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

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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.