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Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun

Nature Biotechnology volume 24, pages 856–863 (2006)Cite this article

A Corrigendum to this article was published on 07 August 2015

This article has been updated

Abstract

Conventional anti-inflammatory strategies induce multiple side effects, highlighting the need for novel targeted therapies. Here we show that knockdown of the basic-region leucine zipper protein, c-Jun, by a catalytic DNA molecule, Dz13, suppresses vascular permeability and transendothelial emigration of leukocytes in murine models of vascular permeability, inflammation, acute inflammation and rheumatoid arthritis. Treatment with Dz13 reduced vascular permeability due to cutaneous anaphylactic challenge or VEGF administration in mice. Dz13 also abrogated monocyte-endothelial cell adhesion in vitro and abolished leukocyte rolling, adhesion and extravasation in a rat model of inflammation. Dz13 suppressed neutrophil infiltration in the lungs of mice challenged with endotoxin, a model of acute inflammation. Finally, Dz13 reduced joint swelling, inflammatory cell infiltration and bone erosion in a mouse model of rheumatoid arthritis. Mechanistic studies showed that Dz13 blocks cytokine-inducible endothelial c-Jun, E-selectin, ICAM-1, VCAM-1 and VE-cadherin expression but has no effect on JAM-1, PECAM-1, p-JNK-1 or c-Fos. These findings implicate c-Jun as a useful target for anti-inflammatory therapies.

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Figure 1: Dz13 localizes to vascular endothelium and inhibits retinal neovascularization and vascular leakiness.
Figure 2: Dz13 inhibits cytokine-inducible monocytic cell–endothelial cell adhesion in vitro and inflammation in mesenteric microcirculation of rats.
Figure 3: Dz13 inhibits gene expression in mesenteric venular endothelium and microvascular endothelial cells.
Figure 4: Dz13 inhibits joint thickness and synovial inflammatory cell infiltration in arthritic mice.

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Change history

  • 10 June 2015

    In the version of this article initially published, the first three bars in the histogram in Figure 1a should have read “No vehicle,” “No Dz” and “Dz13” instead of “No Dz,” “Dz13” and “Dz13scr.” The legend of Figure 1a should have included the sentences: “‘No vehicle’ represents the normoxia control without vehicle (transfection agent) or DNAzyme or siRNA. All other groups contain vehicle.” The H&E-stained images in Figure 1a should have read “Dz13 in hyperoxia-normoxia” and “Dz13scr in hyperoxia-normoxia” instead of “Normoxia” and “Hyperoxia-normoxia.” None of the conclusions is affected by the errors. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank Nick diGirolamo for his expertise in immunohistochemistry, and Ravinay Bhindi and Akiko Maekawa for their assistance with intra-articular and tail vein injections, respectively. This work was supported by grants from the NHMRC, NHF, Diabetes Australia, Cancer Council, Johnson & Johnson Research Pty Limited and the NSW Department of Health. L.M.K. is a Senior Principal Research Fellow of the NHMRC.

Author information

Authors and Affiliations

  1. Centre for Vascular Research, University of New South Wales, Sydney, 2031, NSW, Australia

    Roger G Fahmy, Alla Waldman, Guishui Zhang, Ainslie Mitchell, Colin N Chesterman & Levon M Khachigian

  2. Department of Haematology, The Prince of Wales Hospital, Sydney, 2031, NSW, Australia

    Roger G Fahmy, Alla Waldman, Guishui Zhang, Ainslie Mitchell, Colin N Chesterman & Levon M Khachigian

  3. Department of Pathology, Cytokine Research Unit, University of New South Wales, Sydney, 2052, NSW, Australia

    Nicodemus Tedla, Hong Cai & Carolyn R Geczy

  4. Department of Physiology and Pharmacology, University of New South Wales, Sydney, 2052, NSW, Australia

    Michael Perry

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Contributions

All authors contributed intellectually and/or technically to this project. L.M.K. conceived, designed and supervised all aspects of the project.

Note: Supplementary information is available on the Nature Biotechnology website.

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Correspondence to Levon M Khachigian.

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Supplementary information

Supplementary Table 1

Dz13 inhibits c-Jun, E-selectin, VCAM-1, ICAM-1 and VE-cadherin expression in cytokine-treated mesenteric venules in rats. (PDF 83 kb)

Supplementary Table 2

Dz13 inhibits neutrophil and osteoclast accumulation, and neovascularization, in the synovial lining of the tibiotarsal joints in mice. (PDF 143 kb)

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Fahmy, R., Waldman, A., Zhang, G. et al. Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun . Nat Biotechnol 24, 856–863 (2006). https://doi.org/10.1038/nbt1225

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