PK1/EG-VEGF induces monocyte differentiation and activation

Abstract

Macrophages exist as sentinels in innate immune response and react by expressing proinflammatory cytokines and up-regulating antigen-presenting and costimulatory molecules. We report a novel function for prokineticin-1 (PK1)/endocrine gland-derived vascular endothelial growth factor. Screening of murine tissue sections and cells for specific binding site leads to the identification of macrophages as an in vivo cellular target for PK1. We demonstrate PK1 induces differentiation of murine and human bone marrow cells into the monocyte/macrophage lineage. Human peripheral blood monocytes respond to PK1 by morphological changes and down-regulation of B7-1, CD14, CC chemokine receptor 5, and CXC chemokine receptor 4. Monocytes treated with PK1 have elevated interleukin (IL)-12 and tumor necrosis factor alpha and down-regulated IL-10 production in response to lipopolysaccharide. PK1 induces a distinct monocyte-derived cell population, which is primed for release of proinflammatory cytokines that favor a T helper cell type 1 response.

The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain

“…Because prokineticins are potent chemoattractans for monocytes and macrophages both in vitro and in vivo and are able to stimulate the release of proinflammatory and proalgesic cytokines from macrophages (17)(18)(19)(20) and monocytes (28) we can further hypothesize that PK2, released at the site of inflammation, represents a component of the cytokine-chemokine loop in inflammatory pain, which is initiated by the arrival of granulocyte and maintained by the subsequent recruitment of monocytes and macrophages. Inflammatory stimuli activate the release of the cytokine G-CSF that stimulates the synthesis and release of the chemokine PK2 by neutrophils, and this chemokine, in turn, stimulates macrophage chemotaxis and cytokine release by recruited macrophages.…”

“…Activation of PKRs in primary afferent C fibers sensitizes nociceptors to thermal, mechanical, and chemical stimuli (14)(15)(16). In neutrophils, macrophages, and dendritic cells it promotes chemotaxis and cytokine release (17)(18)(19)(20), and in capillary endothelial cells it stimulates angiogenesis (21). Testis, peripheral blood leukocytes, and macrophages express two mRNA transcripts of PK2, one coding for the canonical PK2 and the other for an elongated form containing additional 21 basic amino acids between Lys-47 and Val-48 of the mature PK2 protein, named PK2L (6,19,22).…”

Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma

“…Interestingly, PKR1 and PKR2 are most strongly expressed by Kupffer cells. Recent reports have demonstrated that PK2/Bv8 has potent cytokine properties, PK2/Bv8 has the ability to stimulate monocyte production, mobilization and differentiation into macrophage like cells [19,20] . Therefore we can speculate that, in normal liver macrophage physiology, PK2/Bv8 could act by an autocrine manner on the resident macrophage population in the liver sinusoids.…”

“…Prokineticins bioactivities includes, smooth muscle contraction in the gastrointestinal tract [14] , supporting neuronal survival, pain sensation and circadian rhythms in the central nervous system [15][16][17] . Prokineticins display also potent cytokine properties, such as inducing bone marrow leukocyte production, and modulating the growth and function of peripheral leukocytes [18][19][20] . These peptides were also shown to act as angiogenic mitogens, indeed, PK1/EG-VEGF and PK2/Bv8 induce proliferation, migration and fenestration of endothelial cells from adrenal capillaries [21,22] .…”

“…Recent reports have demonstrated that PK2/Bv8 has cytokine properties [20] and is strongly expressed by several types of leukocytes including the monocyte/macrophage lineage [19] . We therefore, hypothesized that the liver resident macrophages might be responsible for the expression of PK2/Bv8.…”