title: Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF).
abstract: 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/EBPbeta 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.
authors.affiliation: Fraunhofer Institute, Stuttgart, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Burger-Kentischer
authors.forename: Heike
authors.initials: H
authors.lastname: Göbel
authors.forename: Robert
authors.initials: R
authors.lastname: Kleemann
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Doris
authors.initials: D
authors.lastname: Finkelmeier
authors.forename: Georg
authors.initials: G
authors.lastname: Geiger
authors.forename: Hans E
authors.initials: HE
authors.lastname: Schaefer
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Herwig
authors.initials: H
authors.lastname: Brunner
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rütten
authors.forename: Christian
authors.initials: C
authors.lastname: Ihling
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bernhagen
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology*; D001025:Aortitis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D023201:CD40 Ligand / Q000378:metabolism; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D015870:Gene Expression; D007155:Immunologic Factors / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D007155:Immunologic Factors; D008263:Macrophage Migration-Inhibitory Factors; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D023201:CD40 Ligand; D018664:Interleukin-12; D012313:RNA; D020778:Matrix Metalloproteinase 2