated monocytes were Ն95% viable as determined by trypan blue exclusion and Ն90% CD14 ϩ as determined by flow cytometry analysis of representative samples. Monocytes and not contaminating lymphocytes have been shown to be the effector cell when cells with this degree of purity (95%) are used.…”