title: Interferon Gamma Counteracts the Angiogenic Switch and Induces Vascular Permeability in Dextran Sulfate Sodium Colitis in Mice.
abstract: BACKGROUND
  Interferon (IFN)-γ is a central pathogenesis factor in inflammatory bowel disease (IBD) with pleiotropic effects on many different cell types. However, as yet, the immune modulatory functions of IFN-γ in IBD have been predominantly investigated. Based on previous studies showing that IFN-γ acts antiangiogenic in colorectal carcinoma, we investigated the effects of IFN-γ on the vascular system in IBD.
  
  
  METHODS
  Colon tissues of patients with IBD and dextran sulfate sodium-induced colitis in mice were subjected to immunohistochemistry, quantitative real-time polymerase chain reactions, and in situ hybridization to quantify cell activation, angiogenesis, and immune responses. Vascular structure and permeability in mice were analyzed by ultramicroscopy and in vivo confocal laser endomicroscopy.
  
  
  RESULTS
  We showed a significantly increased blood vessel density in IBD and dextran sulfate sodium colitis. In mice, this was associated with a disorganized blood vessel structure and profound vascular leakage. As compared with genes associated with angiogenesis, genes associated with inflammatory cell activation including IFN-γ were more strongly upregulated in colitis tissues. IFN-γ exerted direct effects on endothelial cells in IBD tissues in vivo, as indicated by the expression of IFN-γ-induced guanylate binding protein 1 (GBP-1). Neutralization of IFN-γ in the acute dextran sulfate sodium colitis model demonstrated that this cytokine exerts endogenous angiostatic activity in IBD and contributes to increased vascular permeability.
  
  
  CONCLUSIONS
  The dissection of the pleiotropic activities of IFN-γ in IBD provides new insights to the pathological functions of this cytokine and may be of high relevance for the optimization of combination therapy approaches.
authors.affiliation: *Division of Molecular and Experimental Surgery, Department of Surgery, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany; †Roche Pharma Research and Early Development, Oncology Discovery, Roche Innovation Center Penzberg, Penzberg, Germany; ‡Institute of Molecular Immunology, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; §Department of Medicine I, University Medical Center Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany; and ‖Institute of Pathology, Klinikum Bayreuth, Bayreuth, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Haep
authors.forename: Nathalie
authors.initials: N
authors.lastname: Britzen-Laurent
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Weber
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Naschberger
authors.forename: Alexander
authors.initials: A
authors.lastname: Schaefer
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Foersch
authors.forename: Michael
authors.initials: M
authors.lastname: Vieth
authors.forename: Werner
authors.initials: W
authors.lastname: Scheuer
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
authors.forename: Maximilian
authors.initials: M
authors.lastname: Waldner
authors.forename: Michael
authors.initials: M
authors.lastname: Stürzl
mesh_terms: D000818:Animals; D001706:Biopsy; D001808:Blood Vessels / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D003106:Colon / Q000098:blood supply* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015212:Inflammatory Bowel Diseases / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D060888:Real-Time Polymerase Chain Reaction; D066253:Vascular Remodeling
chemical_list: D007371:Interferon-gamma; D016264:Dextran Sulfate; D019204:GTP-Binding Proteins