The expression of macrophage migration inhibitory factor 1α (MIF 1α) in human atherosclerotic plaques is induced by different proatherogenic stimuli and associated with plaque instability

Objectives: Macrophage migration inhibitory factor 1alpha (M IF), a cytokine with immunoregulatory functions has been suggested to be involved in atherosclerotic plaque development. However, little is known about MIF-inducing conditions in the atherosclerotic process and the association of MIF with plaque instability. Methods and results: Forty-two carotid endatherectomy samples from 36 patients and 4 aortic samples from young accident victims (as healthy controls) were analyzed for MIF staining. MIF expressing tissues in the atherosclerotic plaques are mainly mononuclear cells (MNCs). but also endothelial cells of intimal microvessels (MVECs). The magnitude and the intensity of their MIF expression was associated with the progression of plaques from early lesions (Stary I-III) to complicated plaque stages (Stary IV-VIII). In highly inflammatory and neovascularized regions of the plaques the colocalization of MIF expressing MNCs with CD40-L+ and angiotensin 11 (Ang II)-producing MNCs could be established. This finding supports the notion that CD40-L fusion protein and Ang 11 are able to induce MIF production in the monocytic cell line THP-1 Furthermore hypoxia (less than or equal to 1% O-2) as a further proinflammatory and especially proangiogenetic factor was able to Stimulale MIF secretion by THP-1, human monocytes and HUVECs. Hyperglycemia and insulin remained without effect. Conclusion: MIF is expressed in advanced atherosclerotic lesions in close correlation with signs of instability such as mononuclear cell inflammation and neointimal microvessel formation. Furthermore, the colocalization of MIF with Ang II-producing MNCs and CD40-(+) cells in these plaques and the finding that proathero- and -angiogenic mediators such as CD40-L Ang 11 and hypoxia are able to stimulate MIF expression in vitro suggest an important role of MIF in the modulation of atherosclerotic plaque stability (C) 2004 Elsevier Ireland Ltd. All rights reserved.