PPARα and PPARγ effectively protect against HIV-induced inflammatory responses in brain endothelial cells

Wen Huang, Geun Bae Rha, Min Joon Han, Sung Yong Eum, Ibolya E. András, Yu Zhong, Bernhard Hennig, Michal Toborek

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which down-regulate inflammatory signaling pathways. Therefore, we hypothesized that alterations of PPAR functions can contribute to human immunodeficiency virus-1 (HIV-1)-induced dysfunction of brain endothelial cells. Indeed, treatment with HIV-1 transactivator of transcription (Tat) protein decreased PPAR transactivation in brain endothelial cells. We next stably over-expressed PPARα and PPARγ in a newly developed cell line of human brain endothelial cells (hCMEC/D3 cells). Tat-induced up-regulation of inflammatory mediators, such as interleukin (IL)-1β, tumor necrosis factor-α, CCL2, and E-selectin were markedly attenuated in hCMEC/D3 over-expressing PPARα or PPARγ. These results were confirmed in CCL2 and E-selectin promoter activity studies. Similar protective effects were observed in hCMEC/D3 after activation of PPARγ by exogenous PPAR agonists (dPGJ2 and rosiglitazone). PPAR over-expression also prevented Tat-induced binding activity and transactivation of nuclear factor-κB. Importantly, increased PPAR activity attenuated induction of IL-1β, tumor necrosis factor-α, CCL2, and E-selectin in hCMEC/D3 cells co-cultured with HIV-1-infected Jurkat cells. The protective effects of PPAR over-expression were reversed by the antagonists of PPARα (MK886) or PPARγ (GW9662). The present data suggest that targeting PPAR signaling may provide a novel therapeutic approach to attenuate HIV-1-induced local inflammatory responses in brain endothelial cells.

Original languageEnglish (US)
Pages (from-to)497-509
Number of pages13
JournalJournal of neurochemistry
Volume107
Issue number2
DOIs
StatePublished - Oct 2008

Keywords

  • Blood-brain barrier
  • Brain endothelial cells
  • Human immunodeficiency virus-1
  • Inflammatory genes
  • Peroxisome proliferator-activated receptor
  • Transactivator of transcription protein

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint Dive into the research topics of 'PPARα and PPARγ effectively protect against HIV-induced inflammatory responses in brain endothelial cells'. Together they form a unique fingerprint.

  • Cite this