Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability.
Interleukin (IL)-18 is the interferon-gamma-inducing factor and has other proinflammatory properties. The precise role of IL-18 in immunoinflammatory diseases remains poorly understood. In this study, we show that in vivo electrotransfer of an expression-plasmid DNA encoding for murine IL-18 binding protein (BP) (the endogenous inhibitor of IL-18) prevents fatty streak development in the thoracic aorta of apoE knockout mice and slows progression of advanced atherosclerotic plaques in the aortic sinus. More importantly, transfection with the IL-18BP plasmid induces profound changes in plaque composition (decrease in macrophage, T cell, cell death, and lipid content and increase in smooth muscle cell and collagen content) leading to a stable plaque phenotype. These results identify for the first time a critical role for IL-18/IL-18BP regulation in atherosclerosis and suggest a potential role for IL-18 inhibitors in reduction of plaque development/progression and promotion of plaque stability. The full text of this article is available at http://www.circresaha.org.
Mallat
Z
Z
Institut National de la Santé et de la Recherche Médicale, Unité 541, et Institut Fédératif de Recherche Paris VII, Hôpital Lariboisière, France. ziad.mallat@inserm.lrb.ap-hop-paris.fr
Corbaz
A
A
Scoazec
A
A
Graber
P
P
Alouani
S
S
Esposito
B
B
Humbert
Y
Y
Chvatchko
Y
Y
Tedgui
A
A
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018076:DNA, Complementary / Q000008:administration & dosage* / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D018274:Electroporation; D015316:Genetic Therapy / Q000379:methods; D006023:Glycoproteins / Q000008:administration & dosage* / Q000235:genetics; D007273:Injections, Intramuscular; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D012850:Sinus of Valsalva / Q000473:pathology; D016896:Treatment Outcome
D001057:Apolipoproteins E; D018076:DNA, Complementary; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; C118370:interleukin-18 binding protein