Nature Biotechnology 24, 856 - 863 (2006)
Published online: 2 July 2006; | doi:10.1038/nbt1225
Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun
Roger G Fahmy1, Alla Waldman1, Guishui Zhang1, Ainslie Mitchell1, Nicodemus Tedla2, Hong Cai2, Carolyn R Geczy2, Colin N Chesterman1, Michael Perry3
& Levon M Khachigian11
Centre for Vascular Research, University of New South Wales, and Department of Haematology, The Prince of Wales Hospital, Sydney
NSW
2031, Australia. 2
Cytokine Research Unit, Department of Pathology, University of New South Wales, Sydney
NSW
2052, Australia. 3
Department of Physiology and Pharmacology, University of New South Wales, Sydney
NSW
2052, Australia.
Correspondence should be addressed to Levon M Khachigian l.khachigian@unsw.edu.au c-JunVEGFc-JunE-selectinICAM-1VCAM-1VE-cadherinJAM-1PECAM-1p-JNK-1c-FosConventional 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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