Chemokines are low molecular weight
cytokines that induce extravasation, 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 bind 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 possess two major binding surfaces: a high affinity site responsible for specific
ligand/receptor interactions and a lower affinity site, also called the
heparin-binding or
glycosaminoglycan-binding domain, believed to be responsible for the establishment and presentation of
chemokine gradients on the surface of endothelial cells and within the extracellular matrix. Although
chemokines are clearly beneficial in wound healing, hemopoiesis, and the clearance of infectious organisms, the continued expression of
chemokines is associated with chronic
inflammation. 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 different but related strategies for antagonizing
chemokine-induced functions, namely, disruption of the low and high affinity binding sites.