Targeting Interferon-γ to Treat Atherosclerosis
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See related article, pages 348–356
The chronic inflammatory nature of atherosclerotic disease is now widely appreciated. Abnormal deposition and oxidative modification of serum lipoproteins in arterial walls stimulates the recruitment of monocytes and their conversion into foam cells. Concurrently, both innate and adaptive immune responses are induced. Cytokines and growth factors produced as part of these responses lead to the remodeling of the arterial wall that typifies atherosclerotic lesions, including SMC accumulation and collagenous matrix deposition in the intima.1 The predominant inflammatory cells found in the atherosclerotic plaques are macrophages and T lymphocytes.2 The majority of T lymphocytes in atherosclerotic lesions are CD4+ T-helper cells expressing markers of activation.3 These activated T lymphocytes have been shown to be important in propagating the inflammatory processes that enhance lesion development.4,5 The majority of these T cells have a phenotype characteristic of the proinflammatory T-helper 1 (Th1) subset, and Th1-mediated immune responses have been shown to correlate with the development of atherosclerosis in mouse models.6–8
The signature cytokine produced by Th1 cells is interferon (IFN)γ. Immunohistochemical and in situ hybridization studies indicate that IFNγ is present in human atherosclerotic plaques.2,9–11 Numerous studies in mice have demonstrated a central role of IFNγ in atherosclerosis. Genetic ablation of IFNγ or IFNγ receptor (IFNγR) expression in mice significantly reduces atherosclerosis,12,13 whereas administration of exogenous IFNγ potentiates atherosclerosis.14 IFNγ has many different biologic effects …