title: Interleukin-15 and its soluble receptor mediate the response to infliximab in patients with Crohn's disease.
abstract: OBJECTIVE
  Infliximab is a monoclonal antibody against tumor necrosis factor that is used to treat patients with inflammatory bowel disease. We investigated serum levels and cellular expression of interleukin (IL)-15 and its receptor (sIL-15Ralpha) in patients with Crohn's disease (CD) treated with infliximab; and the effect on sIL-15Ralpha secretion by epithelial cells.
  
  
  METHODS
  CD patients were given infliximab (n = 40; 3 infusions); 37 healthy controls were studied. Serum levels of IL-15, sIL-15Ralpha, and complex were determined by radioimmunoassay and cytokine levels by enzyme-linked immunosorbent assay. IL-15Ralpha and A Desintegrin and Metalloproteinase 17 levels were assessed by immunohistochemistry. Epithelial cell lines (HT-29 and Caco-2) were cultured with infliximab, adalimumab, or etanercept. Patients were classified as responders and nonresponders according to their Crohn's Disease Activity Index and clinical observations.
  
  
  RESULTS
  Before infliximab, IL-15 was higher in responders than in controls and nonresponders. After infliximab, IL-15 decreased in responders while remaining stable in nonresponders. sIL-15Ralpha and IL-15/sIL-15Ralpha complex levels were higher in CD than in controls and increased only in responders after infliximab. IL-15Ralpha and A Desintegrin and Metalloproteinase 17 colocalized in epithelial cells and were higher in CD patients. In vitro, infliximab but not adalimumab and etanercept induced sIL-15Ralpha secretion by epithelial cells.
  
  
  CONCLUSIONS
  Serum level of sIL-15Ralpha and the IL-15/sIL-15Ralpha complex increased in responder patients and the response was associated with a decrease of IL-15. Infliximab induced the release of the IL-15 receptor alpha, suggesting a specific modulation of IL-15 and its soluble receptor by reverse signaling through transmembrane tumor necrosis factor alpha.
authors.affiliation: INSERM, U892, Equipe Cytokine/Récepteur, Nantes, France. bouchaud-g@univ-nantes.fr
authors.forename: Gregory
authors.initials: G
authors.lastname: Bouchaud
authors.forename: Erwan
authors.initials: E
authors.lastname: Mortier
authors.forename: Mathurin
authors.initials: M
authors.lastname: Flamant
authors.forename: Isabelle
authors.initials: I
authors.lastname: Barbieux
authors.forename: Ariane
authors.initials: A
authors.lastname: Plet
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Galmiche
authors.forename: Yannick
authors.initials: Y
authors.lastname: Jacques
authors.forename: Arnaud
authors.initials: A
authors.lastname: Bourreille
mesh_terms: D051722:ADAM Proteins / Q000032:analysis; D000072198:ADAM17 Protein; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002097:C-Reactive Protein / Q000032:analysis; D003106:Colon / Q000276:immunology; D003424:Crohn Disease / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D006801:Humans; D000069285:Infliximab; D019409:Interleukin-15 / Q000502:physiology*; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D053647:Receptors, Interleukin-15 / Q000032:analysis / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D000911:Antibodies, Monoclonal; D019409:Interleukin-15; D015850:Interleukin-6; D053647:Receptors, Interleukin-15; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D000069285:Infliximab; D051722:ADAM Proteins; D000072198:ADAM17 Protein