Characterization and Regulation of Bv8 in Human Blood Cells

Abstract

PURPOSE: Bv8, also known as prokineticin 2, has been recently shown to be a mediator of myeloid cell-dependent tumor angiogenesis in mouse models. We wished to determine whether these findings might be potentially relevant to human disease. EXPERIMENTAL DESIGN: We characterized Bv8 expression in human blood cells in vitro and in vivo, and did Bv8 immunohistochemistry in human tumor sections. We also partially purified Bv8 from human neutrophils and tested its bioactivity. RESULTS: We found that Bv8 expression is regulated by several cytokines in a cell type-specific fashion. Both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor induced Bv8 expression in neutrophils and bone marrow cells, whereas interleukin 10 up-regulated Bv8 expression in monocytes and lymphocytes. Bv8 potently promoted neutrophil chemotaxis. Bv8 protein isolated from human neutrophils was found to be biologically active. Of the two receptors for Bv8 [prokineticin receptor 1(PKR1)/endocrine gland-derived vascular endothelial growth factor receptor 1 (EG-VEGFR1) and PKR2/EG-VEGFR2], only PKR2/EG-VEGFR2 was detectable in human neutrophils. Also, we found a marked up-regulation of Bv8 mRNA and protein in peripheral blood mononuclear cells from G-CSF-treated donors compared with those from untreated individuals, verifying our in vitro observations. Finally, immunohistochemistry showed Bv8 expression in neutrophils infiltrating human tumors. CONCLUSIONS: These results provide the basis for further investigation of the pathophysiologic role of Bv8 in human tumors and inflammatory disorders and, potentially, for therapeutic application of Bv8 inhibitors.