Enhanced expression of interferon regulatory factor-1 in the mucosa of children with celiac disease.
Celiac disease (CD) is an enteropathy characterized by a Th1-type immune response to the dietary gluten. The transcriptional mechanisms or factors that control Th1 cell development in this condition remain to be elucidated. The aim of this study was to analyze in CD the expression of interferon (IFN) regulatory factor (IRF)-1, a transcription factor that regulates the differentiation and function of Th1 cells. Duodenal biopsies were taken from children with untreated CD and control children, and analyzed for IRF-1 by Southern blotting of reverse-transcriptase PCR products and Western blotting. IRF-1 DNA-binding activity was assessed by electrophoretic shift mobility assay. The effect of gliadin stimulation on IRF-1 induction was investigated in an ex vivo organ culture of treated CD biopsies. Enhanced IRF-1 was seen in untreated CD in comparison with controls. This was evident at both the RNA and protein level. Furthermore, untreated CD samples exhibited stronger nuclear accumulation and DNA-binding activity of IRF-1 than controls. In contrast, IRF-2, a transcriptional repressor that binds the same DNA element and competes with IRF-1, was expressed at the same level in nuclear proteins extracted from both untreated CD and control patients. In explant cultures of treated CD biopsies, gliadin enhanced both IRF-1 RNA and protein. This effect was prevented by a neutralizing IFN-gamma antibody. Furthermore, stimulation of normal duodenal biopsies with IFN-gamma enhanced IRF-1. These data indicate that IRF-1 is a hallmark of the gliadin-mediated inflammation in CD and suggest that IFN-gamma/IRF-1 signaling pathway can play a key role in maintaining and expanding the local Th1 inflammatory response in this disease.
Salvati
Virginia M
VM
Department of Pediatrics and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, Naples, Italy.
MacDonald
Thomas T
TT
del Vecchio Blanco
Giovanna
G
Mazzarella
Giuseppe
G
Monteleone
Ivan
I
Vavassori
Piero
P
Auricchio
Salvatore
S
Pallone
Francesco
F
Troncone
Riccardo
R
Monteleone
Giovanni
G
D000293:Adolescent; D002446:Celiac Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004386:Duodenum / Q000378:metabolism / Q000473:pathology; D005903:Gliadin / Q000378:metabolism; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D014157:Transcription Factors; D007371:Interferon-gamma; D004247:DNA; D005903:Gliadin