Tumor Necrosis Factor-alpha as a target cytokine in vascular disease

Sammanfattning: Inflammation plays an important role in atherosclerosis. One of the most potent pro-inflammatory cytokines is tumor necrosis factor-alpha (TNF-a), a cytokine identified to have a pathogenic role in chronic inflammatory diseases such as rheumatoid arthritis (RA). The major objectives of this investigation was to establish a role for TNF-a in the development of atherosclerosis and neointimal formation. The two pathological conditions have many things in common. Both are hyperplastic events with vesselwall remodeling and an element of inflammation: accumulation of leukocytes and macrophages in a remoding lipid-laden vessel wall. Intimal hyperplasia is a process present both in early atherosclerosis and after vascular intervention such as balloon angioplasty. The processes are inextricably entwined since restenosis is the consequence of interventions done in attempts to sway atherosclerotic disease. We report that atherosclerosis is inhibited in mice when TNF-a is depleted by genetic manipulation, by circulating antagonizers or when it is targeted in hematopoietic cells. This attenuation is caused by TNF-a derived from hematopoietic cells and is independent of circulating lipid levels. We also report that neointimal formation is inhibited by genetic deletion of TNF-a. The reduction is accompanied with less matrix deposition and smaller cell populations in the TNF-a depleted animals. We also report that smooth muscle cells isolated from the neointima of injured rat aortas are characterized by increased expression of TNF-a in response to interleukin-1b and interferon-g compared to medial smooth muscle cells. Cytokine-induced apoptosis in intimal cells was effectively inhibited by treatment with antibodies against TNF-receptors. These findings demonstrate that TNF-a might be actively involved in the progression of atherosclerosis and neointimal hyperplasia. These findings also sugggest that endogenous activation of TNF receptors may represent a way to limit accumulation of smooth muscle cells in injured arteries. This mechanism may also be important in SMC death in advanced atherosclerotic plaques.