title: Enhanced recruitment of CX3CR1+ T cells by mucosal endothelial cell-derived fractalkine in inflammatory bowel disease.
abstract: OBJECTIVE
  Fractalkine (FKN/CX3CL1) is a unique chemokine combining adhesive and chemotactic properties. We investigated FKN production by the mucosal microvasculature in inflammatory bowel disease (IBD), its capacity for leukocyte recruitment into the gut, and the number of CX3CR1+ cells in the circulation and mucosa of IBD patients.
  
  
  METHODS
  The expression of FKN by human intestinal microvascular endothelial cells (HIMECs) and CX3CR1 by circulating cells was evaluated by flow cytometry, and mucosal CX3CR1+ cells were enumerated by immunohistochemistry. The capacity of FKN to mediate leukocyte binding to HIMECs was assessed by immunoblockade, and to induce HIMEC transmigration by a Transwell system.
  
  
  RESULTS
  The spontaneously low HIMEC FKN expression was enhanced markedly by tumor necrosis factor-alpha plus interferon-gamma stimulation, or direct leukocyte contact. This effect was significantly stronger in IBD than control HIMECs. Up-regulation of HIMEC FKN expression was dependent on p38 and extracellular signal-regulated kinase phosphorylation, as was abrogated by selective mitogen-activated protein kinase inhibitors. Circulating T cells contained significantly higher numbers of CX3CR1+ cells in active IBD than inactive IBD or healthy subjects, and IBD mucosa contained significantly more CX3CR1+ cells than control mucosa. Antibody-blocking experiments showed that FKN was a major contributor to T- and monocytic-cell adhesion to HIMECs. Finally, FKN enhanced the expression of active beta1 integrin on leukocytes and mediated leukocyte HIMEC transmigration.
  
  
  CONCLUSIONS
  In view of the capacity of FKN to mediate leukocyte adhesion, chemoattraction, and transmigration, its increased production by mucosal microvascular cells and increased numbers of circulating and mucosal CX3CR1+ cells in IBD point to a significant role of FKN in disease pathogenesis.
authors.affiliation: Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
authors.forename: Miquel
authors.initials: M
authors.lastname: Sans
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.forename: Carol
authors.initials: C
authors.lastname: de la Motte
authors.forename: Heitor S P
authors.initials: HS
authors.lastname: de Souza
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Rivera-Reyes
authors.forename: Gail A
authors.initials: GA
authors.lastname: West
authors.forename: Manijeh
authors.initials: M
authors.lastname: Phillips
authors.forename: Jeffry A
authors.initials: JA
authors.lastname: Katz
authors.forename: Claudio
authors.initials: C
authors.lastname: Fiocchi
mesh_terms: D000073883:CX3C Chemokine Receptor 1; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology; D019012:Integrin beta1 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000098:blood supply / Q000276:immunology; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; D016207:Cytokines; D019012:Integrin beta1; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases