title: Loss of interleukin-10 or transforming growth factor β signaling in the human colon initiates a T-helper 1 response via distinct pathways.
abstract: OBJECTIVE
  Signaling via interleukin (IL)-10 or transforming growth factor (TGF)-β is disrupted in subpopulations of patients with inflammatory bowel disease, but it is not clear how a T-helper (Th) 1 cell response is induced. We studied conversion of human mucosal innate immune cells into inflammatory cells and the initiation of a Th1 cell response following loss of IL-10 or TGF-β signaling.
  
  
  METHODS
  We depleted IL-10 or TGF-β from explant cultures of human normal colonic mucosa using immunoneutralization. Pharmacologic inhibitors and antibodies were used to determine the factors involved in the initiation of an interferon (IFN)-γ response following loss of TGF-β or IL-10 signaling. Cytokines produced by mucosal cells were assessed by enzyme-linked immunosorbent assay and quantitative reverse-transcriptase polymerase chain reaction. The subsets of cells involved in cytokine production were determined by in situ immunofluorescence analysis and flow cytometry after digestion of the explants with collagenase.
  
  
  RESULTS
  Depletion of IL-10 from human normal colonic mucosa resulted in an IFN-γ response, characterized by early-stage secretion of mature IL-18 and production of the active form of caspase-1 by macrophages and some epithelial cells. A caspase-1 inhibitor or the IL-18 antagonist IL-18-binding protein blocked this response. By contrast, depletion of TGF-β resulted in an IFN-γ response that was preceded by and required secretion of IL-12 from macrophages, dendritic cells, and epithelial cells.
  
  
  CONCLUSIONS
  Innate immune cells (macrophages and epithelial cells) activate a Th1 cell response in explant cultures of human normal colonic mucosa depleted in IL-10 or TGF-β via distinct, nonredundant pathways. These pathways might contribute to the pathogenesis of inflammatory bowel disease.
authors.affiliation: EA 4273 Biometadys, Université de Nantes, Faculté de Médecine, Nantes, France. ajarry@univ-nantes.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Jarry
authors.forename: Céline
authors.initials: C
authors.lastname: Bossard
authors.forename: Guillaume
authors.initials: G
authors.lastname: Sarrabayrouse
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Mosnier
authors.forename: Christian L
authors.initials: CL
authors.lastname: Laboisse
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D015212:Inflammatory Bowel Diseases / Q000209:etiology / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000172:deficiency* / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000502:physiology*; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000172:deficiency* / Q000378:metabolism
chemical_list: D020382:Interleukin-18; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; D020170:Caspase 1