Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo 0600815, Japan.
Department of Rheumatology, Endocrinology and Nephrology, Hokkaido University Graduate School of Medicine, Sapporo 0600815, Japan.
Int Immunol. 2021 Jul 23;33(8):423-434. doi: 10.1093/intimm/dxab025.
Sjögren'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-κB) activation in human salivary gland cells via the NF-κB 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-κB 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-κB 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-κB pathway in salivary gland cells. They also suggest that GTF2I could be a new therapeutic target for SS.
干燥综合征（SS）是一种自身免疫性疾病，其特征为炎症伴有淋巴浸润和唾液腺破坏。尽管许多全基因组关联研究已经揭示了与疾病相关的风险等位基因，但这些等位基因的大多数功能仍不清楚。在这里，我们通过使用两个 SS 相关的单核苷酸多态性（SNP），rs73366469 和 rs117026326（GTF2I SNPs），展示了 GTF2I 分子以前未被识别的作用。我们发现 GTF2I SNP 的风险等位基因通过核因子-κB（NF-κB）p65 亚基增加了 GTF2I 在人唾液腺细胞中的表达，并增强了 NF-κB 的激活。事实上，GTF2I 的敲低抑制了小鼠内皮细胞和体内的炎症反应。相反，GTF2I 的过表达增强了 NF-κB 报告基因的活性，这依赖于其与 p65 结合的 N 端亮氨酸拉链结构域。GTF2I 在表达风险等位基因的 SS 患者的人唾液腺细胞中高度表达。一致地，GTF2I SNP 的风险等位基因与 IL-6 扩增子的激活密切相关，IL-6 扩增子是 NF-κB 途径的过度激活机制，并且与 SS 患者唾液腺中的淋巴浸润有关。这些结果表明，在 GTF2I SNP 的风险等位基因存在的情况下，唾液腺中的 GTF2I 表达增加，导致唾液腺细胞中 NF-κB 通路的激活。它们还表明，GTF2I 可能成为 SS 的一个新的治疗靶点。
