çàãðóçêà...
 
Interleukin (IL)-18/IL-18 binding protein signalling modulates atherosclerotic lesion development and stability A. Corbaz, Z. Mallat, A. Scoazec, P. Graber, S. Alouani, B. Esposito,T. Humbert, P. Henry, A. Tedgui, Y. Chvatchko
Ïîâåðíóòèñü äî çì³ñòó

Interleukin (IL)-18/IL-18 binding protein signalling modulates atherosclerotic lesion development and stability A. Corbaz, Z. Mallat, A. Scoazec, P. Graber, S. Alouani, B. Esposito,T. Humbert, P. Henry, A. Tedgui, Y. Chvatchko

Institut National de la Sant? et de la Recherche M?dicale, Unit? 541, et Institut F?d?ratif de Recherche Paris VII, H?pital Lariboisi?re, 41, Bd de la Chapelle, 75475 Paris cedex 10, France;  Serono Pharmaceutical Research Institute, 1228 Plan LesOuates., Geneva, Switzerland;  Service de Cardiologie, H?pital Lariboisi?re, rue Ambroise Par?, 75010 Paris, France.

Atherosclerosis  is  the  leading cause of mortality  in  industrialised countries and carries an  important  socio economic burden. Unabated inflammatory mechanisms are responsible for changes in atherosclerotic plaque composition leading to plaque disruption and to the occurrence of acute ischemic syndromes, namely, myocardial infarction and stroke. Interleukin (IL)-18 is an inducer of IFN? with potent activities on inflammatory and vascular cells and is  thought  to contribute  to  the pathogenesis of chronic  immunoinflammatory processes. We have recently detected increased production of IL-18 by macrophages and smooth muscle cells  in unstable human atherosclerotic plaques  that were  responsible  for strokes compared with stable plaques from asymptomatic patients. We now extend these findings and show increased levels of IL-18 (p < 0,05) in the circulating blood of patients with acute ischemic coronary syndromes  (unstable angina and myocardial  infarction, 30 males, 18 females, mean age 66,2 ± 1,8 years old, of whom 14 had unstable angina and 34 had myocardial infarction; IL-18 levels: 146,9 ± 17,1 pg ml-1) compared with nonischemic patients (10 males, 3  females, mean age 60,0 ± 5,2 years old;  IL18  levels: 73,0 ± 12,2 pg ml1). Taken together, these results obtained in humans suggest a potential role for  IL-18  in plaque destabilisation. An endogenous IL-18 binding protein  (IL-18BP) that neutralises IL-18 has been  identified. However,  the  role of  IL-18BP  in  the modulation of atherogenesis and other chronic  immuno inflammatory diseases  in vivo  is currently unknown.  In  this  study, we show  that  in vivo electrotransfer of an expression plasmid DNA encoding for murine IL-18BP prevents fatty streak developmentin the thoracic aorta of apoE knockout mice (69 % reduction in lesion  size, p < 0,0001) and  slows progression of advanced atherosclerotic plaques in the aortic sinus (24 % reduction in lesion size, p < 0,01). More  importantly, transfection with the IL-18BP plas mid  induces profound changes  (p < 0,001)  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.



çàãðóçêà...