KMID : 0606920120200030293
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Biomolecules & Therapeutics 2012 Volume.20 No. 3 p.293 ~ p.298
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The Changes of P-glycoprotein Activity by Interferon-¥ã and Tumor Necrosis Factor-¥á in Primary and Immortalized Human Brain Microvascular Endothelial Cells
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Lee Na-Young
Rieckmann Peter Kang Young-Sook
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Abstract
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The purpose of this study was to investigate the modification of expression and functionality of the drug transporter P-glycoprotein (P-gp) by tumor necrosis factor-alpha (TNF-¥á) and interferon-gamma (IFN-¥ã) at the blood-brain barrier (BBB). We used immortalized human brain microvessel endothelial cells (iHBMEC) and primary human brain microvessel endothelial cells (pHBMEC) as in vitro BBB model. To investigate the change of p-gp expression, we carried out real time PCR analysis and Western blotting. To test the change of p-gp activity, we performed rhodamin123 (Rh123) accumulation study in the cells. In results of real time PCR analysis, the P-gp mRNA expression was increased by TNF-¥á or IFN-¥ã treatment for 24 hr in both cell types. However, 48 hr treatment of TNF-¥á or IFN-¥ã did not affect P-gp mRNA expression. In addition, co-treatment of TNF-¥á and IFN-¥ã markedly increased the P-gp mRNA expression in both cells. TNF-¥á or IFN-¥ã did not influence P-gp protein expression whatever the concentration of cytokines or duration of treatment in both cells. However, P-gp expression was increased after treatments of both cytokines together in iHBMEC cells only compared with untreated control. Furthermore, in both cell lines, TNF-¥á or IFN-¥ã induced significant decrease of P-gp activity for 24 hr treatment. And, both cytokines combination treatment also decreased significantly P-gp activity. These results suggest that P-gp expression and function at the BBB is modulated by TNF-¥á or/and IFN-¥ã. Therefore, the distribution of P-gp depending drugs in the central nervous system can be modulated by neurological inflammatory diseases.
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KEYWORD
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TNF-¥á, IFN-¥ã, P-glycoprotein, Human brain microvascular endothelial cell, Blood-brain barrier, Efflux transport
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