open access

https://hdl.handle.net/2115/86501

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

英語

Sjogren's syndrome

2021-08

Oxford University Press

International immunology

33(8)

423-434

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.

学術雑誌論文

Accepted Manuscript

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: https://doi.org/10.1093/intimm/dxab025.

0953-8178