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Regulation of major efflux transporters under inflammatory conditions at the blood‐brain barrier in vitro
Author(s) -
Von WedelParlow Magdalena,
Wölte Philipp,
Galla HansJoachim
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06305.x
Subject(s) - abcg2 , atp binding cassette transporter , blood–brain barrier , inflammation , efflux , p glycoprotein , transporter , tumor necrosis factor alpha , biology , proinflammatory cytokine , messenger rna , endocrinology , pharmacology , medicine , biochemistry , immunology , multiple drug resistance , central nervous system , gene , antibiotics
ATP‐driven efflux transport proteins at the blood‐brain barrier protect the healthy brain but impede pharmacotherapy of the disordered CNS. To investigate the question how ATP‐binding cassette (ABC)‐transporters are regulated during inflammation or infection we analysed the effects of the cytokines tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) on the expression of brain multidrug resistance proteins in primary cultures of porcine brain capillary endothelial cells. We found that TNF‐α and IL‐1β rapidly decrease Abcg2 ( BMDP/BCRP ) mRNA expression within 6 h. After 24 and 48 h the mRNA level came back to control values. The mRNA reduction at 6 h was counter‐regulated by the anti‐inflammatory glucocorticoid hydrocortisone. Abcg2 protein levels were suppressed at prolonged stimulations but not after 6 h of stimulation which correlates with Abcg2 specific substrate uptake measurements. Abcb1 (p‐glycoprotein) protein expression was transiently increased after TNF‐α addition within 6 h of incubation followed by a reduction after 24 and 48 h whereas the Abcb1 mRNA levels were not changed. IL‐1β caused a continuous decrease in protein expression of both ABC‐transporters. Long‐term treatment with an assumed TNF‐α‐downstream agent, the vasoconstrictor endothelin‐1, induced Abcg2 protein expression but suppressed Abcb1. Other efflux pumps like multidrug resistance‐associated proteins/Abcc were rarely affected. The present results imply a complex regulation of the two most abundant ABC‐transporters at the blood‐brain barrier during early inflammation stages suggesting that Abcb1 (p‐glycoprotein) is an early target of TNF‐α‐signalling counterbalanced by Abcg2.