Activation pattern of signal transducers and activators of transcription (STAT) factors in inflammatory bowel diseases.
OBJECTIVE
Cytokine signaling pathways involving transcription factors of the signal transducers and activators of transcription (STAT) family play a key role in the pathogenesis of inflammatory bowel diseases (IBD). STAT proteins are latent cytoplasmic transcription factors that induce transcription upon phosphorylation, dimerization, and nuclear translocation. However, their activation pattern in IBD is poorly understood. The aim of our study was to characterize STAT-expression in IBD.


METHODS
Mononuclear cells were isolated from 36 colonic specimens of Crohn's disease, ulcerative colitis, or from control patients. Cells were stimulated overnight with antibodies against human CD2 and CD28 and mononuclear cells were analyzed by flow cytometry. Alternatively, CD4(+) T cells were immunomagnetically separated and then assessed by flow cytometry. Intracellular stainings of the following transcription factors were performed: STAT-1, STAT-2, STAT-3, STAT-4, and STAT-6. In addition, immunofluorescence staining on cryosections for phosphorylated STAT-1 and STAT-3 was performed.


RESULTS
Average expression of the IFN-gamma inducible transcription factor STAT-1 was increased in Crohn's disease as compared to patients with ulcerative colitis and control patients. However, levels of phospho-STAT-1 were surprisingly not markedly upregulated in IBD as compared to controls. In contrast, STAT-3 and phospho-STAT-3 levels were significantly increased in IBD patients as compared to controls (p < 0.01). No differences could be detected in STAT-6 levels. Finally, average expression of STAT-2, which is involved in type I interferon signalling, was downregulated in IBD as compared to control patients.


CONCLUSIONS
The analysis of STAT activation patterns could serve as a helpful tool to characterize intestinal inflammation. Furthermore, the IL-6/STAT-3 rather than the IFN-gamma/STAT-1 signaling pathway emerges as a key target for the development of future therapeutic concepts in IBD.
Mudter
Jonas
J
Department of 1st Medical Clinic, Department of Pathology, Johannes-Gutenberg-University of Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany.
Weigmann
Benno
B
Bartsch
Brigitte
B
Kiesslich
Ralf
R
Strand
Dennis
D
Galle
Peter R
PR
Lehr
Hans A
HA
Schmidt
Jan
J
Neurath
Markus F
MF
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000378:metabolism* / Q000473:pathology; D050794:STAT1 Transcription Factor; D050795:STAT2 Transcription Factor; D050796:STAT3 Transcription Factor; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*
D004268:DNA-Binding Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050795:STAT2 Transcription Factor; C494084:STAT2 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators