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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.