Suppression of vascular permeability and inflammation by targeting of the transcription factor c-Jun.
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.
Fahmy
Roger G
RG
Centre for Vascular Research, University of New South Wales, and Department of Haematology, The Prince of Wales Hospital, Sydney NSW 2031, Australia.
Waldman
Alla
A
Zhang
Guishui
G
Mitchell
Ainslie
A
Tedla
Nicodemus
N
Cai
Hong
H
Geczy
Carolyn R
CR
Chesterman
Colin N
CN
Perry
Michael
M
Khachigian
Levon M
LM
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D002460:Cell Line; D018920:Coculture Techniques / Q000379:methods; D021881:DNA, Catalytic / Q000494:pharmacology*; D042783:Endothelial Cells / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C / Q000276:immunology; D008856:Microscopy, Fluorescence; D009000:Monocytes; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects* / Q000235:genetics; D051381:Rats
D021881:DNA, Catalytic; C485475:Dz13 DNAzyme; D016755:Proto-Oncogene Proteins c-jun