Chronic inflammation up-regulates P-gp in peripheral mononuclear blood cells via the STAT3/Nf-κb pathway in 2,4,6-trinitrobenzene sulfonic acid-induced colitis mice.
Patients with inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, often suffer drug intolerance. This resistance can be divided into intrinsic resistance and acquired resistance. Although there is agreement on acquired resistance, studies regarding intrinsic resistance have demonstrated inconsistencies, especially for Crohn's disease. For this reason, an animal model of Crohn's disease was induced with 2,4,6-trinitrobenzene sulfonic acid solution (TNBS), and intrinsic resistance was analyzed by measuring the function and expression of P-glycoprotein (P-gp) in peripheral mononuclear blood cells (PMBC), followed by mechanistic studies. The results revealed reduced retention of cyclosporine A in PMBC over-expressing P-gp in a TNBS-treated group and enhanced secretion of the cytokines IL-1β, IL-6, IL-17, and TNF-α as well as LPS in plasma. These cytokines and LPS can induce P-gp expression through the STAT3/Nf-κb pathway, contributing to a decrease of cyclosporine A retention, which can be reversed by the application of a P-gp inhibitor. Our results demonstrated that the sustained chronic inflammation could induce the intrinsic resistance presented as P-gp over-expression in PBMC in Crohn's disease through STAT3/Nf-κb pathway and this resistance might be reversed by combinational usage of P-gp inhibitors.
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
Jiali
J
Liu
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.|Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
Fang
F
Zhou
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
Qianying
Q
Chen
School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
An
A
Kang
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
Meng
M
Lu
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
Wenyue
W
Liu
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.
Xiaojie
X
Zang
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.|Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
Guangji
G
Wang
Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.|Jiangsu Key laboratory of drug design and optimization, China Pharmaceutical University, Nanjing, Jiangsu, China.
Jingwei
J
Zhang
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D003106:Colon / Q000473:pathology; D016572:Cyclosporine / Q000032:analysis / Q000493:pharmacokinetics; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D006207:Half-Life; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D016572:Cyclosporine; D014302:Trinitrobenzenesulfonic Acid