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Sjogren's syndrome-associated SNPs increase GTF2I expression in salivary gland cells to enhance inflammation development

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Title: Sjogren's syndrome-associated SNPs increase GTF2I expression in salivary gland cells to enhance inflammation development
Authors: Shimoyama, Shuhei Browse this author
Nakagawa, Ikuma Browse this author
Jiang, Jing-Jing Browse this author
Matsumoto, Isao Browse this author
Chiorini, John A. Browse this author
Hasegawa, Yoshinori Browse this author
Ohara, Osamu Browse this author
Hasebe, Rie Browse this author
Ota, Mitsutoshi Browse this author
Uchida, Mona Browse this author
Kamimura, Daisuke Browse this author
Hojyo, Shintaro Browse this author
Tanaka, Yuki Browse this author
Atsumi, Tatsuya Browse this author
Murakami, Masaaki Browse this author →KAKEN DB
Keywords: GTF2I
IL-6 amplifier
NF-kappa B
Sjogren's syndrome
Issue Date: Aug-2021
Publisher: Oxford University Press
Journal Title: International immunology
Volume: 33
Issue: 8
Start Page: 423
End Page: 434
Publisher DOI: 10.1093/intimm/dxab025
Abstract: Sjogren's syndrome (SS) is an autoimmune disease characterized by inflammation with lymphoid infiltration and destruction of the salivary glands. Although many genome-wide association studies have revealed disease-associated risk alleles, the functions of the majority of these alleles are unclear. Here, we show previously unrecognized roles of GTF2I molecules by using two SS-associated single nucleotide polymorphisms (SNPs), rs73366469 and rs117026326 (GTF2I SNPs). We found that the risk alleles of GTF2I SNPs increased GTF2I expression and enhanced nuclear factor-kappa B (NF-kappa B) activation in human salivary gland cells via the NF-kappa B p65 subunit. Indeed, the knockdown of GTF2I suppressed inflammatory responses in mouse endothelial cells and in vivo. Conversely, the over-expression of GTF2I enhanced NF-kappa B reporter activity depending on its p65-binding N-terminal leucine zipper domain. GTF2I is highly expressed in the human salivary gland cells of SS patients expressing the risk alleles. Consistently, the risk alleles of GTF2I SNPs were strongly associated with activation of the IL-6 amplifier, which is hyperactivation machinery of the NF-kappa B pathway, and lymphoid infiltration in the salivary glands of SS patients. These results demonstrated that GTF2I expression in salivary glands is increased in the presence of the risk alleles of GTF2I SNPs, resulting in activation of the NF-kappa B pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.
Rights: This is a pre-copyedited, author-produced version of an article accepted for publication in International immunology following peer review. The version of record Shuhei Shimoyama, Ikuma Nakagawa, Jing-Jing Jiang, Isao Matsumoto, John A Chiorini, Yoshinori Hasegawa, Osamu Ohara, Rie Hasebe, Mitsutoshi Ota, Mona Uchida, Daisuke Kamimura, Shintaro Hojyo, Yuki Tanaka, Tatsuya Atsumi, Masaaki Murakami, Sjögren’s syndrome-associated SNPs increase GTF2I expression in salivary gland cells to enhance inflammation development, International Immunology, Volume 33, Issue 8, August 2021, Pages 423–434 is available online at:
Type: article (author version)
Appears in Collections:遺伝子病制御研究所 (Institute for Genetic Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 村上 正晃

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