HIV-1 Tat protein-induced alterations of ZO-1 expression are mediated by redox-regulated ERK 1/2 activation.
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 (ERK 1/2) and pretreatment with U 0126, 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 ERK 1/2 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 ERK 1/2 pathway.
Pu
Hong
H
Molecular Neuroscience and Vascular Biology Laboratory, Department of Surgery, University of Kentucky Medical Center, Kentucky 40536, USA.
Tian
Jing
J
Andras
Ibolya E
IE
Hayashi
Kentaro
K
Flora
Govinder
G
Hennig
Bernhard
B
Toborek
Michal
M
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D015696:Gene Products, tat / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus; D007249:Inflammation; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism* / Q000502:physiology; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010750:Phosphoproteins / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D062826:Zonula Occludens-1 Protein
D015696:Gene Products, tat; D008565:Membrane Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; C569043:Tjp1 protein, mouse; D062826:Zonula Occludens-1 Protein; D048052:Mitogen-Activated Protein Kinase 3