CCL16 activates an angiogenic program in vascular endothelial cells

Abstract

Besides regulating leukocyte trafficking in normal and injured tissues, several chemokines may positively or negatively regulate angiogenesis. Here we report that CCL16 activates an angiogenic program in vascular endothelial cells by activating CCR1. CCL16 induces dose-dependent random and directional migration of endothelial cells isolated from large vessels and liver capillaries without inducing their proliferation. It also promotes endothelial differentiation into capillary-like structures in an in vitro assay and is angiogenic in the chick chorionallantoic membrane. These angiogenic activities are neutralized by a specific antibody against CCL16. The direct angiogenic activity of CCL16 is further amplified by its ability to prime endothelium to a mitogen signal induced by vascular endothelial growth factor A and to raise their basal production of CXCL8 and CCL2, 2 other angiogenic chemokines. BX471 ( IntroductionChemokines are polypeptide molecules mainly involved in the control of leukocyte functions and trafficking through the activation of receptors belonging to the 7-transmembrane spanning, G-protein-coupled receptor family. Near the NH 2 end of the molecule, the presence of cysteine residues identifies 4 subfamilies. They are characterized by the presence of a unique C, or of 2 Cs separated by a single (CXC) or 3 amino acids (CXXXC) or adjacent (CC), and show largely overlapping biologic activities. 1 CCL16, also known as liver-expressed chemokine or NCC-4 or lymphocyte and monocyte chemoattractant or HCC-4, is a CC chemokine that specifically attracts lymphocytes, dendritic cells, and monocytes; increases their adhesive properties; and has myelosuppressive activity. [2][3][4][5][6] It is constitutively expressed in liver 3,7 and is increased by interleukin 10 (IL-10) in activated monocytes. 2 Interestingly, CCL16 is present in human plasma suggesting that it may be active outside hepatic tissue. 7 CCR1, CCR2, CCR5, and CCR8 are the functional receptors of this chemokine. 5,7 CCL16 released by engineered tumor cells elicits their rejection by a CD8 ϩ -and neutrophil-dependent mechanism and a rapid induction of a tumor-specific systemic immune response. This suggests that CCL16 improves recognition of poorly immunogenic cells by promoting a cross talk between T lymphocytes and antigenpresenting cells. 8 The histochemical analysis of these tumors showed expression of adhesion molecules by endothelial cells (ECs), without signs of vascular necrosis or inhibition of angiogenesis, in spite of the abundant neutrophil infiltrate that usually characterizes other models of tumor rejection promoted by cytokines, where vasculature is severely affected. [9][10][11][12][13] Chemokines play a role in embryo and adult vascular bed formation. 14,15 Besides an indirect mechanism involving angiogenic inducers released by activated leukocytes, 16,17 both CC and CXC chemokines may directly activate a proangiogenic [18][19][20][21][22][23][24][25][26][27][28] or an angiostatic 19,[29][30][31][32][33][34][35] program in ECs...

CD13/APN transcription is regulated by the proto-oncogene c-Maf via an atypical response element

“…The aberrant and specific upregulation of the expression of cyclin D2, integrin β7, and the chemokine receptor CCR1 genes has been reported in c-Maf overexpressing multiple myeloma cell lines which contributes to tumorigenicity (Hurt et al, 2004). Since endothelial cells normally express these genes (Strasly et al, 2004) they may also be angiogenically relevant targets of c-Maf in endothelial cells. Transcriptional control of regulators of pathologic angiogenesis on activated endothelium is an important aspect of our understanding of those signals and proteins that contribute to the establishment of an actively angiogenic state.…”

A Novel Recombinant Fusion Protein Encoding a 20-Amino Acid Residue of the Third Extracellular (E3) Domain of CCR2 Neutralizes the Biological Activity of CCL2

“…Human cancer cells produce both chemokines (9). CCL16 is also likely to contribute to tumor invasion and angiogenesis (45). Therefore it could be that its neutralization by BL-2030 also contributes to tumor suppression in a xenograft model of cancer (Fig.…”

Chemokines as mediators of angiogenesis

“…While most of the literature on chemokine regulation of angiogenesis has centered on the role of the CXC family, several members of the CC chemokine family, including CCL11, CCL16 and CCL21 have also been implicated in angiogenesis (28)(29)(30). The best studied CC chemokine ligand implicated in angiogenesis, however, is CCL2: endothelial cells express the CCL2 receptor, CCR2, and demonstrate chemotaxis and tube formation in reponse to CCL2 in vitro (31,32).…”