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HIV‐Tat protein induces oxidative and inflammatory pathways in brain endothelium
Author(s) -
Toborek Michal,
Lee Yong Woo,
Pu Hong,
Malecki Andrzej,
Flora Govinder,
Garrido Rosario,
Hennig Bernhard,
Bauer HansChristian,
Nath Avindra
Publication year - 2003
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.01543.x
Subject(s) - oxidative stress , transactivation , chemokine , blood–brain barrier , endothelium , proinflammatory cytokine , biology , inflammation , activator (genetics) , transcription factor , glutathione , chemistry , microbiology and biotechnology , immunology , central nervous system , endocrinology , biochemistry , receptor , gene , enzyme
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 Tat 1−72 , 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. Tat 1−72 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 Tat 1−72 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 Tat 1−72 into the right hippocampus. Tat 1−72 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 Tat 1−72 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.