title: Critical role of the CD40 CD40-ligand pathway in regulating mucosal inflammation-driven angiogenesis in inflammatory bowel disease.
abstract: OBJECTIVE
  Angiogenesis is a novel component in inflammatory bowel disease (IBD) pathogenesis. We have previously shown that immune-nonimmune interactions through the CD40-CD40-ligand (CD40L) pathway might sustain gut inflammation, although their effect on regulating inflammation-driven angiogenesis is unknown. The present study evaluated the role of the CD40-CD40L interaction in the promotion of immune-mediated angiogenesis in IBD.
  
  
  METHODS
  Human nonimmune cells of colonic origin-namely, human intestinal fibroblasts (HIFs) and human intestinal microvascular endothelial cells (HIMECs)-were activated with either soluble CD40L (sCD40L), or CD40(+) D1.1 cells or CD40L-activated lamina propria T (LPT) cells before measuring pro-angiogenic cytokine release. Blocking antibodies to either CD40 or CD40L were used to disrupt the CD40-CD40L interaction. The dextran sodium sulphate (DSS) model of experimental colitis in CD40 and CD40L knockout mice was established to assess whether the CD40-CD40L pathway was implicated in controlling inflammation-driven angiogenesis in vivo.
  
  
  RESULTS
  Engagement of CD40 on HIFs promoted the release of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and hepatocyte growth factor (HGF). LPT cells were potent inducers of pro-angiogenic cytokine secretion by HIFs. Supernatants from sCD40L-activated HIFs induced migration of HIMECs and tubule formation, both of which were inhibited by blocking antibodies to either VEGF, IL-8 or HGF. Both CD40- and CD40L-deficient mice were protected from DSS-induced colitis and displayed a significant impairment of gut inflammation-driven angiogenesis, as assessed by microvascular density.
  
  
  CONCLUSIONS
  The CD40-CD40L pathway appears to be crucially involved in regulating inflammation-driven angiogenesis, suggesting that strategies aimed at blocking CD40-CD40L interactions might be beneficial in acute and chronic intestinal injury.
authors.affiliation: Division of Gastroenterology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy. sdanese@hotmail.com
authors.forename: S
authors.initials: S
authors.lastname: Danese
authors.forename: F
authors.initials: F
authors.lastname: Scaldaferri
authors.forename: S
authors.initials: S
authors.lastname: Vetrano
authors.forename: T
authors.initials: T
authors.lastname: Stefanelli
authors.forename: C
authors.initials: C
authors.lastname: Graziani
authors.forename: A
authors.initials: A
authors.lastname: Repici
authors.forename: R
authors.initials: R
authors.lastname: Ricci
authors.forename: G
authors.initials: G
authors.lastname: Straface
authors.forename: A
authors.initials: A
authors.lastname: Sgambato
authors.forename: A
authors.initials: A
authors.lastname: Malesci
authors.forename: C
authors.initials: C
authors.lastname: Fiocchi
authors.forename: S
authors.initials: S
authors.lastname: Rutella
mesh_terms: D000818:Animals; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003092:Colitis / Q000276:immunology; D003106:Colon / Q000276:immunology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology; D005347:Fibroblasts / Q000276:immunology; D017228:Hepatocyte Growth Factor / Q000032:analysis; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D016209:Interleukin-8 / Q000032:analysis; D007413:Intestinal Mucosa / Q000098:blood supply / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
chemical_list: D019013:CD40 Antigens; D016209:Interleukin-8; D042461:Vascular Endothelial Growth Factor A; D023201:CD40 Ligand; D017228:Hepatocyte Growth Factor