Increased mucosal expression of GATA‐3 and STAT‐4 in pediatric ulcerative colitis

Ohtani, Kiyotaka; Ohtsuka, Yoshikazu; Ikuse, Tamaki; Baba, Yosuke; Yamakawa, Yoko; Aoyagi, Yo; Fujii, Tohru; Kudo, Toshifumi; Nagata, Satoru; Shimizu, Toshiaki

doi:10.1111/j.1442-200x.2009.03019.x

Cited by 48 publications

(32 citation statements)

References 30 publications

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“…However, studies of NOX1 expression in Caco-2 human colorectal cancer cells demonstrated that binding of the transcription factor GATA6 to the NOX1 promoter played an important role in the regulation of NOX1 expression [66, 67]. In contrast, initiation of IL-4 transcription in naïve T cells is regulated by GATA3 [29]; and the expression of GATA3 is significantly increased in the bowel mucosae of children with the inflammatory bowel disease, ulcerative colitis [68]. Thus, we evaluated potential GATA3 binding sites in the HT-29 cell promoter, and found by mutational analysis that the conserved consensus sequence required for the binding of GATA3 to the NOX1 promoter is located at bp -321/−315.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-4 and interleukin-13 increase NADPH oxidase 1-related proliferation of human colon cancer cells

et al. 2017

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Human colon cancers express higher levels of NADPH oxidase 1 [NOX1] than adjacent normal epithelium. It has been suggested that reactive oxygen species [ROS] derived from NOX1 contribute to DNA damage and neoplastic transformation in the colon, particularly during chronic inflammatory stress. However, the mechanism(s) underlying increased NOX1 expression in malignant tumors or chronic inflammatory states involving the intestine are poorly characterized. We examined the effects of two pro-inflammatory cytokines, IL-4 and IL-13, on the regulation of NOX1. NOX1 expression was increased 4- to 5-fold in a time- and concentration-dependent manner by both cytokines in human colon cancer cell lines when a functional Type II IL-4 receptor was present. Increased NOX1 transcription following IL-4/IL-13 exposure was mediated by JAK1/STAT6 signaling, was associated with a ROS-related inhibition of protein tyrosine phosphatase activity, and was dependent upon activation and specific binding of GATA3 to the NOX1 promoter. NOX1-mediated ROS production increased cell cycle progression through S-phase leading to a significant increase in cellular proliferation. Evaluation of twenty pairs of surgically-resected colon cancers and their associated uninvolved adjacent colonic epithelium demonstrated a significant increase in the active form of NOX1, NOX1-L, in tumors compared to normal tissues, and a significant correlation between the expression levels of NOX1 and the Type II IL-4 receptor in tumor and the uninvolved colon. These studies imply that NOX1 expression, mediated by IL-4/IL-13, could contribute to an oxidant milieu capable of supporting the initiation or progression of colonic cancer, suggesting a role for NOX1 as a therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Interleukin-4 and interleukin-13 increase NADPH oxidase 1-related proliferation of human colon cancer cells

et al. 2017

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“…STAT4 is constitutively expressed in intestinal T cells of CD patients and there are increased levels of phosphorylated STAT4 in the mucosal cells of UC patients 35, 36 . Increased mucosal expression of STAT4 has also been reported in pediatric UC but no significant difference was observed in pediatric CD patients 40 . In mouse models of IBD, STAT4 is required for the development of disease, and transgenic expression of STAT4 promotes disease 41–44 .…”

Section: Introductionmentioning

confidence: 97%

Altered STAT4 Isoform Expression in Patients with Inflammatory Bowel Disease

Jabeen

Miller

Yao

et al. 2015

Inflammatory Bowel Diseases

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BACKGROUND & AIMS Crohn’s disease (CD) and ulcerative colitis (UC) are major forms of inflammatory bowel disease (IBD) and pathogenesis involves a complex interplay between 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 performed a study where we collected biopsy samples from both newly diagnosed CD and UC patients. We further collected blood samples from newly diagnosed CD and UC patients as well as patients who had a flare-up after being in clinical remission, and examined the ratios of STAT4β/STAT4α mRNA. In addition to STAT4 isoforms we measured the expression of the cytokines TNFα, IFNγ, GM-CSF and IL-17 using PCR of biopsy samples and multiplex analysis of patient serum samples. RESULTS Ratios of STAT4β/STAT4α were increased in specific GI tract segments in both CD and UC patients that correlate with location and severity of inflammation. In contrast, we did not observe changes in STAT4β/STAT4α ratios in biopsy specimens from eosinophilic esophagitis patients. We also observed increased STAT4β/STAT4α ratios in the peripheral blood mononuclear cells of UC and CD patients, compared to healthy controls. Ratios were normalized after patient treatment with steroids. CONCLUSIONS Collectively, these data indicate that STAT4 isoforms could be an important non-invasive biomarker in the diagnosis and treatment of IBD, and that expression of these isoforms might provide further insight into the pathogenesis of IBD.

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“…In human UC, several studies of the mucosal cytokine profile, especially containing IL-4, IL-5 and IL-13, supported the hypothesis of UC as a Th2-associated inflammation [103,104,105,106,107,108,109,110]. As a histopathological characteristic of UC, mucosal IgG1 + plasma cell infiltration is observed, suggesting Th2 polarization.…”

Section: Ulcerative Colitismentioning

confidence: 75%

“…The missing efficacy of type 1 IFN in clinical trials for human UC also contradicts the hypothesis of the Th2 dominance [120]. Since Th1 and Th2 cytokines are found in the inflamed colon in UC [105,110], the Th1/Th2 balance may vary depending on the severity and duration of the disease [105,108]. Recently, several reports suggested enhanced production of IL-13 by mucosal NKT cells [121,122].…”

Section: Ulcerative Colitismentioning

confidence: 97%

The Role of T-Cell Subsets in Chronic Inflammation in Celiac Disease and Inflammatory Bowel Disease Patients: More Common Mechanisms or More Differences?

Hisamatsu

Erben²,

Kühl³

2016

Inflamm Intest Dis

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Background: Chronic intestinal inflammation due to noninfectious causes represents a growing health issue all over the world. Celiac disease as well as inflammatory bowel diseases (IBD) like Crohn's disease and ulcerative and microscopic colitis involve uncontrolled T-cell activation and T-cell-mediated damage as common denominators. Therefore, diagnosis and treatment decisions clearly benefit from the knowledge of the intricacies of the systemic and the local T-cell activity. Summary: Depending on the cytokine milieu, CD4⁺ T cells can differentiate into proinflammatory T helper 1 (Th1), anti-inflammatory Th2, antimicrobial Th17, pleiotropic Th9, tissue-instructing Th22 cells, and in the regulatory compartment forkhead box protein 3⁺ Treg, suppressive Tr1 or Th3 cells. Additionally, follicular Th cells provide B-cell help in antibody class switching; cytotoxic CD8⁺ T cells target virus-infected or tumor cells. This review discusses our current knowledge on the contribution of defined T-cell subpopulations to establishing and maintaining chronic intestinal inflammation in either of the above entities. It also puts emphasis on the differences in the prevalence of these diseases between Eastern and Western countries. Key Messages: In celiac disease, the driving role of T cells in the lamina propria and in the epithelium mainly specific for two defined antigens is well established. Differences in genetics and lifestyle between Western and Eastern countries were instrumental in understanding underlying mechanisms. In IBD, the vast amount of potential antigens and the corresponding antigen-specific T cells makes it unlikely to find universal triggers. Increased mucosal CD4⁺ regulatory T cells in all four entities fail to control or abrogate local inflammatory processes. Thus, prevailing differences in the functional T-cell subtypes driving chronic intestinal inflammation in celiac disease and IBD at best allow some overlap in the treatment options for either disease.

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Increased mucosal expression of GATA‐3 and STAT‐4 in pediatric ulcerative colitis

Abstract: IL-4 and its signaling molecule GATA-3, as well as the Th1 signaling molecule STAT-4, are involved in the pathogenesis of acute phase of pediatric UC.

Cited by 48 publications

References 30 publications

Interleukin-4 and interleukin-13 increase NADPH oxidase 1-related proliferation of human colon cancer cells

Interleukin-4 and interleukin-13 increase NADPH oxidase 1-related proliferation of human colon cancer cells

Altered STAT4 Isoform Expression in Patients with Inflammatory Bowel Disease

The Role of T-Cell Subsets in Chronic Inflammation in Celiac Disease and Inflammatory Bowel Disease Patients: More Common Mechanisms or More Differences?

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