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


OBJECTIVE
To analyse expression of transcription factors which control the Th1 cell commitment in CD.


METHODS
Duodenal mucosal samples were taken from untreated CD patients and normal controls.


METHODS
Interferon gamma (IFN-gamma) 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-gamma 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-gamma 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-gamma 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-gamma promotes T-bet in CD mucosa.
Monteleone
I
I
Dipartimento di Medicina Interna e Centro di Eccellenza per lo studio delle malattie complesse e multifattoriali, Università Tor Vergata, Rome, Italy. Gi.Monteleone@Med.uniroma2.it
Monteleone
G
G
Del Vecchio Blanco
G
G
Vavassori
P
P
Cucchiara
S
S
MacDonald
T T
TT
Pallone
F
F
D000328:Adult; D002446:Celiac Disease / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D050993:GATA6 Transcription Factor; D005903:Gliadin / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis / Q000235:genetics; D015847:Interleukin-4 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008875:Middle Aged; D012313:RNA / Q000032:analysis; D050794:STAT1 Transcription Factor; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D015398:Signal Transduction; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D015847:Interleukin-4; D012313:RNA; D007371:Interferon-gamma; D005903:Gliadin