Cyclooxygenase-2 is involved in HIV-1 Tat-induced inflammatory responses in the brain

Govinder Flora, Hong Pu, Bernhard Hennig, Michal Toborek

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Cyclooxygenase (COX)-2, a rate-limiting enzyme for prostanoid synthesis, can be involved in inflammatory-mediated cytotoxicity. Although the contribution of COX-2 to peripheral inflammation is well understood, its role in brain inflammation is not fully recognized. In particular, COX-2 involvement in inflammatory responses induced by HIV proteins in the central nervous system is not known. Therefore, the present study focused on COX-2 expression and its role in modulating the expression of brain inflammatory-related genes following exposure to the HIV-1 transactivating protein Tat. Intrahippocampal injections of Tat induced dose-dependent upregulation of COX-2 mRNA and protein levels in C57BL/6 mice. COX-2 immunoreactivity was primarily localized in microglial cells and astrocytes. Tat-induced COX-2 expression was partially prevented by pyrrolidine dithiocarbamate, a potent antioxidant and an inhibitor of the transcription factor, nuclear factor κB. Most importantly, administration of the COX-2 inhibitor NS-398 attenuated Tat-mediated upregulation of mRNAand protein expression of inflammatory mediators, such as monocyte chemoattractant protein-1, interleukin-1Β, tumor necrosis factor-α, and inducible nitric oxide synthase. Moreover, treatment with NS-398 significantly attenuated Tatinduced activation of microglial cells. These results provide evidence that COX-2 overexpression can modulate induction of brain inflammatory mediators in response to HIV-1 Tat protein. Such alterations may play an important role in the development of brain inflammatory reactions in HIV-infected patients and contribute to the development of neurological complications in the course of HIV-1 infection.

Original languageEnglish
Pages (from-to)337-351
Number of pages15
JournalNeuroMolecular Medicine
Volume8
Issue number3
DOIs
Publication statusPublished - Sep 2006

Keywords

  • CNS
  • COX
  • HIV-1
  • HIV-associated dementia
  • Inflammation
  • NF-κB
  • Tat

ASJC Scopus subject areas

  • Molecular Medicine
  • Neurology
  • Cellular and Molecular Neuroscience

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