Author:
Furukawa Ryutaro,Kuwatani Masaki,Jiang Jing-Jing,Tanaka Yuki,Hasebe Rie,Murakami Kaoru,Tanaka Kumiko,Hirata Noriyuki,Ohki Izuru,Takahashi Ikuko,Yamasaki Takeshi,Shinohara Yuta,Nozawa Shunichiro,Hojyo Shintaro,Kubota Shimpei I.,Hashimoto Shigeru,Hirano Satoshi,Sakamoto Naoya,Murakami Masaaki
Abstract
AbstractPost-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.
Funder
Japan Society for the Promotion of Science
Takeda Science Foundation
Japan Science and Technology Agency
Japan Agency for Medical Research and Development
Grant for Joint Research Program of the Institute for Genetic Medicine, Hokkaido University
Grant for the Photo-Excitonix Project, Hokkaido University
Grant for the Promotion Project for Young Investigators at Hokkaido University
Publisher
Springer Science and Business Media LLC