Interferon-γ elicits arteriosclerosis in the absence of leukocytes

Atherosclerosis and post-transplant graft arteriosclerosis are both characterized by expansion of the arterial intima as a result of the infiltration of mononuclear leukocytes, the proliferation of vascular smooth muscle cells (VSMCs) and the accumulation of extracellular matrix. They are also assoc...

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Bibliographic Details
Published in:	Nature (London) 2000-01, Vol.403 (6766), p.207-211
Main Authors:	Tellides, George, Tereb, Denis A, Kirkiles-Smith, Nancy C, Kim, Richard W, Wilson, Jean H, Schechner, Jeffrey S, Lorber, Marc I, Pober, Jordan S
Format:	Article
Language:	eng
Subjects:	Adult Animals Arteriosclerosis - etiology Arteriosclerosis - immunology Atherosclerosis (general aspects, experimental research) Biological and medical sciences Blood and lymphatic vessels Cardiology. Vascular system Cardiovascular disease Cell Division - physiology Cells Cells, Cultured Coronary Vessels - transplantation g-Interferon Histocompatibility Antigens - biosynthesis Humans Image Processing, Computer-Assisted Immunohistochemistry Immunology Interferon-gamma - physiology Leukocytes - immunology Leukocytes - physiology Medical sciences Mice Mice, SCID mitogenesis Muscle, Smooth, Vascular - cytology Muscle, Smooth, Vascular - physiology Muscular system Platelet-Derived Growth Factor - biosynthesis Platelet-Derived Growth Factor - physiology Receptor, Platelet-Derived Growth Factor beta - biosynthesis Receptor, Platelet-Derived Growth Factor beta - physiology Rodents Swine Transplantation, Heterologous
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Summary:	Atherosclerosis and post-transplant graft arteriosclerosis are both characterized by expansion of the arterial intima as a result of the infiltration of mononuclear leukocytes, the proliferation of vascular smooth muscle cells (VSMCs) and the accumulation of extracellular matrix. They are also associated with the presence of the immunomodulatory cytokine interferon-γ (IFN-γ). Moreover, in mouse models of atheroma formation or allogeneic transplantation, the serological neutralization or genetic absence of IFN-γ markedly reduces the extent of intimal expansion. However, other studies have found that exogenous IFN-γ inhibits cultured VSMC proliferation and matrix synthesis, and reduces intimal expansion in response to mechanical injury. This discrepancy is generally explained by the idea that IFN-γ either directly activates macrophages, or, by increasing antigen presentation, indirectly activates T cells within the lesions of atherosclerosis and graft arteriosclerosis. These activated leukocytes are thought to express the VSMC-activating cytokines and cell-surface molecules that cause the observed arteriosclerotic responses. Here we have inserted pig and human arteries into the aorta of immunodeficient mice, and we show that IFN-γ can induce arteriosclerotic changes in the absence of detectable immunocytes by acting on VSMCs to potentiate growth-factor-induced mitogenesis.
ISSN:	0028-0836 1476-4687