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

Michal Toborek, Yong Woo Lee, H. Pu, Andrzej Malecki, Govinder Flora, Rosario Garrido, Bernhard Hennig, Hans Christian Bauer, Avindra Nath

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

Impaired function of the brain vasculature might contribute to the development of HIV-associated dementia. For example, injury or dysfunction of brain microvascular endothelial cells (BMEC) can lead to the breakdown of the blood-brain barrier (BBB) and thus allow accelerated entry of the HIV-1 virus into the CNS. Mechanisms of injury to BMEC during HIV-1 infection are not fully understood, but the viral gene product Tat may be, at least in part, responsible for this effect. Tat can be released from infected perivascular macrophages in the CNS of patients with AIDS, and thus BMEC can be directly exposed to high concentrations of this protein. To study oxidative and inflammatory mechanisms associated with Tat-induced toxicity, BMEC were exposed to increasing doses of Tat1-72, and markers of oxidative stress, as well as redox-responsive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), were measured. Tat1-72 treatment markedly increased cellular oxidative stress, decreased levels of intracellular glutathione and activated DNA binding activity and transactivation of NF-κB and AP-1. To determine if Tat1-72 can stimulate inflammatory responses in brain endothelium in vivo, expression of monocyte chemoattractant protein-1 (MCP-1), an NF-κB and AP-1-dependent chemokine, was studied in brain tissue in mice injected with Tat1-72 into the right hippocampus. Tat1-72 markedly elevated the MCP-1 mRNA levels in brain tissue. In addition, a double immunohistochemistry study revealed that MCP-1 protein was markedly overexpressed on brain vascular endothelium. These data indicate that Tat1-72 can induce redox-related inflammatory responses both in in vitro and in vivo environments. These changes can directly lead to disruption of the BBB. Thus, Tat can play an important role in the development of detrimental vascular changes in the brains of HIV-infected patients.

Original languageEnglish
Pages (from-to)169-179
Number of pages11
JournalJournal of Neurochemistry
Volume84
Issue number1
DOIs
Publication statusPublished - Jan 2003

Fingerprint

Human Immunodeficiency Virus tat Gene Products
Endothelium
Brain
Endothelial cells
Chemokine CCL2
Transcription Factor AP-1
Endothelial Cells
Oxidative stress
Blood-Brain Barrier
Oxidation-Reduction
HIV-1
Oxidative Stress
AIDS Dementia Complex
Tissue
Vascular Endothelium
Viral Proteins
Macrophages
Chemokines
Brain Injuries
Transcriptional Activation

Keywords

  • AIDS
  • Blood-brain barrier
  • Endothelial cells
  • Virotoxins

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. / Toborek, Michal; Lee, Yong Woo; Pu, H.; Malecki, Andrzej; Flora, Govinder; Garrido, Rosario; Hennig, Bernhard; Bauer, Hans Christian; Nath, Avindra.

In: Journal of Neurochemistry, Vol. 84, No. 1, 01.2003, p. 169-179.

Research output: Contribution to journalArticle

Toborek, M, Lee, YW, Pu, H, Malecki, A, Flora, G, Garrido, R, Hennig, B, Bauer, HC & Nath, A 2003, 'HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium', Journal of Neurochemistry, vol. 84, no. 1, pp. 169-179. https://doi.org/10.1046/j.1471-4159.2003.01543.x
Toborek, Michal ; Lee, Yong Woo ; Pu, H. ; Malecki, Andrzej ; Flora, Govinder ; Garrido, Rosario ; Hennig, Bernhard ; Bauer, Hans Christian ; Nath, Avindra. / HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. In: Journal of Neurochemistry. 2003 ; Vol. 84, No. 1. pp. 169-179.
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