Role of Interferon-γ in Hypercholesterolemia-Induced Leukocyte–Endothelial Cell Adhesion

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Abstract
Background— A T-cell–mediated inflammatory response occurs in the microcirculation during acute hypercholesterolemia. The objective of this study was to define the contribution of T-lymphocyte–derived interferon-γ (IFN-γ) to the leukocyte–endothelial cell adhesion induced by hypercholesterolemia. Methods and Results— Intravital videomicroscopy was used to quantify the adhesion and emigration of leukocytes and oxidant stress (dihydrorhodamine [DHR] oxidation) in cremasteric venules. Wild-type (WT), IFN-γ−/−, and severe combined immunodeficiency (SCID) mice were placed on either a normal (ND) or high-cholesterol (HC) diet for 2 weeks. WT-HC mice exhibited exaggerated adhesion and emigration of leukocytes and enhanced DHR oxidation compared with WT-ND. The exaggerated adhesion responses and increased DHR oxidation were not seen in IFN-γ−/−–HC mice. SCID-HC mice also exhibited attenuated inflammatory responses compared with WT-HC. Reconstitution of either SCID-HC or IFN-γ−/−–HC mice with WT-HC splenocytes restored the inflammatory responses, whereas reconstitution of SCID-HC with IFN-γ−/−–HC splenocytes did not. The HC-induced oxidant stress was restored in IFN-γ−/−–HC mice reconstituted with WT-HC splenocytes. Conclusions— These findings implicate IFN-γ as a cause of the inflammatory phenotype that is assumed by the microvasculature of hypercholesterolemic mice and suggest that T lymphocytes are a major source of this proinflammatory cytokine.

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