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Regulation of the T helper cell type 1 transcription factor T-bet in coeliac disease mucosa
  1. I Monteleone1,*,
  2. G Monteleone1,*,
  3. G Del Vecchio Blanco1,
  4. P Vavassori1,
  5. S Cucchiara2,
  6. T T MacDonald3,
  7. F Pallone1
  1. 1Dipartimento di Medicina Interna e Centro di Eccellenza per lo studio delle malattie complesse e multifattoriali, Università Tor Vergata, Rome, Italy
  2. 2Pediatric Unit, University “La Sapienza”, Rome, Italy
  3. 3Division of Infection, Inflammation, and Repair, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK
  1. Correspondence to:
    Dr G Monteleone
    Dipartimento di Medicina Interna, Università Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy; Gi.MonteleoneMed.uniroma2.it

Abstract

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
  • T-bet
  • STAT-1
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Footnotes

  • * I Monteleone and G Monteleone contributed equally to the study.

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