Interferon-gamma 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 associated with the presence of the immunomodulatory cytokine interferon-gamma (IFN-gamma). Moreover, in mouse models of atheroma formation or allogeneic transplantation, the serological neutralization or genetic absence of IFN-gamma markedly reduces the extent of intimal expansion. However, other studies have found that exogenous IFN-gamma 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-gamma 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-gamma can induce arteriosclerotic changes in the absence of detectable immunocytes by acting on VSMCs to potentiate growth-factor-induced mitogenesis.
Tellides
G
G
Interdepartmental Program in Vascular Biology and Transplantation, Boyer Center for Molecular Medicine, and the Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA. george.tellides@yale.edu
Tereb
D A
DA
Kirkiles-Smith
N C
NC
Kim
R W
RW
Wilson
J H
JH
Schechner
J S
JS
Lorber
M I
MI
Pober
J S
JS
D000328:Adult; D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology* / Q000276:immunology; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000637:transplantation; D006649:Histocompatibility Antigens / Q000096:biosynthesis; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology / Q000502:physiology*; D051379:Mice; D016513:Mice, SCID; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000096:biosynthesis / Q000502:physiology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000096:biosynthesis / Q000502:physiology; D013552:Swine; D014183:Transplantation, Heterologous
D006649:Histocompatibility Antigens; D010982:Platelet-Derived Growth Factor; D007371:Interferon-gamma; D020797:Receptor, Platelet-Derived Growth Factor beta