Tumor Necrosis Factor α and Endothelin-1 Increase P-Glycoprotein Expression and Transport Activity at the Blood-Brain Barrier
Abstract
The ATP-driven drug efflux pump, P-glycoprotein, is a critical and selective element of the blood-brain barrier and a primary impediment to pharmacotherapy of central nervous system (CNS) disorders. Thus, an understanding of how P-glycoprotein function is regulated has the potential to improve CNS therapy. We recently demonstrated rapid (minutes) and reversible inactivation of P-glycoprotein in rat brain capillaries signaled through tumor necrosis factor-alpha (TNF-alpha) and endothelin-1 (ET-1), components of the brain's innate immune response. In this study, we examined the longer-term consequences of continuous exposure of rat brain capillaries to low levels of TNF-alpha and ET-1. Exposing brain capillaries to TNF-alpha or ET-1 caused a rapid decrease in P-glycoprotein transport activity with no change in transporter protein expression. This was followed by a 2- to 3-h plateau at the low activity level and then by a sharp increase in both transport activity and protein expression. After 6 h, transport activity and transporter protein expression was double that of control samples. TNF-alpha signaled through TNF-R1, which in turn caused ET release and action through ETA and ETB receptors, nitric-oxide synthase, protein kinase C and nuclear factor-kappaB (NF-kappaB) and finally increased P-glycoprotein expression and transport activity. Assuming similar effects occur in vivo, the present results imply a tightening of the selective blood-brain barrier with chronic inflammation and thus reduced efficacy of CNS-acting drugs that are P-glycoprotein substrates. Moreover, involvement of NF-kappaB raises the possibility that other effectors acting through this transcription factor may have similar effects on this key blood-brain barrier transporter.
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Chronic, low dose TNF-α has been found to increase the expression and activity of the p-glycoprotein pump, while higher doses and acute administration of this cytokine inhibited pump activity.
“Chronic, low dose TNF-α has been found to increase the expression and activity of the p-glycoprotein pump, while higher doses and acute administration of this cytokine-inhibited pump activity.84”
From Cytokines and Glucocorticoid Receptor Signaling (2009) · cites this paper as [84]
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- Authors
- Bauer, B., Hartz, A. M. S., & Miller, D. S.
- Affiliations
- National Institutes of Health (US)
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2007-03
- Volume
- 71
- Issue
- 3
- Pages
- 667-675
- ISSN
- 0026-895X (ISSN-L)
- OpenAlex
- W2127993357
- Cited by
- 275
- References
- 0
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 17 · 2023: 4 · 2022: 11 · 2021: 14 · 2020: 8 · 2019: 13 · 2018: 8 · 2017: 16 · 2016: 23 · 2015: 15 · 2014: 11 · 2013: 23 · 2012: 25
- FWCI
- 6.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- P-glycoprotein, blood-brain barrier, TNF-α, endothelin-1, drug efflux, brain capillaries, NF-κB, protein kinase C, nitric oxide synthase, TNF receptor 1, endothelin receptors, chronic inflammation, brain drug delivery
- MeSH terms
- Animals, Blood-Brain Barrier, Brain, Capillaries, Male, Protein Kinase C, Tumor Necrosis Factor-alpha, NF-kappa B, Rats, Sprague-Dawley, Endothelin-1, ATP Binding Cassette Transporter, Subfamily B, Member 1, Protein Transport, Receptors, Tumor Necrosis Factor, Type I, Rats
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