Regulation of the T helper cell type 1 transcription factor T-bet in coeliac disease mucosa

Monteleone, I.; Monteleone, G.; del Vecchio Blanco, G.; Vavassori, P.; Cucchiara, S.; MacDonald, T. T.; Pollone, F.
August 2004
Gut;Aug2004, Vol. 53 Issue 8, p1090
Academic Journal
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. 1-bet and STAT-4, two Th1 promoting transcription factors, and STAI-6 and GATA-3, transcription factors which govern 1 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 1-bet was examined in an ex viva 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. GAIA-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-i dependent mechanism. Challenge of treated CD but not control biopsies with gliadin enhanced 1-bet and this effect was also inhibited by STAT-1 inhibition. Conclusions: This study shows that activation of STAT-1 by IFN-γ promotes 1-bet in CD mucosa.


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