The chemokine network. I. How the genomic organization of chemokines contains clues for deciphering their functional complexity

Chemokines are a superfamily of small structurally related cytokines that have evolved to form a complex network of proteins that typically regulate leucocyte traffic but also carry very diverse sets of immune and non-immune functions. Two general features of cytokines, redundancy and promiscuity, are particularly prominent in chemokines. In part, these properties result from repeated processes of gene duplication and diversification, which has led to the present complex genomic map of chemokines, which contains cases of non-allelic isoforms, copy number polymorphisms and classical allelic variation. This genomic complexity is compounded with pre-translational and post-translational mechanisms resulting in a complex network of proteins whose essential functions are maintained, constituting a remarkable case of robustness reminiscent of crucial metabolic pathways. This reflects the adaptation of a system under strong evolutive pressure, supporting the concept that the chemokine system is essential for the coordination, regulation and fine-tuning of the type of immune response. In this first review, we analyse currently available data on the chemokine superfamily, focusing on its complex genomic organization. Genes encoding essential inflammatory chemokines are grouped into defined chromosomal locations as clusters and miniclusters that, from the genetic point of view, can be considered single entities given their overall functions (many ligands of a cluster bind to a few shared receptors). We will try to interpret this genomic organization of chemokines in relation to the main functions acquired by each individual member or by each cluster. In a second review, we shall focus on the relationship of chemokine variability and disease susceptibility.