title: Inhibition of plasmin protects against colitis in mice by suppressing matrix metalloproteinase 9-mediated cytokine release from myeloid cells.
abstract: OBJECTIVE
  Activated proteases such as plasmin and matrix metalloproteinases (MMPs) are activated in intestinal tissues of patients with active inflammatory bowel diseases. We investigated the effect of plasmin on the progression of acute colitis.
  
  
  METHODS
  Colitis was induced in Mmp9(-/-), Plg(-/-), and C57BL/6 (control) mice by the administration of dextran sulfate sodium, trinitrobenzene sulfonic acid, or CD40 antibody. Plasmin was inhibited in control mice by intraperitoneal injection of YO-2, which blocks its active site. Mucosal and blood samples were collected and analyzed by reverse-transcription polymerase chain reaction and immunohistochemical analyses, as well as for mucosal inflammation and levels of cytokines and chemokines.
  
  
  RESULTS
  Circulating levels of plasmin were increased in mice with colitis, compared with controls. Colitis did not develop in control mice injected with YO-2 or in Plg(-/-) mice. Colons from these mice had reduced infiltration of Gr1+ neutrophils and F4/80+ macrophages, and reduced levels of inflammatory cytokines and chemokines. Colonic inflammation and colitis induction required activation of endogenous MMP9. After colitis induction, mice given YO-2, Plg(-/-) mice, and Mmp9(-/-) mice had reduced serum levels of tumor necrosis factor and C-X-C motif chemokine ligand 5, compared with control mice.
  
  
  CONCLUSIONS
  In mice, plasmin induces a feedback mechanism in which activation of the fibrinolytic system promotes the development of colitis via activation of MMP9 or proteolytic enzymes. The proteolytic environment stimulates the influx of myeloid cells into the colonic epithelium and the production of tumor necrosis factor and C-X-C motif chemokine ligand 5. In turn, myeloid CD11b+ cells release the urokinase plasminogen activator, which accelerates plasmin production. Disruption of the plasmin-induced chronic inflammatory circuit therefore might be a strategy for colitis treatment.
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Department of Coloproctological Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Munakata
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Department of Coloproctological Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan; Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tashiro
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Chiemi
authors.initials: C
authors.lastname: Nishida
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Aki
authors.initials: A
authors.lastname: Sato
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Department of Coloproctological Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Komiyama
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimazu
authors.affiliation: Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Douaa
authors.initials: D
authors.lastname: Dhahri
authors.affiliation: Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Salama
authors.affiliation: Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Salita
authors.initials: S
authors.lastname: Eiamboonsert
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Ikawadani-cho, Nishi-ku, Kobe, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.affiliation: Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Ikawadani-cho, Nishi-ku, Kobe, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.affiliation: Department of Coloproctological Surgery, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Sakamoto
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Stem Cell Dynamics, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Atopy (Allergy) Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Beate
authors.initials: B
authors.lastname: Heissig
authors.affiliation: Stem Cell Regulation, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science at the University of Tokyo, Minato-ku, Tokyo, Japan; Atopy (Allergy) Center, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. Electronic address: khattori@ims.u-tokyo.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000037:antagonists & inhibitors; D054365:Chemokine CXCL5 / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D005341:Fibrinolysin / Q000037:antagonists & inhibitors* / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D019013:CD40 Antigens; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D004151:Dipeptides; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C419205:YO 2 compound; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D005341:Fibrinolysin; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: IBD; Mouse Model; Plasminogen; UC