PPARalpha and PPARgamma effectively protect against HIV-induced inflammatory responses in brain endothelial cells.
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 PPARalpha and PPARgamma 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)-1beta, tumor necrosis factor-alpha, CCL2, and E-selectin were markedly attenuated in hCMEC/D3 over-expressing PPARalpha or PPARgamma. These results were confirmed in CCL2 and E-selectin promoter activity studies. Similar protective effects were observed in hCMEC/D3 after activation of PPARgamma by exogenous PPAR agonists (dPGJ(2) and rosiglitazone). PPAR over-expression also prevented Tat-induced binding activity and transactivation of nuclear factor-kappaB. Importantly, increased PPAR activity attenuated induction of IL-1beta, tumor necrosis factor-alpha, 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 PPARalpha (MK886) or PPARgamma (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.
Huang
Wen
W
Molecular Neuroscience and Vascular Biology Laboratory, Department of Neurosurgery, University of Kentucky, Lexington, Kentucky, USA.
Rha
Geun Bae
GB
Han
Min-Joon
MJ
Eum
Sung Yong
SY
András
Ibolya E
IE
Zhong
Yu
Y
Hennig
Bernhard
B
Toborek
Michal
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology; D002461:Cell Line, Transformed; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D015696:Gene Products, tat / Q000494:pharmacology; D006678:HIV / Q000502:physiology*; D006801:Humans; D055806:Microvessels / Q000166:cytology*; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection / Q000379:methods; D015854:Up-Regulation / Q000187:drug effects
D000970:Antineoplastic Agents; D016207:Cytokines; D019040:E-Selectin; D015696:Gene Products, tat; D047493:PPAR alpha; D047495:PPAR gamma; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2