Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which downregulate inflammatory signaling pathways. Therefore, we hypothesized that alterations of PPAR functions can contribute to HIV-1-induced dysfunction of brain endothelial cells. Indeed, treatment with HIV-1 Tat protein decreased PPAR transactivation in brain endothelial cells. We next stably overexpressed PPARα and PPARγ in a newly developed cell line of human brain endothelial cells (hCMEC/D3 cells). Tat-induced upregulation of inflammatory mediators, such as interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), CCL2 and E-selectin were markedly attenuated in hCMEC/D3 overexpressing 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 (dPGJ
2
and rosiglitazone). PPAR overexpression also prevented Tat-induced binding activity and transactivation of nuclear factor-kappaB (NF-κB). Importantly, increased PPAR activity attenuated induction of IL-1β, TNF-α, CCL2, and E-selectin in hCMEC/D3 cells co-cultured with HIV-1-infected Jurkat cells. The protective effects of PPAR overexpression 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.
