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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

IL-17 increased P-gp expression through the STAT3-dependent Nf-κb pathway.(A) THP-1 cells were treated with 50 ng/ml TNF-α or 2 μg/ml LPS for different periods of time. CCRF-CEM cells were treated with 50 ng/ml TNF-α for different periods of time. Nuclear and cytosolic p65 and phosphorylated p65 were detected by Western blot. (B) CCRF-CEM cells were treated with 200 ng/ml IL-17 in the absence or presence of the STAT3 inhibitor Stattic for different periods of time. Total STAT3 and phosphorylated STAT3 and nuclear and cytosolic p65 and phosphorylated p65 were detected by Western blot.
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f7: IL-17 increased P-gp expression through the STAT3-dependent Nf-κb pathway.(A) THP-1 cells were treated with 50 ng/ml TNF-α or 2 μg/ml LPS for different periods of time. CCRF-CEM cells were treated with 50 ng/ml TNF-α for different periods of time. Nuclear and cytosolic p65 and phosphorylated p65 were detected by Western blot. (B) CCRF-CEM cells were treated with 200 ng/ml IL-17 in the absence or presence of the STAT3 inhibitor Stattic for different periods of time. Total STAT3 and phosphorylated STAT3 and nuclear and cytosolic p65 and phosphorylated p65 were detected by Western blot.

Mentions: LPS and the cytokine TNF-α could stimulate both p65 and phosphorylated p65 expression in the cytosol and nuclei of THP-1 cells in a time-dependent manner (Fig. 7A). In CCRF-CEM cells, TNF-α promoted the translocation of p65 from cytosol to nuclei, with decreased p65 expression in the cytosol and increased p65 expression in the nuclei. Furthermore, TNF-α also enhanced the phosphorylation of p65 in the nuclei in a time-dependent manner (Fig. 7A).


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)

IL-17 increased P-gp expression through the STAT3-dependent Nf-κb pathway.(A) THP-1 cells were treated with 50 ng/ml TNF-α or 2 μg/ml LPS for different periods of time. CCRF-CEM cells were treated with 50 ng/ml TNF-α for different periods of time. Nuclear and cytosolic p65 and phosphorylated p65 were detected by Western blot. (B) CCRF-CEM cells were treated with 200 ng/ml IL-17 in the absence or presence of the STAT3 inhibitor Stattic for different periods of time. Total STAT3 and phosphorylated STAT3 and nuclear and cytosolic p65 and phosphorylated p65 were detected by Western blot.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: IL-17 increased P-gp expression through the STAT3-dependent Nf-κb pathway.(A) THP-1 cells were treated with 50 ng/ml TNF-α or 2 μg/ml LPS for different periods of time. CCRF-CEM cells were treated with 50 ng/ml TNF-α for different periods of time. Nuclear and cytosolic p65 and phosphorylated p65 were detected by Western blot. (B) CCRF-CEM cells were treated with 200 ng/ml IL-17 in the absence or presence of the STAT3 inhibitor Stattic for different periods of time. Total STAT3 and phosphorylated STAT3 and nuclear and cytosolic p65 and phosphorylated p65 were detected by Western blot.
Mentions: LPS and the cytokine TNF-α could stimulate both p65 and phosphorylated p65 expression in the cytosol and nuclei of THP-1 cells in a time-dependent manner (Fig. 7A). In CCRF-CEM cells, TNF-α promoted the translocation of p65 from cytosol to nuclei, with decreased p65 expression in the cytosol and increased p65 expression in the nuclei. Furthermore, TNF-α also enhanced the phosphorylation of p65 in the nuclei in a time-dependent manner (Fig. 7A).

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