STAT3 and importins are novel mediators of early molecular and cellular responses in experimental duodenal ulceration.

Abstract

OBJECTIVES:

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that directly upregulates VEGF, Ref-1, p21, and anti-apoptotic genes such as Bcl-xL. In this study, we hypothesized that STAT3 signaling is activated and provides a critical protective role that is required for enterocyte survival during the early phases of cysteamine-induced duodenal ulcers.

METHODS:

We studied the effect of inhibition of STAT3 activity on cysteamine-induced duodenal ulcers in rats and egr-1 knockout mice using STAT3/DNA binding assay, immunohistochemistry, immunoblot, and quantitative reverse transcriptase PCR analyses.

RESULTS:

We found that G-quartet oligodeoxynucleotides T40214, a specific inhibitor of STAT3/DNA binding, aggravated cysteamine-induced duodenal ulcers in rats 2.8-fold (p < 0.05). In the pre-ulcerogenic stage, cysteamine induced STAT3 tyrosine phosphorylation, its translocation to nuclei, an increased expression and nuclear translocation of importin α and β in the rat duodenal mucosa. Cysteamine enhanced the binding of STAT3 to its DNA consensus sequences at 6, 12, and 24 h after cysteamine by 1.5-, 1.8-, and 3.5-fold, respectively, and activated the expression of STAT3 target genes such as VEGF, Bcl-xL, Ref-1, and STAT3-induced feedback inhibitor, a suppressor of cytokine signaling 3. We also demonstrated that egr-1 knockout mice, which are more susceptible to cysteamine-induced duodenal ulcers, had lower levels of STAT3 expression, its phosphorylation, expression of importin α or β, and STAT3/DNA binding than wild-type mice in response to cysteamine.

CONCLUSIONS:

Thus, STAT3 represents an important new molecular mechanism in experimental duodenal ulceration.

• Authors: Tetyana Khomenko, Xiaoming Deng, Amrita Ahluwalia, Andrzej Tarnawski, Khushin N Patel, Zsuzsanna Sandor, Sandor Szabo
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 59 Issue 2 Pg. 297-306 (Feb 2014) ISSN: 1573-2568 [Electronic] United States
• PMID: 24385009 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Early Growth Response Protein 1
• Egr1 protein, mouse
• GQ-ODN T40214
• Oligodeoxyribonucleotides
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Stat3 protein, rat
• alpha Karyopherins
• beta Karyopherins
• Epirizole
• Tyrosine
• Cysteamine

Topics

• Active Transport, Cell Nucleus
• Animals
• Apoptosis
• Cysteamine
• Disease Models, Animal
• Duodenal Ulcer (chemically induced, genetics, metabolism, pathology, prevention & control)
• Duodenum (drug effects, metabolism, pathology)
• Early Growth Response Protein 1 (deficiency, genetics)
• Epirizole
• Female
• Gene Expression Regulation
• Mice
• Mice, Knockout
• Oligodeoxyribonucleotides (pharmacology)
• Phosphorylation
• Rats
• Rats, Sprague-Dawley
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Tyrosine
• alpha Karyopherins (metabolism)
• beta Karyopherins (metabolism)