Regulation of major efflux transporters under inflammatory conditions at the blood-brain barrier in vitro

J Neurochem. 2009 Oct;111(1):111-8. doi: 10.1111/j.1471-4159.2009.06305.x. Epub 2009 Jul 25.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / classification
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Analysis of Variance
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Blood-Brain Barrier / physiology*
  • Brain / cytology
  • Cells, Cultured
  • Electric Impedance
  • Endothelial Cells / drug effects
  • Endothelial Cells / physiology*
  • Endothelin-1 / adverse effects
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Hydrocortisone / pharmacology
  • Inflammation / chemically induced
  • Inflammation / drug therapy
  • Inflammation / pathology*
  • Interleukin-1beta / adverse effects
  • Swine
  • Time Factors
  • Tumor Necrosis Factor-alpha / adverse effects

Substances

  • ATP-Binding Cassette Transporters
  • Anti-Inflammatory Agents
  • Endothelin-1
  • Interleukin-1beta
  • Tumor Necrosis Factor-alpha
  • Hydrocortisone