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Altered STAT4 Isoform Expression in Patients with Inflammatory Bowel Disease
Rukhsana Jabeen1, Lucy Miller, Weiguo Yao
1*Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; †Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana; and ‡Division of Pediatric Gastroenterology/Hepatology/Nutrition, Indiana University School of Medicine, Indianapolis, Indiana.
Insights
Altered STAT4 (Signal Transducer and Activator of Transcription 4) isoform ratios in the gut and blood may help diagnose inflammatory bowel disease (IBD). These STAT4 isoform changes normalized with steroid treatment in Crohn's disease and ulcerative colitis patients.
Area of Science:
- Immunology
- Gastroenterology
- Molecular Biology
Background:
- Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), arises from complex genetic, environmental, and immune interactions.
- Signal Transducer and Activator of Transcription 4 (STAT4) is an IL-12-activated transcription factor implicated in immune responses.
Purpose of the Study:
- To investigate the expression of STAT4 isoforms (STAT4β/STAT4α) in pediatric patients with CD and UC.
- To determine if STAT4 isoform ratios can serve as biomarkers for IBD diagnosis and pathogenesis.
Main Methods:
- Biopsy and blood samples were collected from newly diagnosed CD and UC patients, and from patients experiencing flares or in remission.
- STAT4β/STAT4α mRNA ratios were analyzed in tissue and peripheral blood mononuclear cells.
- Expression of cytokines (TNFα, IFNγ, GM-CSF, IL-17) was measured using PCR and multiplex analysis.
Main Results:
- Increased STAT4β/STAT4α ratios were observed in specific gastrointestinal segments of CD and UC patients, correlating with inflammation severity and location.
- Elevated STAT4β/STAT4α ratios were also found in peripheral blood of CD and UC patients compared to healthy controls.
- No changes in STAT4 ratios were seen in eosinophilic esophagitis, and ratios normalized with steroid treatment in IBD patients.
Conclusions:
- STAT4 isoforms represent potential noninvasive biomarkers for diagnosing and monitoring inflammatory bowel disease.
- STAT4 isoform expression patterns may offer insights into the underlying pathogenesis of IBD.
Background:
Crohn's disease (CD) and ulcerative colitis (UC) are the major forms of inflammatory bowel disease, and pathogenesis involves a complex interplay among genetic, environmental, and immunological factors. We evaluated isoform expression of the IL-12-activated transcription factor STAT4 in children with CD and UC.
Methods:
We collected biopsy samples from both patients newly diagnosed with CD and with UC. We further collected blood samples from patients newly diagnosed with CD and with UC as well as from patients who had a flare-up after being in clinical remission, and we examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms, we measured the expression of the cytokines TNFα, IFNγ, granulocyte macrophage-colony stimulating factor, and IL-17 using polymerase chain reaction of biopsy samples and multiplex analysis of patient serum samples.
Results:
Ratios of STAT4β/STAT4α were increased in specific gastrointestinal tract segments in both patients with CD and those with UC that correlate with the location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from patients with eosinophilic esophagitis. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of patients with UC and those with CD, compared with healthy controls. Ratios were normalized after patients were treated with steroids.
Conclusions:
Collectively, these data indicate that STAT4 isoforms could be an important noninvasive biomarker in the diagnosis and treatment of inflammatory bowel disease and that expression of these isoforms might provide further insight into the pathogenesis of IBD.
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