Loss of interleukin-10 or transforming growth factor ß signaling in the human colon initiates a T-helper 1 response via distinct pathways.
Gastroenterology
; 141(5): 1887-96.e1-2, 2011 Nov.
Article
en En
| MEDLINE
| ID: mdl-21839042
ABSTRACT
BACKGROUND & AIMS:
Signaling via interleukin (IL)-10 or transforming growth factor (TGF)-ß 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-ß signaling.METHODS:
We depleted IL-10 or TGF-ß 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-ß 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-ß 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-ß via distinct, nonredundant pathways. These pathways might contribute to the pathogenesis of inflammatory bowel disease.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
/
Factor de Crecimiento Transformador beta
/
Interleucina-10
/
Colon
/
Células TH1
Tipo de estudio:
Etiology_studies
Límite:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Gastroenterology
Año:
2011
Tipo del documento:
Article
País de afiliación:
Francia