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. 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.

Stat1-independent regulation of gene expression in response to IFN-γ

“…IFN-␥ potentiates PDGF-mediated mitogenesis under pathological conditions, i.e., in arteriosclerosis (32). Furthermore, a switch from PDGF-dependent signaling to IFN-␥-dependent signaling was observed in 3T3 cells expressing the chimeric PDGF receptor Chi R (Y771), which retains only a single tyrosine residue, at the RAS-GAP site, in its cytoplasmic domain (24).…”

Interferon-γ Induces X-linked Inhibitor of Apoptosis-associated Factor-1 and Noxa Expression and Potentiates Human Vascular Smooth Muscle Cell Apoptosis by STAT3 Activation

“…tor are highly species-restricted, there were no effects on the mouse recipients (29). Artery grafts that were not treated with IFN-␥ showed no histological changes of the vessel cells in response to administration of oligos alone (data not shown).…”

Linking immune-mediated arterial inflammation and cholesterol-induced atherosclerosis in a transgenic mouse model

“…Beside the atherogenic effects of hypercholesterolemia, long-lasting exposure of the vascular wall to interferon-␥ and probably other cytokines might induce SM cell proliferation and subsequent intimal thickening (29,30). However, such strong effects of exclusively immune-mediated intima proliferation probably are restricted to posttransplant graft rejection and therefore are clearly distinct from the multigenic processes of atherosclerosis.…”