PMID- 34217990 OWN - NLM STAT- MEDLINE DCOM- 20220124 LR - 20240226 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 99 DP - 2021 Oct TI - IL-6 downregulates hepatic carboxylesterases via NF-kappaB activation in dextran sulfate sodium-induced colitis. PG - 107920 LID - S1567-5769(21)00556-7 [pii] LID - 10.1016/j.intimp.2021.107920 [doi] AB - Ulcerative colitis (UC) is associated with increased levels of inflammatory factors, which is attributed to the abnormal expression and activity of enzymes and transporters in the liver, affecting drug disposition in vivo. This study aimed to examine the impact of intestinal inflammation on the expression of hepatic carboxylesterases (CESs) in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Two major CESs isoforms, CES1 and CES2, were down-regulated, accompanied by decreases in hepatic microsomal metabolism of clopidogrel and irinotecan. Meanwhile, IL-6 levels significantly increased compared with other inflammatory factors in the livers of UC mice. In contrast, using IL-6 antibody simultaneously reversed the down-regulation of CES1, CES2, pregnane X receptor (PXR), and constitutive androstane receptor (CAR), as well as the nuclear translocation of NF-kappaB in the liver. We further confirmed that treatment with NF-kappaB inhibitor abolished IL-6-induced down-regulation of CES1, CES2, PXR, and CAR in vitro. Thus, it was concluded that IL-6 represses hepatic CESs via the NF-kappaB pathway in DSS-induced colitis. These findings indicate that caution should be exercised concerning the proper and safe use of therapeutic drugs in patients with UC. CI - Copyright (c) 2021 Elsevier B.V. All rights reserved. FAU - Li, Min AU - Li M AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. FAU - Lan, Lulu AU - Lan L AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. FAU - Zhang, Si AU - Zhang S AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. FAU - Xu, Yanjiao AU - Xu Y AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. FAU - He, Wenxi AU - He W AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. FAU - Xiang, Dong AU - Xiang D AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. FAU - Liu, Dong AU - Liu D AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. Electronic address: ld2069@outlook.com. FAU - Ren, Xiuhua AU - Ren X AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. Electronic address: 271052026@qq.com. FAU - Zhang, Chengliang AU - Zhang C AD - Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province 430043, China. Electronic address: clzhang@tjh.tjmu.edu.cn. LA - eng PT - Journal Article DEP - 20210701 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Antibodies) RN - 0 (Cytokines) RN - 0 (NF-kappa B) RN - 0 (Platelet Aggregation Inhibitors) RN - 0 (Topoisomerase I Inhibitors) RN - 7673326042 (Irinotecan) RN - 9007-41-4 (C-Reactive Protein) RN - 9042-14-2 (Dextran Sulfate) RN - A74586SNO7 (Clopidogrel) RN - EC 1.11.1.7 (Peroxidase) RN - EC 2.6.1.1 (Aspartate Aminotransferases) RN - EC 2.6.1.2 (Alanine Transaminase) RN - EC 3.1.1.- (Carboxylic Ester Hydrolases) RN - EC 3.1.1.- (carboxylesterase 1, mouse) RN - EC 3.1.1.1 (Carboxylesterase) RN - EC 3.1.1.1 (Ces2c protein, mouse) SB - IM MH - Alanine Transaminase/blood MH - Animals MH - Antibodies/pharmacology MH - Aspartate Aminotransferases/blood MH - C-Reactive Protein/analysis MH - Carboxylesterase/*immunology MH - Carboxylic Ester Hydrolases/*immunology MH - Cell Line MH - Clopidogrel/pharmacology MH - Colitis/blood/chemically induced/*immunology/pathology MH - Colon/immunology/pathology MH - Cytokines/antagonists & inhibitors/genetics/*immunology MH - Dextran Sulfate MH - Humans MH - Irinotecan/pharmacology MH - Liver/*immunology/pathology MH - Male MH - Mice, Inbred C57BL MH - Microsomes, Liver/immunology MH - NF-kappa B/*immunology MH - Peroxidase/immunology MH - Platelet Aggregation Inhibitors/pharmacology MH - Topoisomerase I Inhibitors/pharmacology MH - Mice OTO - NOTNLM OT - Carboxylesterase OT - IL-6 OT - Inflammation OT - Ulcerative colitis EDAT- 2021/07/05 06:00 MHDA- 2022/01/27 06:00 CRDT- 2021/07/04 20:47 PHST- 2021/03/26 00:00 [received] PHST- 2021/06/13 00:00 [revised] PHST- 2021/06/21 00:00 [accepted] PHST- 2021/07/05 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/07/04 20:47 [entrez] AID - S1567-5769(21)00556-7 [pii] AID - 10.1016/j.intimp.2021.107920 [doi] PST - ppublish SO - Int Immunopharmacol. 2021 Oct;99:107920. doi: 10.1016/j.intimp.2021.107920. Epub 2021 Jul 1.