The Soluble Form of the Cellular Prion Protein Enhances Phagocytic Activity and Cytokine Production by Human Monocytes Via Activation of ERK and NF-κB

Abstract

The PrPC is expressed in many types of immune cells including monocytes and macrophages, however, its function in immune regulation remains to be elucidated. In the present study, we examined a role for PrPC in regulation of monocyte function. Specifically, the effect of a soluble form of PrPC was studied in human monocytes. A recombinant fusion protein of soluble human PrPC fused with the Fc portion of human IgG1 (designated as soluble PrPC-Fc) bound to the cell surface of monocytes, induced differentiation to macrophage-like cells, and enhanced adherence and phagocytic activity. In addition, soluble PrPC-Fc stimulated monocytes to produce pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Both ERK and NF-κB signaling pathways were activated in soluble PrPC-treated monocytes, and inhibitors of either pathway abrogated monocyte adherence and cytokine production. Taken together, we conclude that soluble PrPC-Fc enhanced adherence, phagocytosis, and cytokine production of monocytes via activation of the ERK and NF-κB signaling pathways.

Activation of human natural killer cells by the soluble form of cellular prion protein

“…A previous report showed that a PrP C -Fc fusion protein induced phosphorylation of ERK and PI3K in a macrophage-like cell line [10]. In addition, a recent study from our group showed that PrP C -Fc activates monocytes via the ERK-1/2 and NF-kB signaling pathways [11]. The discrepancies of signaling pathways involved in the immune cell activation by soluble PrP C -Fc protein may arise from differences in cell types, particularly the difference between monocyte/macrophage cells and NK cells.…”

“…A recombinant soluble human PrP C protein was generated and purified as previously described [11]. Briefly, a plasmid encoding PrP C -Fc, composed of amino acids 21e230 of human PrP C fused with the Fc portion of human IgG1 at the C-terminus, was expressed in HEK293E cells.…”

“…A previous study examined the effect of soluble PrP C protein on monocyte/macrophage cells and found that ERK-1/2 and Akt kinase are activated by soluble PrP C protein [10]. Recently, we generated a soluble form of recombinant PrP C protein by fusing it with the Fc portion of human IgG 1 (PrP C -Fc) and found that it increased phagocytic activity and cytokine production of human monocytes via the ERK and NF-kB pathways [11].…”

Prion Protein Signaling in the Nervous System—A Review and Perspective

“…11 Levels of prion protein expressed in mouse neutrophils have also been shown to be dependent on HPA axis activation during inflammation events. 173 Interestingly, no other bone marrow cell showed this response.…”

“…PrP C appears to be neuroprotective against the build-up of α-synuclein, β-amyloid, and tau plaques, 245 possibly as a result of its influence on phagocytosis and neuroregulation. 11 PrP C has also recently been suggested as a therapeutic agent in the treatment of Alzheimer's disease. 246,247 The relationship between PrP C and Alzheimer's disease has been the subject of a number of recent reviews.…”