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Epithelial-derived nuclear IL-33 aggravates inflammation in the pathogenesis of reflux esophagitis

  • Original Article—Alimentary Tract
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Abstract

Background

IL-33 is a new tissue-derived cytokine constitutively expressed in epithelial cells and plays a role in sensing damage caused by inflammatory diseases. The function of IL-33 in the esophageal mucosa has not been previously described. Accordingly, we examined the expression of IL-33 and its role in the pathogenesis of reflux esophagitis (RE).

Methods

IL-33 in the esophageal mucosa of RE patients and in an in vitro stratified normal esophageal squamous epithelial model was examined at the messenger RNA and protein levels. The correlation of the level of IL-33 and IL-8 or IL-6 was examined. Cell layers were stimulated with bile acids and cytokines. IL-33 was knocked down by small interfering RNA (siRNA). Pharmacological inhibitors and signal transducer and activator of transcription 1 (STAT1) siRNA were used.

Results

IL-33 was significantly upregulated in RE patients, and was located in the nuclei of basal and suprabasal layers. Upregulated IL-33 messenger RNA expression was correlated with IL-8 and IL-6 expression. In vitro, IL-33 was upregulated in the nuclei of basal and suprabasal layers by interferon-γ (IFNγ), and the upregulation was aggravated by the combination of deoxycholic acid (DCA) and IFNγ. IL-33 knockdown dampened IFNγ- and DCA-induced IL-8 and IL-6 production. IFNγ-induced IL-33 was inhibited by a Janus kinase inhibitor, a p38 mitogen-activated protein kinase inhibitor, and STAT1 siRNA.

Conclusions

Nuclear IL-33 is upregulated in erosive mucosa of RE patients and is correlated with IL-8 and IL-6 levels. The normal esophageal epithelial model enables us to show for the first time that epithelial-cell-derived nuclear but not exogenous IL-33 is located upstream of the production of inflammatory cytokines and can aggravate the inflammation.

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Acknowledgments

We thank Noriko Kamiya for excellent technical assistance. This study was supported by a Grant-in Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (25460939 to T.O.).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan

    Jing Shan, Tadayuki Oshima, Hirokazu Fukui, Jiro Watari & Hiroto Miwa

  2. Department of Immunology and Medical Zoology, Hyogo College of Medicine, Nishinomiya, Japan

    Taichiro Muto, Koubun Yasuda & Kenji Nakanishi

  3. Department of Gastroenterology, The Third People’s Hospital of Chengdu, Chengdu, China

    Jing Shan

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  1. Jing Shan
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Correspondence to Tadayuki Oshima.

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Shan, J., Oshima, T., Muto, T. et al. Epithelial-derived nuclear IL-33 aggravates inflammation in the pathogenesis of reflux esophagitis. J Gastroenterol 50, 414–423 (2015). https://doi.org/10.1007/s00535-014-0988-1

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  • DOI: https://doi.org/10.1007/s00535-014-0988-1

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