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(1-3). They are also associated with the presence of the immunomodulatory cytokine interferon-gamma (IFN-gamma)(2,3). Moreover, in mouse models of atheroma formation or allogeneic transplantation, the serological neutralization(4) or genetic absence(5-8) of IFN-gamma markedly reduces the extent of intimal expansion. However, other studies have found that exogenous IFN-gamma inhibits Cultured VSMC proliferation(9-14) and matrix synthesis(15), and reduces intimal expansion in response to mechanical injury(16-18). 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(1-3) and cell-surface molecules(19) that cause the observed arteriosclerotic responses. Here we have inserted pig and human arteries into the aorta of immunodeficient 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.