Atherosclerosis is an inflammatory response of the arterial wall to "injury", which is prominently driven by cytokines. The inflammatory mediator macrophage migration inhibitory factor (MIF) is a unique cytokine that was recently associated with atherogenesis. Here, we have investigated whether MIF has a role in spontaneous atherosclerosis by studying apolipoprotein E-deficient (ApoE-/-) mice treated with neutralizing anti-MIF monoclonal antibody and comparison with isotype IgG-treated controls. After 14 weeks, the aortas and heart valves were analyzed for inflammatory status, macrophage content and plaque areas. MIF expression in the aortic wall was elevated upon spontaneous atherogenesis, with foam cells representing a major source. Of note, MIF blockade led to a marked reduction in intimal Mac-1-positive macrophages. Similarly, treatment with anti-MIF antibody led to a reduction of a variety of inflammatory mediators typically associated with atherosclerosis including the circulating levels of fibrinogen, MIF and IL-6. Importantly, the local aortic expression of ICAM-1, MMP-2, TNF, IL-12, and CD40L was reduced by MIF blockade, as were the levels of the phospho-c-Jun and C/EBPβ transcription factors. The observed strong reduction of inflammatory parameters by anti-MIF treatment was associated with a small, yet non-significant, reduction in aortic plaque area. Thus, although MIF's role is not directly linked to plaque volume expansion, in this mouse model of spontaneous atherogenesis, MIF plays an important role in intimal inflammation. © 2005 Elsevier Ireland Ltd. All rights reserved. Chemicals / CAS: CD40 ligand, 226713-27-5; fibrinogen, 9001-32-5; gelatinase A, 146480-35-5; immunoglobulin G, 97794-27-9; intercellular adhesion molecule 1, 126547-89-5; interleukin 12, 138415-13-1; stress activated protein kinase, 155215-87-5; Antibodies, Monoclonal; Apolipoproteins E; CD40 Ligand, 147205-72-9; Immunologic Factors; Intercellular Adhesion Molecule-1, 126547-89-5; Interleukin-12, 187348-17-0; Macrophage Migration-Inhibitory Factors; Matrix Metalloproteinase 2, EC 3.4.24.24; RNA, 63231-63-0; Tumor Necrosis Factor-alpha