title: Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease.
abstract: OBJECTIVE
  Early onset inflammatory bowel diseases (EO-IBD) developing during the first year of life are likely to reflect inherited defects in key mechanism(s) controlling intestinal homeostasis, as recently suggested for interleukin 10 (IL10). Thus, we aimed to further elaborate the hypothesis of defective anti-inflammatory responses in patients with IBD.
  
  
  METHODS
  The capacities of transforming growth factor β (TGFβ) and IL10 to inhibit proinflammatory cytokine production by monocyte-derived dendritic cells (MoDC) or peripheral blood cells (PBMC) was analyzed in 75 children with IBD, including 13 infants with EO-IBD (in whom autoimmune diseases or classical immunodeficiencies were ruled out). IL10 receptor-A/-B expression, STAT3 activation in response to IL6, IL10, IL21, IL22 were analyzed by FACS and western blotting. IL10RA and B genes were sequenced. The response to IL22 was tested in ileal/colonic tissue cultures. Tissue gene expression was analyzed by Taqman real-time polymerase chain reaction.
  
  
  RESULTS
  Production of IL10 in response to bacterial motifs was normal in all IBD patients. In contrast to our original hypothesis, no defect of the anti-inflammatory potential of TGFβ and IL10 was observed in children with IBD or EO-IBD except two infants who presented with granuloma-positive colitis at 3 months of life: no response to IL10 was observed secondary to mutations in the α (p.R262C) or β (p.E141X) chain of IL10R, respectively, although a fully functional Jak-STAT3 pathway was present in both patients. When analyzing the regulation of intestinal bacterial clearance, we detected a defect in the patient with absent IL10 RB to upregulate protective transcripts in response to IL22, whereas all other EO-IBD patients, including the patient with an abnormal α chain, responded normally.
  
  
  CONCLUSIONS
  Impaired IL10 signaling characterizes a subgroup of IBD patients, whereas the majority of children with severe IBD including EO forms normally produces and responds to IL10. Defective IL22 signaling may additionally impair intestinal epithelial clearance. Our data point out the complexity of IBD, which represent a group of distinct diseases with several pathogenetic abnormalities.
authors.affiliation: INSERM U989, Paris, France.
authors.forename: Bernadette
authors.initials: B
authors.lastname: Begue
authors.forename: Julien
authors.initials: J
authors.lastname: Verdier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Olivier
authors.initials: O
authors.lastname: Goulet
authors.forename: Alain
authors.initials: A
authors.lastname: Morali
authors.forename: Danielle
authors.initials: D
authors.lastname: Canioni
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Hugot
authors.forename: Cécile
authors.initials: C
authors.lastname: Daussy
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Pigneur
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Christoph
authors.initials: C
authors.lastname: Klein
authors.forename: Nadine
authors.initials: N
authors.lastname: Cerf-Bensussan
authors.forename: Frank M
authors.initials: FM
authors.lastname: Ruemmele
mesh_terms: D015153:Blotting, Western; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000276:immunology*; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism*; D053710:Interleukin-10 Receptor beta Subunit / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D018396:Mucin-1 / Q000378:metabolism; D009077:Mucins / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D016133:Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D023083:beta-Defensins / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D016753:Interleukin-10; D053710:Interleukin-10 Receptor beta Subunit; D007378:Interleukins; D018396:Mucin-1; D009077:Mucins; D010446:Peptide Fragments; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D023083:beta-Defensins; D000097043:Interleukin-22; C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; C081846:IL10RB protein, human; C520326:MUC-1 protein, human (950-958); C429552:MUC13 protein, human; C494086:STAT3 protein, human