HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK1/2 activation

Hong Pu, Jing Tian, Ibolya Edit Andras, Kentaro Hayashi, Govinder Flora, Bernhard Hennig, Michal J Toborek

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

HIV-1 Tat protein plays an important role in inducing monocyte infiltration into the brain and may alter the structure and functions of the blood-brain barrier (BBB). The BBB serves as a frontline defense system, protecting the central nervous system from infected monocytes entering the brain. Therefore, the aim of the present study was to examine the mechanisms of Tat effect on the integrity of the BBB in the mouse brain. Tat was injected into the right hippocampi of C57BL/6 mice and expression of tight junction protein zonula occludens-1 (ZO-1) was determined in control and treated mice. Tat administration resulted in decreased mRNA levels of ZO-1 and marked disruption of ZO-1 continuity. These changes were associated with accumulation of inflammatory cells in brain tissue of Tat-treated mice. Further experiments indicated that Tat-mediated alterations of redox-related signaling may be responsible for decreased ZO-1 expression. Specifically, injections with Tat resulted in activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and pretreatment with U0126, a specific inhibitor of ERK kinase, effectively ameliorated the Tat-induced diminished ZO-1 levels. In addition, administration of N-acetylcysteine (NAC), a precursor of glutathione and a potent antioxidant, attenuated both Tat-induced ERK1/2 activation and alterations in ZO-1 expression. These results indicate that Tat-induced oxidative stress can play an important role in affecting the integrity of the BBB through the ERK1/2 pathway.

Original languageEnglish
Pages (from-to)1325-1335
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume25
Issue number10
DOIs
StatePublished - Oct 1 2005
Externally publishedYes

Fingerprint

Human Immunodeficiency Virus tat Gene Products
Mitogen-Activated Protein Kinase 3
Tight Junctions
Mitogen-Activated Protein Kinase 1
Oxidation-Reduction
HIV-1
Blood-Brain Barrier
Brain
Monocytes
Tight Junction Proteins
Acetylcysteine
Inbred C57BL Mouse
Glutathione
Hippocampus
Oxidative Stress
Phosphotransferases
Central Nervous System
Antioxidants
Messenger RNA
Injections

Keywords

  • Antioxidants
  • Blood-brain barrier
  • HIV-1
  • Redox-regulated mechanisms
  • Signal transduction
  • Tight junctions

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK1/2 activation. / Pu, Hong; Tian, Jing; Andras, Ibolya Edit; Hayashi, Kentaro; Flora, Govinder; Hennig, Bernhard; Toborek, Michal J.

In: Journal of Cerebral Blood Flow and Metabolism, Vol. 25, No. 10, 01.10.2005, p. 1325-1335.

Research output: Contribution to journalArticle

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abstract = "HIV-1 Tat protein plays an important role in inducing monocyte infiltration into the brain and may alter the structure and functions of the blood-brain barrier (BBB). The BBB serves as a frontline defense system, protecting the central nervous system from infected monocytes entering the brain. Therefore, the aim of the present study was to examine the mechanisms of Tat effect on the integrity of the BBB in the mouse brain. Tat was injected into the right hippocampi of C57BL/6 mice and expression of tight junction protein zonula occludens-1 (ZO-1) was determined in control and treated mice. Tat administration resulted in decreased mRNA levels of ZO-1 and marked disruption of ZO-1 continuity. These changes were associated with accumulation of inflammatory cells in brain tissue of Tat-treated mice. Further experiments indicated that Tat-mediated alterations of redox-related signaling may be responsible for decreased ZO-1 expression. Specifically, injections with Tat resulted in activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and pretreatment with U0126, a specific inhibitor of ERK kinase, effectively ameliorated the Tat-induced diminished ZO-1 levels. In addition, administration of N-acetylcysteine (NAC), a precursor of glutathione and a potent antioxidant, attenuated both Tat-induced ERK1/2 activation and alterations in ZO-1 expression. These results indicate that Tat-induced oxidative stress can play an important role in affecting the integrity of the BBB through the ERK1/2 pathway.",
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