The role of heparin/heparan sulphate in the IFN-γ-led Arena

Abstract

IFN-γ (Interferon-gamma) is a pleiotropic cytokine. It is often involved in a variety of physiological processes by binding to the cell surface transmembrane receptor (IFN-γR) to initiate a series of signalling pathways that transmit external signals from cell surface receptors to the cell nucleus. Heparan sulphate (HS), a highly sulphated linear polysaccharide, is ubiquitous on the mammalian cell surface and extracellular matrix. Electrostatic interactions can be generated between the highly sulphated HS region and specific basic amino acid residues in the IFN-γ structure, thereby detaining IFN-γ on the cell surface, and the concentration of IFN-γ on the cell surface is thus, changed. IFN-γ retained on the cell surface will optimize the binding of IFN-γ to the transmembrane receptor resulting in high efficiency signalling. Heparin is a glycosaminoglycan with a structure similar to HS. The structural similarity provides a basis for modelling exogenous heparin dependence for interference with IFN-γ function. This model can be summarized as follows: First, the competitive binding effect; heparin bound to cytokines by competing with membrane-associated HS, causes a decrease in cytokine concentration on the cell surface. Second, the principle of priority occupancy; heparin can occupy the receptor binding site on cytokines, partially preventing the IFN-γ-IFN-γR interaction. These two models interfere with IFN-γ signal transmission. To decipher the mechanism by which heparin influences IFN-γ activity, studies of the structure-activity relationship are in progress. This paper summarizes research progress on the IFN-γ signalling pathway, heparin interference with IFN-γ activity and the structure-activity relationship between heparin and IFN-γ.

Keywords: Heparan sulphate; Heparin; IFN-γ; Structure-activity relationship.