Interferon-γ elicits arteriosclerosis in the absence of leukocytes

Abstract

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^1,2,3. They are also associated with the presence of the immunomodulatory cytokine interferon-γ (IFN-γ)^2,3. Moreover, in mouse models of atheroma formation or allogeneic transplantation, the serological neutralization⁴ or genetic absence^5,6,7,8 of IFN-γ markedly reduces the extent of intimal expansion. However, other studies have found that exogenous IFN-γ inhibits cultured VSMC proliferation^{9,10,11,12,13,14} and matrix synthesis¹⁵, and reduces intimal expansion in response to mechanical injury^16,17,18. 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^1,2,3 and cell-surface molecules¹⁹ 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.