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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.

Liu J, Zhou F, Chen Q, Kang A, Lu M, Liu W, Zang X, Wang G, Zhang J - Sci Rep (2015)

Bottom Line: This resistance can be divided into intrinsic resistance and acquired resistance.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.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Elevated expression and function of P-gp in the PBMC of TNBS-induced mice.PBMC were isolated from the peripheral blood of mice in the control group and the TNBS-treated model group on the 3rd and 7th days post vehicle or TNBS challenge. The gene expression of mdr1a in the PMBC was analyzed by qPCR (A). The function of P-gp in the PBMC was assayed by incubating the PBMC with the P-gp substrate probe Rho 123 (B) or the P-gp substrate immunosuppressant Cys A (C) for 2 h to determine its intracellular retention. Data are presented as the mean ± S.E.M., *p<0.05, **p<0.01 between the model group versus the corresponding control group; n = 8/group.
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f2: Elevated expression and function of P-gp in the PBMC of TNBS-induced mice.PBMC were isolated from the peripheral blood of mice in the control group and the TNBS-treated model group on the 3rd and 7th days post vehicle or TNBS challenge. The gene expression of mdr1a in the PMBC was analyzed by qPCR (A). The function of P-gp in the PBMC was assayed by incubating the PBMC with the P-gp substrate probe Rho 123 (B) or the P-gp substrate immunosuppressant Cys A (C) for 2 h to determine its intracellular retention. Data are presented as the mean ± S.E.M., *p<0.05, **p<0.01 between the model group versus the corresponding control group; n = 8/group.

Mentions: Model mice were successfully treated with TNBS and kept for 3 days (acute model) and 7 days (subacute model) (Supplementary Fig 1). As shown in Fig 2A, the expression of the mdr1a gene in PBMC isolated from model mice treated with TNBS for 3 days exhibited no difference from the control groups. However, when these model mice were treated with TNBS for 7 days, mdr1a gene expression in the PBMC of the model group was significantly elevated to approximately 4.65-fold of that in the control group (p < 0.05).


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.

Liu J, Zhou F, Chen Q, Kang A, Lu M, Liu W, Zang X, Wang G, Zhang J - Sci Rep (2015)

Elevated expression and function of P-gp in the PBMC of TNBS-induced mice.PBMC were isolated from the peripheral blood of mice in the control group and the TNBS-treated model group on the 3rd and 7th days post vehicle or TNBS challenge. The gene expression of mdr1a in the PMBC was analyzed by qPCR (A). The function of P-gp in the PBMC was assayed by incubating the PBMC with the P-gp substrate probe Rho 123 (B) or the P-gp substrate immunosuppressant Cys A (C) for 2 h to determine its intracellular retention. Data are presented as the mean ± S.E.M., *p<0.05, **p<0.01 between the model group versus the corresponding control group; n = 8/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555107&req=5

f2: Elevated expression and function of P-gp in the PBMC of TNBS-induced mice.PBMC were isolated from the peripheral blood of mice in the control group and the TNBS-treated model group on the 3rd and 7th days post vehicle or TNBS challenge. The gene expression of mdr1a in the PMBC was analyzed by qPCR (A). The function of P-gp in the PBMC was assayed by incubating the PBMC with the P-gp substrate probe Rho 123 (B) or the P-gp substrate immunosuppressant Cys A (C) for 2 h to determine its intracellular retention. Data are presented as the mean ± S.E.M., *p<0.05, **p<0.01 between the model group versus the corresponding control group; n = 8/group.
Mentions: Model mice were successfully treated with TNBS and kept for 3 days (acute model) and 7 days (subacute model) (Supplementary Fig 1). As shown in Fig 2A, the expression of the mdr1a gene in PBMC isolated from model mice treated with TNBS for 3 days exhibited no difference from the control groups. However, when these model mice were treated with TNBS for 7 days, mdr1a gene expression in the PBMC of the model group was significantly elevated to approximately 4.65-fold of that in the control group (p < 0.05).

Bottom Line: This resistance can be divided into intrinsic resistance and acquired resistance.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.

View Article: PubMed Central - PubMed

Affiliation: Key Lab of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus