HIV‐Tat protein induces oxidative and inflammatory pathways in brain endothelium

Toborek, Michał; Lee, Yong Woo; Peng, Hong; Małecki, Andrzej; Flora, Govinder; Garrido, Rosario; Hennig, Bernhard; Bauer, H.; Nath, Avindra

doi:10.1046/j.1471-4159.2003.01543.x

Cited by 190 publications

(174 citation statements)

References 58 publications

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“…Here, we show that NF-B is activated in ECs following extracellular interaction of Tat with ␣ v ␤ 3 and the consequent activation of FAK, RhoA and pp60 src . In ECs, NF-B activation by Tat has, to date, been connected to the overexpression of surface adhesive molecules and/or activation of inflammatory pathways (Cooper et al, 1996;Cota-Gomez et al, 2002;Pieper et al, 2002;Toborek et al, 2003). The data here reported implicate NF-B in the motogenic activity exerted by Tat in vitro, suggesting its involvement also in the neovascularization induced by Tat in vivo.…”

Section: Tat/␣ V ␤ 3 Interaction Promotes Fak Activationmentioning

confidence: 50%

“…Tat has been shown to activate NF-B in different cell types including astrocytes (Conant et al, 1998), macrophages (Kumar et al, 1999), T-cells (Li-Weber et al, 2000) and ECs (Cooper et al, 1996;Cota-Gomez et al, 2002;Pieper et al, 2002;Toborek et al, 2003), but the mechanism(s) of activation are not fully elucidated. Indeed, Tat can induce NF-B activation both when administered extracellularly (Cota-Gomez et al, 2002) and when produced endogenously…”

Section: Tat/␣ V ␤ 3 Interaction Promotes Fak Activationmentioning

confidence: 99%

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αvβ3-integrin-dependent activation of focal adhesion kinase mediates NF-κB activation and motogenic activity by HIV-1 Tat in endothelial cells

Urbinati

Bugatti

Giacca

et al. 2005

Journal of Cell Science

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Once in the extracellular environment, the transactivator protein HIV-1 Tat exerts several pleiotropic effects by interacting with different cellular receptors, including integrin αvβ3. Real-time surface plasmon resonance analysis reveals that Tat/αVβ3 interaction occurs with rapid kinetics (association and dissociation rates equal to 1.16×107 M-1 s-1 and 3.78×10-1 s-1, respectively) and high affinity (dissociation constant = 32 nM). Through this interaction, substratum-immobilized Tat promotes adhesion and motogenic activity in endothelial cells. Also, αvβ3/Tat interaction triggers the activation of focal adhesion kinase, RhoA and pp60src. Overexpression of the dominant negative form of focal adhesion kinase, but not of an inactive Leu1034Ser substitution mutant isoform, impairs the activation of focal adhesion kinase and RhoA, but not that of pp60src, without affecting endothelial cell adhesion and spreading. αvβ3/Tat interaction triggers the activation of NF-κB in endothelial cells in a focal adhesion kinase-, RhoA- and pp60src-dependent manner, as shown in dominant negative focal adhesion kinase transfectants or using specific pharmacological inhibitors. Finally, the activation of focal adhesion kinase, RhoA, NF-κB and pp60src are required to mediate the motogenic activity of Tat in endothelial cells. Since Tat accumulates in an immobilized form in the extracellular matrix, these results provide new biochemical and biological insights about αvβ3/Tat interaction exploitable for the design of anti-Tat strategies.

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Section: Tat/␣ V ␤ 3 Interaction Promotes Fak Activationmentioning

confidence: 50%

Section: Tat/␣ V ␤ 3 Interaction Promotes Fak Activationmentioning

confidence: 99%

αvβ3-integrin-dependent activation of focal adhesion kinase mediates NF-κB activation and motogenic activity by HIV-1 Tat in endothelial cells

Urbinati

Bugatti

Giacca

et al. 2005

Journal of Cell Science

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“…For example, disruption of the bloodbrain barrier is widely believed to be the main route by which HIV enters the CNS. The Tat protein, which is released from HIV-infected cells, alters vascular inflammatory responses as well as blood-brain barrier structure and function both in vitro and in vivo (Andras et al, 2003;Toborek et al, 2003). Exposure of primary cultures of brain microvascular endothelial cells (BMEC) to Tat(1-72) for 24 hours results in a decrease of claudin-1, claudin-5 and ZO-2 expression, whereas total levels of occludin and ZO-1 remained unchanged.…”

Section: Claudin Genes and Claudin Gene Expressionmentioning

confidence: 99%

Barriers built on claudins

Turksen¹,

Troy²

2004

Journal of Cell Science

361

288

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We wish to correct some errors that we inadvertently introduced in revising and editing our recent Commentary. In the text, we incorrectly cited (Wolburg et al., 2003) in reference to the downregulation of claudin-23 in gastric cancer; the reference should be (Katoh and Katoh, 2003) as correctly cited in Table 3. (Peacock et al., 1997) was mistakenly inserted in relation to the discussion of the number of claudin genes. We also wrote the number of human claudin genes as 24, the number currently ascribed to the mouse claudin genes (GenBank). The correct number ascribed to human claudin genes by (Katoh and Katoh, 2003) is 23, up from the originally predicted 20 (Venter et al., 2001). In this regard, it is worth noting that, since our Commentary was published, (Loh et al., 2004) have annotated the claudins in the teleost Fugu rubripes genome and reported 56 claudin genes, of which only 35 can be assigned orthology to 17 mammalian claudin genes, with the remaining 21 being specific to the fish lineage and most of the 56 expressed in a more or less tissue-specific fashion, or at particular developmental stages. This, along with other issues we raised, suggests that additional annotation of multiple other genomes and other functional genomics approaches will be useful to advance our understanding of claudin biology and physiology. Finally, based on a Clustal analysis of full-length claudins, we reported that there is a highly conserved WWCC motif of unknown function within the first loop of the claudins analysed; a motif also reported in alignments of claudins carried out by (Katoh and Katoh, 2003). IntroductionIn multicellular organisms, certain tissues must be separated from each other and protected against the external environment. Epithelial and endothelial sheets achieve this by providing cellular borders that cover external and internal surfaces throughout the body. Complexes between adjacent cells in these sheets include gap junctions, desmosomes, adherence junctions and tight junctions (TJs) -also known as the zonula occludens. Early ultrastructural and morphological data revealed TJs as continuous circumferential intercellular contacts between epithelial cells (Farquhar and Palade, 1963) that create a barrier to the paracellular movement of water, solutes and immune cells (Madara, 1998;Nusrat et al., 2000). Later work showed that this epithelial barrier is heterogeneous in tightness and dynamics depending on the tissue. In addition it is physiologically regulated, and its disruption contributes to human disease. Numerous in-depth reviews on TJs exist (Begley and Brightman, 2003;Fanning et al., 1999; GonzalezMariscal et al., 2003;Heiskala et al., 2001;Madara, 1989;Mitic and Anderson, 1998;Stevenson, 1999;Tsukita and Furuse, 2000a;Tsukita and Furuse, 2000b;Tsukita et al., 2001;Zahraoui et al., 2000). Here we therefore only briefly summarize their essential features and then focus on the recent identification of claudins and our evolving understanding of their contribution to TJ structure and function. Tight...

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“…It is well accepted that both chemokines and their receptors play a key role in HIV infection and progression. In addition, studies have shown that chemokines and their receptors are involved in the neuropathogenesis of HIV-1 infection in the CNS (Rappaport et al, 1999;Petito et al, 1999;McManus et al, 2000;Wesselingh and Thompson, 2001;Toborek et al, 2003). Chemokine receptors are important HIV-1 co-receptors, in combination with the T lymphocyte receptor, CD4.…”

Section: Introductionmentioning

confidence: 99%

Synergistic increases in intracellular Ca²⁺, and the release of MCP‐1, RANTES, and IL‐6 by astrocytes treated with opiates and HIV‐1 Tat

El‐Hage

Gurwell

Singh

et al. 2005

Glia

Self Cite

209

257

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Recent evidence suggests that injection drug users who abuse heroin are at increased risk for CNS complications from human immunodeficiency virus (HIV) infection. Opiate drugs may intrinsically alter the pathogenesis of HIV by directly modulating immune function and by directly modifying the CNS response to HIV. Despite this, the mechanisms by which opiates increase the neuropathogenesis of HIV are uncertain. Herein we describe the effect of morphine and the HIV-1 protein toxin Tat 1-72 on astroglial function in cultures derived from ICR mice. Astroglia maintain the blood brain barrier and influence inflammatory signaling in the CNS. Astrocytes can express μ opioid receptors, and are likely targets for abused opiates, which preferentially activate μ-opioid receptors. While Tat alone disrupts astrocyte function, when combined with morphine, Tat causes synergistic increases in [Ca 2+ ] i. . Moreover, astrocyte cultures treated with morphine and Tat showed exaggerated increases in chemokine release including monocyte chemoattractant protein-1 (MCP-1) and regulated on activation, normal T cell expressed and secreted (RANTES), as well as interleukin-6 (IL-6). Morphine-Tat interactions were prevented by the μ-opioid receptor antagonist β-funaltrexamine, or by immunoneutralizing Tat 1-72 or substituting a non-toxic, deletion mutant (Tat Δ31-61 ). Our findings suggest that opiates may increase the vulnerability of the CNS to viral entry (via recruitment of monocytes/macrophages) and ensuing HIV encephalitis by synergistically increasing MCP-1 and RANTES release by astrocytes. The results further suggest ‡ Abbreviations: alpha chemokine receptor (CXCR); beta chemokine ligand (CCL); beta chemokine receptor (CCR); β-funaltrexamine (β-FNA); calcium-induced calcium release (CICR); excitatory amino acid transporter-2 (EAAT2); granulocyte macrophage colony stimulating factor (GM-CSF); granulocyte-colony stimulating factor (G-CSF); human immunodeficiency virus (HIV); human immunodeficiency virus encephalitis (HIVE); inositol trisphosphate (IP 3 ); interferon (IFN); interleukin (IL); intracellular Ca 2+ ([Ca 2+ ] i ); monocyte chemoattractant protein (MCP); nor-binaltorphimine (nor-BNI); phosphatidylinositol 3-kinase (PI3-kinase); phospholipase C-γ (PLCγ); regulated on activation, normal T cell expressed and secreted (RANTES); soluble TNF receptor subunit (sTNFR1); stem cell factor (SCF); thrombopoietin (TPO); transactivator of transcription (Tat); tumor necrosis factor-α (TNF-α); vascular endothelial growth factor (VEGF).

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HIV‐Tat protein induces oxidative and inflammatory pathways in brain endothelium

Cited by 190 publications

References 58 publications

αvβ3-integrin-dependent activation of focal adhesion kinase mediates NF-κB activation and motogenic activity by HIV-1 Tat in endothelial cells

αvβ3-integrin-dependent activation of focal adhesion kinase mediates NF-κB activation and motogenic activity by HIV-1 Tat in endothelial cells

Barriers built on claudins

Synergistic increases in intracellular Ca²⁺, and the release of MCP‐1, RANTES, and IL‐6 by astrocytes treated with opiates and HIV‐1 Tat

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HIV‐Tat protein induces oxidative and inflammatory pathways in brain endothelium

Cited by 190 publications

References 58 publications

αvβ3-integrin-dependent activation of focal adhesion kinase mediates NF-κB activation and motogenic activity by HIV-1 Tat in endothelial cells

αvβ3-integrin-dependent activation of focal adhesion kinase mediates NF-κB activation and motogenic activity by HIV-1 Tat in endothelial cells

Barriers built on claudins

Synergistic increases in intracellular Ca2+, and the release of MCP‐1, RANTES, and IL‐6 by astrocytes treated with opiates and HIV‐1 Tat

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Product

Resources

About

Synergistic increases in intracellular Ca²⁺, and the release of MCP‐1, RANTES, and IL‐6 by astrocytes treated with opiates and HIV‐1 Tat