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Expression of macrophage migration inhibitory factor in different stages of human atherosclerosis

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Author: Burger-Kentischer, A. · Goebel, H. · Seiler, R. · Fraedrich, G. · Schaefer, H.E. · Dimmeler, S. · Kleemann, R. · Bernhagen, J. · Ihling, C.
Institution: Gaubius Instituut TNO
Source:Circulation, 13, 105, 1561-1566
Identifier: 236510
doi: doi10.1161/01.CIR.0000012942.49244.82
Keywords: Aortic Diseases · Arteriosclerosis · Carotid Artery Diseases · Cells, Cultured · Coronary Arteriosclerosis · Disease Progression · DNA-Binding Proteins · Endothelium, Vascular · Fibrosis · Humans · Immunohistochemistry · Inflammation · Intracellular Signaling Peptides and Proteins · Lipoproteins, LDL · Macrophage Migration-Inhibitory Factors · Macrophages · Mammary Arteries · Peptide Hydrolases · Transcription Factors · Transcription, Genetic · Up-Regulation


Background - Atherosclerosis is a chronic inflammatory response of the arterial wall to injury. Macrophage migration inhibitory factor (MIF), a cytokine with potent inflammatory functions, was thus considered to be important in atherosclerotic lesion evolution. Methods and Results - We studied the presence and distribution of MIF immunoreactivity (MIF-IR) and MIF mRNA in internal mammary arteries with a normal histology and arteries with plaques in different stages of human atherosclerosis. To address a potential role for the coactivator Jab1 as a cellular mediator of MIF effects in vascular tissue, we correlated the expression of MIF to that of Jab1 by using immunohistochemistry and coimmunoprecipitation. We further sought to determine a potential functional role for endothelium-derived MIF in early atherogenesis by studying the effects of oxidized LDL on MIF expression in cultured human umbilical vascular endothelial cells. The results showed that MIF-IR and Jab1-IR are found in all cell types present in atherosclerotic lesions, that MIF-IR is upregulated during progression of atherosclerosis, that MIF is produced locally in the arterial wall, and that all MIF+ cells are simultaneously Jab1 +. Coimmunoprecipitation experiments demonstrated in vivo complex formation between MIF and Jab1 in plaques. MIF expression in human umbilical vascular endothelial cells and a macrophage line was upregulated after stimulation with oxidized LDL. Conclusions - MIF is produced abundantly by various cells in all types of human atherosclerotic lesions and thus may play an important role in early plaque development and advanced complicated lesions. MIF-Jab1 complexes could serve critical regulatory functions in atherosclerotic lesion evolution. Chemicals/CAS: COPS5 protein, human, EC 3.4.-.-; DNA-Binding Proteins; Intracellular Signaling Peptides and Proteins; Lipoproteins, LDL; Macrophage Migration-Inhibitory Factors; oxidized low density lipoprotein; Peptide Hydrolases, EC 3.4.-; Transcription Factors