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Published online before print May 22, 2003

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(Journal of Leukocyte Biology. 2003;74:118-125.)
© 2003 by Society for Leukocyte Biology

Activation by prion peptide PrP_106–126 induces a NF-B-driven proinflammatory response in human monocyte-derived dendritic cells

Silvia M. Bacot^*, Petra Lenz, Michelle R. Frazier-Jessen^* and Gerald M. Feldman^*

^* Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland; and
Laboratory of Cellular Oncology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Correspondence: Gerald M. Feldman, Ph.D., Food and Drug Administration, HFB-564, Bldg. 29A, Rm. 3C24, 29 Lincoln Drive, Bethesda, MD 20892. E-mail: feldman{at}cber.fda.gov

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-B within 15 min of exposure, with as little as 25 µM peptide. This signaling cascade results in the up-regulation of inflammatory cytokines interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF-) at the mRNA and protein levels. Phenotypic activation of DCs exposed to PrP_106–126 is partly a result of an autocrine TNF- 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.

Key Words: TSE • cell signaling • inflammation

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