CXC Chemokines in Angiogenesis Relevant to Chronic Fibroproliferation

The CXC chemokines are an unique family of cytokines known for their ability to behave in a disparate manner in the regulation of angiogenesis. The mechanisms for the different activity in regulating angiogenesis by members of this chemokine family is related to the following: 1) the presence or absence of the structural / functional motif (Glutamic acid-Leucine-Arginine; ‘ELR’ motif) that immediately precedes the first cysteine amino acid residue in the primary structure of these cytokines; 2) interferon-inducible gene expression; and 3) receptors that these chemokines use to mediate their biological activity. Members that contain the ‘ELR’ motif (ELR+) are potent promoters of angiogenesis, and mediate their angiogenic activity via binding and activating CXCR2 on endothelium. In contrast, members that are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis, and bind to the alternatively splice variant of CXCR3, CXCR3B on endothelium. This review will discuss the biology of these angiogenic and angiostatic CXC chemokines, and discuss their disparate angiogenic activity in the context of a variety of chronic fibroproliferative disorders.