Influence of tumor necrosis factor-α on the expression and function of P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT

Théron, David; Lagerie, Sylvie Barraud de; Tardivel, Sylviane; Pélerin, Hélène; Demeuse, Philippe; Mercier, Claire; Mabondzo, Aloı̈se; Farinotti, Robert; Lacour, Bernard; Roux, Françoise; Gimenez, François

doi:10.1016/s0006-2952(03)00340-x

Cited by 47 publications

(29 citation statements)

References 26 publications

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“…In particular, transcription factors Atf3/LRF1 and NGFI-B/Nurr77, the cytokine bone morphogenic protein 2 (Bmp2), the Ser/Thr kinase Map3K8, and the membrane channel protein connexin 37 are each reported to be pro-apoptotic (Patriotis et al, 2001;Watanabe et al, 2001;Zhang et al, 2001;Hartman et al, 2004;Kume and Kita, 2004;Seul et al, 2004) and up-regulated by TNF␣ or to mediate its actions (van Rijen et al, 1998;Dumitru et al, 2000;Mashima et al, 2001;Gruber et al, 2003;Hofnagel et al, 2004;Inoue et al, 2004). Other robustly up-regulated genes, including the hyaluronan binding protein; TSG-6; the enzyme that makes hyaluronan, hyaluronan synthase 2 (Has2); the urokinase/tPA receptor (uPAR-1); and the p-glycoprotein multidrug resistance gene (Mdr1a), although not directly linked to apoptosis, are reported to either mediate TNF-␣ actions or to be up-regulated by TNF-␣ (Lee et al, 1993;Piguet et al, 1999;Ijuin et al, 2001;Theron et al, 2003). A shared link between many of the remaining genes and apoptotic pathways or TNF-␣ signaling is not readily apparent.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Gqα, G14α, and G15α on Vascular Smooth Muscle Cell Survival and Gene Expression Profiles

Peavy¹,

Hubbard²,

Lau³

et al. 2005

Mol Pharmacol

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Gq␣ family members (Gq␣, G11␣, G14␣, and G15/16␣) stimulate phospholipase C␤ (PLC␤) and inositol lipid signaling but differ markedly in amino acid sequence and tissue distribution predicting unappreciated functional diversity. To examine functional differences, we compared the signaling properties of Gq␣, G14␣, and G15␣ and their cellular responses in vascular smooth muscle cells (VSMC). Constitutively active forms of Gq␣, G14␣, or G15␣ elicit markedly different responses when introduced to VSMC. Whereas each G␣ stimulated PLC␤ to similar extents when expressed at equal protein levels, Gq␣ and G14␣ but not G15␣ initiated profound cell death within 48 h. This response was the result of activation of apoptotic pathways, because Gq␣ and G14␣, but not G15␣, stimulated caspase-3 activation and did not alter phospho-Akt, a regulator of cell survival pathways. Gq␣ and G14␣ stimulate nuclear factor of activated T cell (NFAT) activation in VSMC, but G␣-induced cell death seems independent of PKC, InsP 3 /Ca 2ϩ , and NFAT, in that pharmacological inhibitors of these pathways did not block cell death. Gene expression analysis indicates that Gq␣, G14␣, and G15␣ each elicit markedly different profiles of altered gene sets in VSMC after 24 h. Whereas all three G␣ stimulated changes (Ն2-fold) in 50 shared mRNA, Gq␣ and G14␣ (but not G15␣) stimulated changes in 221 shared mRNA, many of which are reported to be pro-apoptotic and/or involved with TNF-␣ signaling. We were surprised to find that each G␣ also stimulated changes in nonoverlapping G␣-specific gene sets. These findings demonstrate that Gq␣ family members activate both overlapping and distinct signaling pathways and are more functionally diverse than previously thought.

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Section: Discussionmentioning

confidence: 99%

Differential Effects of Gqα, G14α, and G15α on Vascular Smooth Muscle Cell Survival and Gene Expression Profiles

Peavy¹,

Hubbard²,

Lau³

et al. 2005

Mol Pharmacol

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“…Inflammatory mediators (e.g., TNF-␣, IL-1␤, and interferon-␥) can increase junctional permeability, and recent evidence shows that inflammation alters P-glycoprotein expression in the brain and in brain capillary endothelial cells (Tan et al, 2002;Théron et al, 2003;Seelbach et al, 2007). However, both increases and decreases in transporter expression have been observed, and it is not clear from these studies what mechanisms are responsible and whether the changes in tight junction structure and function are somehow linked to altered P-glycoprotein expression.…”

Section: B At the Blood-brain Barriermentioning

confidence: 99%

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

Miller

Bauer²,

Hartz³

2008

Pharmacol Rev

339

275

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“…Inflammatory mediators, such as TNF-␣, IL-1␤, and interferon-␥, can increase junctional permeability and cause leakage of plasma constituents into the CNS. Moreover, recent evidence also shows that inflammation can alter P-glycoprotein expression in several tissues (including brain) and in brain capillary endothelial cells in particular (Tan et al, 2002;Goralski et al, 2003;Theron et al, 2003). These studies have focused on changes taking place over periods of hours to days, and it is not clear whether Pglycoprotein activity is also altered in the short term.…”

mentioning

confidence: 99%

Rapid Modulation of P-Glycoprotein-Mediated Transport at the Blood-Brain Barrier by Tumor Necrosis Factor-α and Lipopolysaccharide

Hartz

Bauer²,

Fricker³

et al. 2005

Mol Pharmacol

184

234

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At the blood-brain barrier, P-glycoprotein, an ATP-driven drug efflux pump, selectively limits drug access to the brain parenchyma, impeding pharmacotherapy of a number of central nervous system (CNS) disorders. We previously used confocal imaging to demonstrate in isolated rat brain capillaries that endothelin-1 (ET-1), acting through an ET B receptor, NO synthase, and protein kinase C, rapidly and reversibly reduces P-glycoprotein transport function. In this study, we define a link between the brain's innate immune response and functional regulation of P-glycoprotein. We show that exposing brain capillaries to the inflammatory cytokine tumor necrosis factor-␣ (TNF-␣), activated a TNF-R1 receptor, released ET-1, activated ET B receptor signaling, and essentially abolished P-glycoprotein-mediated transport. Bacterial lipopolysaccharide, a potent activator of the brain's innate immune response, reduced Pglycoprotein activity through TNF-␣ release, ET-1 release, and ET B receptor signaling. TNF-␣ and LPS effects had a rapid onset (minutes), were reversible, and did not involve changes in tight junctional permeability. These findings define a signaling pathway through which P-glycoprotein activity is acutely modulated. They show that this key component of the selective/ active blood-brain barrier is an early target of cytokine signaling during the innate immune response and suggest ways to manipulate the barrier for improved CNS pharmacotherapy.

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Influence of tumor necrosis factor-α on the expression and function of P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT

Cited by 47 publications

References 26 publications

Differential Effects of Gqα, G14α, and G15α on Vascular Smooth Muscle Cell Survival and Gene Expression Profiles

Differential Effects of Gqα, G14α, and G15α on Vascular Smooth Muscle Cell Survival and Gene Expression Profiles

Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy

Rapid Modulation of P-Glycoprotein-Mediated Transport at the Blood-Brain Barrier by Tumor Necrosis Factor-α and Lipopolysaccharide

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