May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Regulation of CCL2 Production via NAD(P)H Oxidase-Modulated Stat3 Activation in Endothelial Cells
Author Affiliations & Notes
  • W. Zhang
    Medical College of Georgia, Augusta, Georgia
    Vascular Biology Center,
  • M. Bartoli
    Department of Ophthalmology, University of South Carolina, Columbia, South Carolina
  • M. Rojas
    Medical College of Georgia, Augusta, Georgia
    Vascular Biology Center,
  • N.-T. Tsai
    Medical College of Georgia, Augusta, Georgia
    Vascular Biology Center,
  • B. Lilly
    Medical College of Georgia, Augusta, Georgia
    Vascular Biology Center,
  • R. W. Caldwell
    Medical College of Georgia, Augusta, Georgia
    Department of Pharmacology and Toxicology,
  • R. B. Caldwell
    Medical College of Georgia, Augusta, Georgia
    Vascular Biology Center,
  • Footnotes
    Commercial Relationships  W. Zhang, None; M. Bartoli, None; M. Rojas, None; N. Tsai, None; B. Lilly, None; R.W. Caldwell, None; R.B. Caldwell, None.
  • Footnotes
    Support  NIH Grant EY04618, EY11766, VA Merit Review Award, Postdoctoral Fellowship Award AHASE00015
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 5891. doi:https://doi.org/
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    • Get Citation

      W. Zhang, M. Bartoli, M. Rojas, N.-T. Tsai, B. Lilly, R. W. Caldwell, R. B. Caldwell; Regulation of CCL2 Production via NAD(P)H Oxidase-Modulated Stat3 Activation in Endothelial Cells. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5891. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Both vascular inflammation and oxidative stress are critically involved in the pathogenesis of diabetic retinopathy, retinopathy of prematurity (ROP), and uveitis. CCL2 [monocyte chemoattractant protein (MCP)-1], plays an important role in vascular inflammation by inducing leukocyte recruitment. This study was undertaken to determine if and how NAD(P)H oxidase, a major source of reactive oxygen species in vascular cells, regulates CCL2 production in vascular inflammation.

Methods: : These experiments were performed in the mouse model for oxygen-induced retinopathy (OIR) and in cultured endothelial cells (ECs).

Results: : Expression of TNF-α, VEGF and CCL2 increased during relative hypoxia in the OIR mouse retina. Since it is known that TNF-α induces CCL2 expression in EC via activation of NF-kB and p38MAPK, we determined if NAD(P)H oxidase regulates TNF-α-induced CCL2 expression via NF-kB and p38MAPK. Studies using RT-PCR and ELISA demonstrated that inhibition of NAD(P)H oxidase completely blocked TNF-α-induced CCL2 expression in human ECs. However, inhibition of NAD(P)H oxidase did not block TNF-α-induced p38MAPK activation and only partially blocked TNF-α-induced NF-kB activation, suggesting that other mediators serve as downstream targets for NAD(P)H oxidase. Analysis of the promoter region of CCL2 disclosed a conserved STAT/GAS binding site. Detecting STATs phosphorylation revealed that TNF-α robustly induced STAT3 phosphorylation and weakly activated STAT1 but had no effect on STAT5 or STAT6. Stattic, a specific inhibitor for STAT3, dose dependently blocked TNF-α-induced STAT3 phosphorylation and also abolished TNF-α-induced CCL2 production. Moreover, inhibition of NAD(P)H oxidase completely blocked TNF-α-induced STAT3 activation. Parallel studies using VEGF revealed that the same signaling pathway is responsible for VEGF-induced CCL2 production.

Conclusions: : This research demonstrates that TNF-α and VEGF stimulate CCL2 production through NAD(P)H oxidase regulation of the STAT3 pathway. Modulation of NAD(P)H oxidase/STAT3 pathway may provide therapeutic benefit for the treatment of retina vascular inflammation.

Keywords: inflammation • gene/expression • signal transduction 
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