Division of Molecular Psychoneuroimmunology, Institute for Genetic Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo, 060-0815, Japan.
Department of Gastroenterology and Hepatology, Hokkaido University Faculty of Medicine and Graduate School of Medicine, Sapporo, Japan.
Sci Rep. 2024 May 28;14(1):12224. doi: 10.1038/s41598-024-60312-2.
Post-ERCP pancreatitis (PEP) is an acute pancreatitis caused by endoscopic-retrograde-cholangiopancreatography (ERCP). About 10% of patients develop PEP after ERCP. Here we show that gamma-glutamyltransferase 1 (GGT1)-SNP rs5751901 is an eQTL in pancreatic cells associated with PEP and a positive regulator of the IL-6 amplifier. More PEP patients had the GGT1 SNP rs5751901 risk allele (C) than that of non-PEP patients at Hokkaido University Hospital. Additionally, GGT1 expression and IL-6 amplifier activation were increased in PEP pancreas samples with the risk allele. A mechanistic analysis showed that IL-6-mediated STAT3 nuclear translocation and STAT3 phosphorylation were suppressed in GGT1-deficient cells. Furthermore, GGT1 directly associated with gp130, the signal-transducer of IL-6. Importantly, GGT1-deficiency suppressed inflammation development in a STAT3/NF-κB-dependent disease model. Thus, the risk allele of GGT1-SNP rs5751901 is involved in the pathogenesis of PEP via IL-6 amplifier activation. Therefore, the GGT1-STAT3 axis in pancreas may be a prognosis marker and therapeutic target for PEP.
经内镜逆行胰胆管造影术（ERCP）后胰腺炎（PEP）是一种由内镜逆行胰胆管造影术引起的急性胰腺炎。大约 10%的 ERCP 术后患者会发生 PEP。在这里，我们表明 γ-谷氨酰转移酶 1（GGT1）-SNP rs5751901 是与 PEP 相关的胰腺细胞中的一个 eQTL，也是 IL-6 放大器的正调节剂。在北海道大学医院，PEP 患者的 GGT1 SNP rs5751901 风险等位基因（C）比非 PEP 患者多。此外，在具有风险等位基因的 PEP 胰腺样本中，GGT1 表达和 IL-6 放大器激活增加。机制分析表明，在 GGT1 缺陷细胞中，IL-6 介导的 STAT3 核易位和 STAT3 磷酸化受到抑制。此外，GGT1 直接与 gp130 相关，gp130 是 IL-6 的信号转导物。重要的是，GGT1 缺陷抑制了 STAT3/NF-κB 依赖性疾病模型中炎症的发展。因此，GGT1-SNP rs5751901 的风险等位基因通过 IL-6 放大器的激活参与了 PEP 的发病机制。因此，胰腺中的 GGT1-STAT3 轴可能是 PEP 的预后标志物和治疗靶标。
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