NEW STRATEGIES FOR CHEMOKINE INHIBITION AND MODULATION - YOU TAKE THEHIGH ROAD AND ILL TAKE THE LOW ROAD

Chemokines are low molecular weight cytokines that induce extravasatio n, chemotaxis, and activation of a wide variety of leukocytes. Members of the different chemokine families are defined by the orientation of specific critical cysteine residues, and are designated as C-X-C (e.g . interleukin-8), C-C (e.g. regulated upon activation normally T cell expressed and secreted, RANTES), or C (lymphotactin). All chemokines b ind to members of a G-protein coupled serpentine receptor superfamily that span the leukocyte cell surface membrane seven times and mediate the biological activities of the individual ligands. Most chemokines p ossess two major binding surfaces: a high affinity site responsible fo r specific ligand/receptor interactions and a lower affinity site, als o called the heparin-binding or glycosaminoglycan-binding domain, beli eved to be responsible for the establishment-and presentation of chemo kine gradients on the surface of endothelial cells and within the extr acellular matrix. Although chemokines are clearly beneficial in wound healing, hemopoiesis, and the clearance of infectious organisms, the c ontinued expression of chemokines is associated with chronic inflammat ion. Therefore, this class of cytokines are attractive targets for the creation of antagonists that abrogate one or more chemokine functions . It is envisioned that such antagonists could serve as a new class of anti-inflammatory drugs. In this commentary, we will discuss two diff erent but related strategies for antagonizing chemokine-induced functi ons, namely, disruption of the low and high affinity binding sites. (C ) 1997 Elsevier Science Inc.