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Activation by prion peptide PrP106-126 induces a NF-kappaB-driven proinflammatory response in human monocyte-derived
Silvia M Bacot1, Petra Lenz, Michelle R Frazier-Jessen
1Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
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.
Insights
Prion peptides like PrP(106-126) activate immune cells called dendritic cells (DCs). This activation involves signaling pathways and inflammatory cytokines, suggesting DCs play a role in prion disease.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Monocytic cells may contribute to prion disease transmission and pathogenesis.
- Prion peptides can mimic the pathological prion protein (PrP) and cause neurotoxicity.
Purpose of the Study:
- To investigate the activation of signaling pathways in human monocyte-derived dendritic cells (DCs) by the prion peptide PrP(106-126).
Main Methods:
- Electrophoretic mobility shift assays (EMSA) were used to detect transcription factor activation.
- Quantitative analysis of mRNA and protein levels for inflammatory cytokines.
- Flow cytometry was used to assess DC phenotypic activation and function.
Main Results:
- Prion peptide PrP(106-126) activates nuclear factor-kappaB (NF-κB) in DCs within 15 minutes.
- Activation leads to increased expression of inflammatory cytokines: interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α).
- PrP(106-126) induces DC phenotypic activation, enhancing lymphocyte proliferation, partly via TNF-α.
Conclusions:
- Dendritic cells are activated by PrP(106-126) through distinct receptors, suggesting their involvement in prion disease pathogenesis.
- The study highlights the role of immune cells in prion disease mechanisms.
- Prion peptides can modulate immune cell function, impacting disease progression.