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 Edit Andras, Yu Zhong, Bernhard Hennig, Michal J Toborek

Research output: Contribution to journalArticle

29 Citations (Scopus)

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
Pages (from-to)497-509
Number of pages13
JournalJournal of Neurochemistry
Volume107
Issue number2
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Fingerprint

Peroxisome Proliferator-Activated Receptors
Endothelial cells
Brain
Endothelial Cells
HIV
Viruses
E-Selectin
Trans-Activators
HIV-1
Transcription
rosiglitazone
Interleukin-1
Transcriptional Activation
Tumor Necrosis Factor-alpha
Jurkat Cells
Cytoplasmic and Nuclear Receptors

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

Cite this

PPARα and PPARγ effectively protect against HIV-induced inflammatory responses in brain endothelial cells. / Huang, Wen; Rha, Geun Bae; Han, Min Joon; Eum, Sung Yong; Andras, Ibolya Edit; Zhong, Yu; Hennig, Bernhard; Toborek, Michal J.

In: Journal of Neurochemistry, Vol. 107, No. 2, 01.10.2008, p. 497-509.

Research output: Contribution to journalArticle

Huang, Wen ; Rha, Geun Bae ; Han, Min Joon ; Eum, Sung Yong ; Andras, Ibolya Edit ; Zhong, Yu ; Hennig, Bernhard ; Toborek, Michal J. / PPARα and PPARγ effectively protect against HIV-induced inflammatory responses in brain endothelial cells. In: Journal of Neurochemistry. 2008 ; Vol. 107, No. 2. pp. 497-509.
@article{1d3fd140a669421b9d4ca8f30bcecbe8,
title = "PPARα and PPARγ effectively protect against HIV-induced inflammatory responses in brain endothelial cells",
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.",
keywords = "Blood-brain barrier, Brain endothelial cells, Human immunodeficiency virus-1, Inflammatory genes, Peroxisome proliferator-activated receptor, Transactivator of transcription protein",
author = "Wen Huang and Rha, {Geun Bae} and Han, {Min Joon} and Eum, {Sung Yong} and Andras, {Ibolya Edit} and Yu Zhong and Bernhard Hennig and Toborek, {Michal J}",
year = "2008",
month = "10",
day = "1",
doi = "10.1111/j.1471-4159.2008.05626.x",
language = "English",
volume = "107",
pages = "497--509",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "2",

}

TY - JOUR

T1 - PPARα and PPARγ effectively protect against HIV-induced inflammatory responses in brain endothelial cells

AU - Huang, Wen

AU - Rha, Geun Bae

AU - Han, Min Joon

AU - Eum, Sung Yong

AU - Andras, Ibolya Edit

AU - Zhong, Yu

AU - Hennig, Bernhard

AU - Toborek, Michal J

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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.

AB - 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.

KW - Blood-brain barrier

KW - Brain endothelial cells

KW - Human immunodeficiency virus-1

KW - Inflammatory genes

KW - Peroxisome proliferator-activated receptor

KW - Transactivator of transcription protein

UR - http://www.scopus.com/inward/record.url?scp=53149100494&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=53149100494&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2008.05626.x

DO - 10.1111/j.1471-4159.2008.05626.x

M3 - Article

C2 - 18710415

AN - SCOPUS:53149100494

VL - 107

SP - 497

EP - 509

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 2

ER -