Modulation of cytokine function by heparan sulfate proteoglycans: sophisticated models for the regulation of cellular responses to cytokines

Cytokines are diffusible, soluble factors with pleiotropic actions. The ability of some cytokines to blind to and be immobilized by heparan sulfate proteoglycan (HS-PG) on either the surface of cells or within the extracellular matrix accentuates their action by 1) promoting the accumulation of cytokines at high concentrations in the appropriate location to encounter their target cells; 2) activating cytokines by inducing conformational changes in the bound cytokine; 3) promoting conformation-dependent association or polymerization of cytokines and their cell-surface receptors and facilitating the assembly of the appropriate molecular complex to initiate signal transduction; and 4) protecting cytokines from both chemical and physiological degradation. Furthermore, many interactions between HS-PG and cytokines are highly specific. Thus, variations in the HS-PG, core protein, or carbohydrate sequences that are seen at different sites or that occur with inflammation will determine which cytokines bind to a particular HS-PG, providing multiple options for cytokine binding and regulation. HS-PG therefore plays a pivotal role in regulating the function of the large number of heparin-binding cytokines. The involvement of HS-PG in promoting paracrine, autocrine, juxtacrine, and matricrine functions provides a powerful and sophisticated model for regulating cytokine-mediated cellular interactions. These functions of HS-PG have direct relevance for the control of cell growth as well as for the pathogenesis of leukocyte trafficking and inflammation, cell infiltration, and tumor metastasis. Therapies aimed at modulating HS-PG/cytokine binding may provide powerful tools for inhibiting unwanted cytokine effects in several disease processes.