Stabilization of Atherosclerotic Plaques by Blockade of Macrophage Migration Inhibitory Factor After Vascular Injury in Apolipoprotein E–Deficient Mice

Abstract

Background-Macrophage migration inhibitory factor (MIF), a cytokine that controls cell-mediated inflammatory responses, is upregulated in atherogenesis; however, its functional contribution to lesion development has not been evaluated. Methods and Results-We studied the role of MIF on neointima lesion formation after wire-induced injury of carotid arteries in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice. Immunohistochemistry revealed that MIF expression was detectable in endothelial cells before injury and upregulated in smooth muscle cells (SMCs) 24 hours after endothelial denudation. Three weeks after injury, MIF was predominantly found in endothelial cells and macrophage-derived foam cells. Neutralizing MIF with a monoclonal antibody resulted in a marked reduction of neointimal macrophages and inhibited transformation of macrophages into foam cells. Conversely, the content of SMCs and of collagen in the neointima were increased, amounting to a slight but not significant reduction in neointima and media size after 3 weeks of MIF monoclonal antibody treatment. Notably, serum levels of the cytokines IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor were increased in MIF monoclonal antibody-treated mice. In vitro flow assays revealed that MIF pretreatment of aortic endothelium enhanced monocyte recruitment and that the monocyte arrest induced by oxidized LDL is mediated by endothelial MIF, as shown by monoclonal antibody inhibition. Conclusions-Inhibition

Association of Systemic Concentrations of Macrophage Migration Inhibitory Factor With Impaired Glucose Tolerance and Type 2 Diabetes

“…In addition, MIF participates in the development of atherosclerosis and restenosis in different mouse models (17)(18)(19) and regulates cell proliferation and differentiation, promotes tumor growth and neovascularization, and may link type 2 diabetes and increased incidence of cancer (20). Taken together, our data strongly suggest that elevations of systemic MIF precede the onset of type 2 diabetes, but prospective studies are required to test the hypothesis that measurement of MIF may be useful for disease prediction.…”

The Potential Role of Macrophage Migration Inhibitory Factor on the Migration of Vascular Smooth Muscle Cells

“…These clinical findings suggest the contribution of MIF to the development of atherosclerosis and support our hypothesis. The MIF inhibitor has been shown to inhibit the pro-inflammatory activity of MIF 32) , and neutralizing anti-MIF antibody has been shown to inhibit the progression of atherosclerosis in vivo 15,21) ; however, these therapies have not been established in humans and further study is needed to confirm the effect of MIF blockade on the prevention of cardiovascular events.…”

“…Interestingly, increased production of MIF has been observed in VSMCs during the progression of atherosclerotic plaque evolution in humans and in a hypercholesterolemic rabbit model 6,14) . Recent in vivo studies have provided evidence of the role of MIF in accelerated atherosclerosis and re-stenosis 15) . Pan et al demonstrated that MIF / /LDL-R / double knockout mice had reduced intimal thickening in the aortic arch and the atherosclerotic lesion area in the abdominal aorta, accompanied by diminished VSMC proliferation and proteolytic capacity 16) .…”

Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

“…Sheep anti-mouse (Fab 0 ) 2 and donkey anti-rabbit Ig, conjugated with peroxidase, were from Amersham Biosciences (Munich, Germany). Neutralizing MIF mAb (IIID.9) and isotype IgG were prepared as described (Schober et al, 2004) and were used at a 100-fold molar excess.…”