Enhanced expression of transcription factor GATA-4 in inflammatory bowel disease and its possible regulation by TGF-beta1.
BACKGROUND
Transforming growth factor beta 1 (TGF-beta1) promotes epithelial healing in inflammatory bowel disease. We hypothesized that GATA-4, a transcription factor cooperating with TGF-beta signaling pathway, is upregulated by TGF-beta1 in the inflamed intestinal epithelium.


METHODS
Normal and inflamed intestinal samples were subjected to immunohistochemistry for GATA-4/6 and the TGF-beta signaling pathway components Smad2/3/4. Proliferation and apoptosis were analyzed using Ki-67 and in situ DNA 3'-end labeling assays and Bax and Bcl-2 immunohistochemistry. Furthermore, GATA-4 was assessed in intestinal Caco-2 cells stimulated with TGF-beta1, or interleukin-6 and tumor necrosis factor alpha.


RESULTS
GATA-4 was detected in only 20% of normal intestinal samples, but was upregulated in corresponding inflamed regions. GATA-6 expression remained unchanged during inflammation. TGF-beta1 and Smad3/4, but not Smad2, were expressed concomitantly with GATA-4 in inflamed bowel mucosa. In intestinal Caco-2 cells, TGF-beta1 upregulated GATA-4 and Smad2/3/4, whereas treatment with control cytokines had no effect. Inflammation was associated with increased epithelial cell apoptosis and the enhancement of Bcl-2, but not Bax.


CONCLUSIONS
We surmise GATA-4 expression is upregulated in inflamed intestine correlating with the activation of TGF-beta signaling pathway. We speculate that TGF-beta1 drives GATA-4 expression during intestinal inflammation, these two components cooperating to promote epithelial healing.
Haveri
Hanna
H
Children's Hospital, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Ashorn
Merja
M
Iltanen
Sari
S
Wilson
David B
DB
Andersson
Leif C
LC
Heikinheimo
Markku
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D050991:GATA4 Transcription Factor / Q000819:agonists / Q000096:biosynthesis*; D050993:GATA6 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000473:pathology; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D051785:Smad Proteins / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000276:immunology / Q000378:metabolism
D050991:GATA4 Transcription Factor; D050993:GATA6 Transcription Factor; C508600:IL6 protein, human; D015850:Interleukin-6; D019253:Proto-Oncogene Proteins c-bcl-2; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein