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DMBT1 is a novel gene induced by IL-22 in ulcerative colitis

Authors

  • Hirokazu Fukui MD., PhD,

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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    • The first two authors contributed equally to this work.

  • Akira Sekikawa MD., PhD,

    Corresponding author
    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
    • Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, 880 Kitakobayshi, Mibu, Shimotsuga, Tochigi, 321-0293 Japan
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    • The first two authors contributed equally to this work.

  • Hiroyuki Tanaka MD,

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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  • Yukari Fujimori MD,

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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  • Yoshinori Katake MD,

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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  • Shigehiko Fujii MD., PhD,

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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  • Kazuhito Ichikawa MD., PhD,

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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  • Shigeki Tomita MD., PhD,

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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  • Johji Imura MD., PhD,

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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  • Tsutomu Chiba MD., PhD,

    1. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Takahiro Fujimori MD., PhD

    1. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Japan
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Abstract

Background:

Interleukin (IL)-22 is a recently identified cytokine that is suggested to play pivotal roles in various inflammatory diseases. Although the IL-22 receptor 1 (IL-22R1) is restrictively expressed in epithelial cells in the colon, the role of IL-22 in colonic diseases still remains unclear. In this study microarray analyses revealed that deleted in malignant brain tumors 1 (DMBT1) is a novel upregulated gene in IL-22-stimulated colon cancer cells. Therefore, we investigated the involvement of DMBT1 and IL-22 in ulcerative colitis (UC) tissues and examined the mechanism regulating the expression of DMBT1 in response to IL-22 stimulation.

Methods:

Changes of gene expression in IL-22-stimulated SW403 cells were investigated by microarray analyses. The effects of IL-22 on DMBT1 expression were examined in SW403 cells using a small interfering RNA (si)RNA for STAT3 or inhibitors for MEK, PI3K, and nuclear factor kappa B (NF-κB). The element responsible for IL-22-induced DMBT1 promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay (EMSA). Expression of IL-22, IL-22R1, and DMBT1 in UC tissues was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry.

Results:

IL-22 treatment enhanced the expression of DMBT1 through STAT3 tyrosine phosphorylation and NF-κB activation in colon cancer cells. The IL-22-responsive element was located between −187 and −179 in the DMBT1 promoter region. In the UC mucosa the levels of DMBT1 and IL-22 mRNA expression were significantly enhanced and positively correlated, the numbers of IL-22-positive lymphocytes were increased, and the expression of IL-22R1 and DMBT1 was enhanced in the inflamed epithelium.

Conclusions:

The IL-22/DMBT1 axis may play a pivotal role in the pathophysiology of UC. (Inflamm Bowel Dis 2010;)

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