Background: In coeliac disease (CD) mucosa, the histological lesion is associated with marked infiltration of T helper cell type 1 (Th1) cells. However, the molecular mechanisms which regulate Th1 cell differentiation in CD mucosa are unknown.
Aims: To analyse expression of transcription factors which control the Th1 cell commitment in CD.
Patients: Duodenal mucosal samples were taken from untreated CD patients and normal controls.
Methods: Interferon γ (IFN-γ) and interleukin (IL)-4 RNA expression was examined in T lamina propria lymphocytes by quantitative reverse transcription-polymerase chain reaction. T-bet and STAT-4, two Th1 promoting transcription factors, and STAT-6 and GATA-3, transcription factors which govern T helper cell type 2 (Th2) cell polarisation, were examined in duodenal biopsies by western blotting. The effect of gliadin and IFN-γ on expression of T-bet was examined in an ex vivo culture of biopsies taken from normal and treated CD patients.
Results: As expected, IFN-γ but not IL-4 RNA transcripts were increased in the mucosa of CD patients in comparison with controls. CD mucosal samples consistently exhibited higher levels of T-bet than controls. However, no difference in active STAT-4 expression was seen between CD patients and controls, suggesting that Th1 polarisation was not induced by local IL-12. GATA-3 and STAT-6 were also low in both CD and control mucosa. In normal duodenal biopsies, IFN-γ stimulated T-bet through a STAT-1 dependent mechanism. Challenge of treated CD but not control biopsies with gliadin enhanced T-bet and this effect was also inhibited by STAT-1 inhibition.
Conclusions: This study shows that activation of STAT-1 by IFN-γ promotes T-bet in CD mucosa.
- CD, coeliac disease
- Th1, T helper cell type 1
- Th2, T helper cell type 2
- IFN, interferon
- IL, interleukin
- T-LPL, lamina propria T lymphocytes
- EMA, antiendomysial antibodies
- DMSO, dimethylsulphoxide
- PT, peptic-tryptic digest of gliadin
- LPMC, lamina propria mononuclear cells
- coeliac disease
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