Regulation of major efflux transporters under inflammatory conditions at the blood-brain barrier in vitro.
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-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) on the expression of brain multidrug resistance proteins in primary cultures of porcine brain capillary endothelial cells. We found that TNF-alpha and IL-1beta 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-alpha addition within 6 h of incubation followed by a reduction after 24 and 48 h whereas the Abcb1 mRNA levels were not changed. IL-1beta caused a continuous decrease in protein expression of both ABC-transporters. Long-term treatment with an assumed TNF-alpha-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-alpha-signalling counterbalanced by Abcg2.
von Wedel-Parlow
Magdalena
M
Institut für Biochemie, Westfälische Wilhelms-Universität Münster, Münster, Germany.
Wölte
Philipp
P
Galla
Hans-Joachim
HJ
D018528:ATP-Binding Cassette Transporters / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D019332:Endothelin-1 / Q000009:adverse effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006854:Hydrocortisone / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D053583:Interleukin-1beta / Q000009:adverse effects; D013552:Swine; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects
D018528:ATP-Binding Cassette Transporters; D000893:Anti-Inflammatory Agents; D019332:Endothelin-1; D053583:Interleukin-1beta; D014409:Tumor Necrosis Factor-alpha; D006854:Hydrocortisone