The antagonism of interferon-gamma (IFN-gamma) by heparin: examination of the blockade of class II MHC antigen and heat shock protein-70 expression.
IFN-gamma is a pleiotropic cytokine that is primarily involved in the regulation of immune cell activation and the development of tissue inflammation. It is capable of activating a range of non-immune cells, including those of the vascular endothelium. These cells respond by increasing the expression of intracellular and cell-surface molecules such as class II MHC antigens and adhesion molecules that, together, increase the tendency for interaction with immune cells. It is known that IFN-gamma can bind cell surface and extracellular heparan sulphate. Furthermore, soluble heparin can inhibit the function of this cytokine, presumably by competitive displacement from the cell surface, resulting in the failure of normal receptor signal transduction. In this study it is shown that heparin can prevent normal induction of the class II transactivator and heat shock cognate protein-70 in an IFN-gamma-treated endothelial cell line. Both of these molecules are dependent on the activation of intracytoplasmic STAT-1, which is the most receptor proximal component of their respective induction pathways. This provides further evidence for the blockade by heparin of ligand activation of the specific IFN-gamma receptor.
Fritchley
S J
SJ
Surgical Immunobiology Unit, Department of Surgery, The Medical School, University of Newcastle, Newcastle upon Tyne, UK.
Kirby
J A
JA
Ali
S
S
D002460:Cell Line; D004336:Drug Antagonism; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D006493:Heparin / Q000494:pharmacology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics*
D018840:HSP70 Heat-Shock Proteins; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D015534:Trans-Activators; D007371:Interferon-gamma; D006493:Heparin