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Significance of Interleukin-6/STAT Pathway for the Gene Expression of REG Iα, a New Autoantigen in Sjögren’s Syndrome Patients, in Salivary Duct Epithelial Cells

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Abstract

The regenerating gene, Reg, was originally isolated from a rat regenerating islet complementary DNA (cDNA) library, and its human homologue was named REG Iα. Recently, we reported that REG Iα messenger RNA (mRNA), as well as its product, was overexpressed in ductal epithelial cells in the salivary glands of Sjögren’s syndrome patients. Furthermore, autoantibodies against REG Iα were found in the sera of Sjögren’s syndrome patients, and the patients who were positive for the anti-REG Iα antibody showed significantly lower saliva secretion than antibody-negative patients. We found the mechanism of REG Iα induction in salivary ductal epithelial cells. Reporter plasmid containing REG Iα promoter (−1190/+26) upstream of a luciferase gene was introduced into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with several cytokines (interleukin (IL)-6, IL-8, etc.), upregulated in Sjögren’s syndrome salivary ducts, and the transcriptional activity was measured. IL-6 stimulation significantly enhanced the REG Iα promoter activity in both cells. Deletion analysis revealed that the −141∼−117 region of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transducer and activator of transcription (STAT) binding. The introduction of small interfering RNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results indicated that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the REG Iα promoter in salivary ductal cells. This dependence of REG Iα induction upon IL-6/STAT in salivary duct epithelial cells may play an important role in the pathogenesis/progression of Sjögren’s syndrome.

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Acknowledgments

The authors are grateful to Dr. Masayuki Azuma from the Tokushima University School of Dentistry for providing NS-SV-DC human salivary ductal cells and Dr. Bruce J. Baum from the National Institute of Dental and Craniofacial Research, NIH for providing A5 rat salivary ductal cells. We are also grateful to Drs. Shinobu Nakamura and Yoshiko Dohi from the Nara Medical University for encouragement. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and Japan Science and Technology Agency.

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Authors and Affiliations

  1. Department of Biochemistry, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Nara, Japan

    Takanori Fujimura, Asako Itaya-Hironaka, Tomoko Miyaoka, Kiyomi Yoshimoto, Sumiyo Sakuramoto-Tsuchida, Akiyo Yamauchi, Maiko Takeda, Hiroki Tsujinaka & Shin Takasawa

  2. The Center for Rheumatic Diseases, Nara Medical University Hospital, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan

    Takanori Fujimura, Takashi Fujimoto, Tomoko Miyaoka & Yasuhito Tanaka

  3. Department of General Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan

    Kiyomi Yoshimoto

  4. Department of Diagnostic Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan

    Maiko Takeda

  5. Department of Ophthalmology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8522, Nara, Japan

    Hiroki Tsujinaka

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  1. Takanori Fujimura
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Correspondence to Shin Takasawa.

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Takanori Fujimura, Takashi Fujimoto, Asako Itaya-Hironaka, Tomoko Miyaoka, Kiyomi Yoshimoto, Sumiyo Sakuramoto-Tsuchida, Akiyo Yamauchi, Maiko Takeda, Hiroki Tsujinaka, Yasuhito Tanaka, and Shin Takasawa declare that they have no conflict of interest.

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Fujimura, T., Fujimoto, T., Itaya-Hironaka, A. et al. Significance of Interleukin-6/STAT Pathway for the Gene Expression of REG Iα, a New Autoantigen in Sjögren’s Syndrome Patients, in Salivary Duct Epithelial Cells. Clinic Rev Allerg Immunol 52, 351–363 (2017). https://doi.org/10.1007/s12016-016-8570-7

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