title: IFN-gamma, tumor necrosis factor-alpha, and urokinase regulate the expression of urokinase receptors on human monocytes.
abstract: The ability of macrophages to reach inflammatory loci is crucial in the function of cellular immunity. Invasive properties of macrophages may be due to the proteinase urokinase which binds to cell surface receptors, and thereby confers on macrophages the capacity for localized proteolysis of the interstitium. Here, we investigated the role of the macrophage-activating factors IFN-gamma, TNF-alpha, and granulocyte-macrophage-CSF and of urokinase on the expression of urokinase receptors by human cultured monocytes. IFN-gamma and TNF-alpha induced increased urokinase binding to human cultured monocytes in a time- and dose-dependent fashion. At optimal concentrations, IFN-gamma (200 U/ml) increased the number of receptors/cell from 14,000 to 64,000, TNF-alpha (50 U/ml) to 30,000, and combinations of IFN-gamma and TNF-alpha to 90,000. Granulocyte-macrophage-CSF had no effect. The enhanced urokinase binding is due to increased numbers of urokinase receptors and not an increased affinity of the receptor for urokinase. In the presence of urokinase during monocyte activation, IFN-gamma induced only 25,000 receptors/cell. However, urokinase does not inhibit increased receptor expression when the cells are activated with TNF-alpha. The effect of urokinase on induction of urokinase receptors by combinations of IFN-gamma and TNF-alpha varied with the dosage of TNF-alpha: A combination of IFN-gamma (200 U/ml) and TNF-alpha (15 U/ml) induced 38,000 receptors/cell in the presence and 90,000 receptors/cells in the absence of urokinase, whereas IFN-gamma (200 U/ml) and TNF-alpha (20 U/ml) induced 90,000 receptors/cell in the absence and presence of urokinase. These studies demonstrate that IFN-gamma, TNF-alpha, and urokinase collectively regulate the number of urokinase receptors on human monocytes. The induction of urokinase receptors may be responsible for increased invasiveness of the activated macrophage.
authors.affiliation: Department of Rheumatology and Immunology, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: J C
authors.initials: JC
authors.lastname: Kirchheimer
authors.forename: Y H
authors.initials: YH
authors.lastname: Nong
authors.forename: H G
authors.initials: HG
authors.lastname: Remold
mesh_terms: D001667:Binding, Competitive; D002478:Cells, Cultured; D006801:Humans; D006861:Hydrogen Peroxide / Q000096:biosynthesis; D007371:Interferon-gamma / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects*; D055293:Receptors, Urokinase Plasminogen Activator; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C524898:PLAUR protein, human; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D014568:Urokinase-Type Plasminogen Activator