title: Treatment with a Urokinase Receptor-derived Cyclized Peptide Improves Experimental Colitis by Preventing Monocyte Recruitment and Macrophage Polarization.
abstract: Leukocyte migration across the blood barrier and into tissues represents a key process in the pathogenesis of inflammatory bowel diseases. The urokinase receptor (urokinase-type plasminogen activator receptor) is a master regulator of leukocyte recruitment. We recently found that cyclization of the urokinase-type plasminogen activator receptor-derived peptide Ser-Arg-Ser-Arg-Tyr [SRSRY] inhibits transendothelial migration of monocytes. Now, we have explored the effects of [SRSRY] administration during experimental colitis.
  
  
  
  The effects of [SRSRY] on cytokine profile, cytoskeletal organization, and cell migration were investigated using phorbol-12-myristate acetate-differentiated THP-1 cells exposed to polarizing stimuli. In vivo, [SRSRY] was intraperitoneally administered during dextran sodium sulfate- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in wild-type or urokinase-type plasminogen activator receptor knockout mice. Levels of pro-inflammatory cytokines and inflammatory monocytes in mucosal infiltrates were assessed by enzyme-linked immunosorbent assay and flow cytometry, respectively.
  
  
  
  [SRSRY] prevents M0 to M1 transition and migration of M1 polarized macrophages. In vivo, [SRSRY] reduces intestinal inflammation diminishing body weight loss and disease activity index. These beneficial effects are accompanied by a reduction of interleukin 1β, interleukin 6, and tumor necrosis factor α, an increase of interleukin 10, and an abridged recruitment of inflammatory monocytes to the inflamed tissue.
  
  
  
  Altogether, these findings indicate that [SRSRY] may be considered as a new drug useful for the pharmacological treatment of chronic inflammatory diseases, such as inflammatory bowel diseases.
authors.affiliation: *IBD Center, Humanitas Research Institute, Rozzano, Italy; †Department of Translational Medicine, Università degli Studi di Milano, Milan, Italy; ‡Neoplastic Progression Unit, Department of Experimental Oncology, IRCCS Istituto Nazionale Tumori "Fondazione G. Pascale," Naples, Italy; §SUN, Second University of Naples, Naples, Italy; ‖Department of Pharmacy, University Federico II, Naples, Italy; and ¶Hunimed-Humanitas University, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Genua
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ingangi
authors.forename: Philippe
authors.initials: P
authors.lastname: Fonteyne
authors.forename: Andrea
authors.initials: A
authors.lastname: Piontini
authors.forename: Ali M
authors.initials: AM
authors.lastname: Yousif
authors.forename: Francesco
authors.initials: F
authors.lastname: Merlino
authors.forename: Paolo
authors.initials: P
authors.lastname: Grieco
authors.forename: Alberto
authors.initials: A
authors.lastname: Malesci
authors.forename: Maria V
authors.initials: MV
authors.lastname: Carriero
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D016764:Cell Polarity / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D016207:Cytokines / Q000187:drug effects; D016264:Dextran Sulfate; D004797:Enzyme-Linked Immunosorbent Assay; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D009000:Monocytes / Q000187:drug effects*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D012720:Severity of Illness Index; D015431:Weight Loss / Q000187:drug effects
chemical_list: D016207:Cytokines; D009842:Oligopeptides; D016264:Dextran Sulfate