Evidence for altered interleukin 18 (IL)-18 pathway in human heart failure.
Interleukin (IL)-18 is the interferon-gamma-inducing factor and has potent proinflammatory activities. IL-18 has been recently implicated in atherosclerotic plaque instability and myocardial ischemia-reperfusion injury. However, it is unknown whether IL-18 expression is increased in human myocardium or if it has any role in heart failure. We analyzed the expression of IL-18, its receptor IL-18Ralpha, and its endogenous inhibitor, IL-18 binding protein (IL-18BP) in myocardial tissue from patients with end-stage heart failure (ischemic or dilated cardiomyopathy) and controls by use of quantitative real-time reverse transcriptase polymerase chain reaction, Western blot or immunohistochemical techniques. Plasma levels of IL-18 were also determined in 48 patients with heart failure. IL-18 mRNA and protein levels were up-regulated in the myocardium of patients with ischemic cardiomyopathy. Both ischemic and dilated myocardium showed increased IL-18Ralpha levels, suggesting potential biological effects. In addition, mRNA levels of IL-18 BP were down-regulated in the failing myocardium. Finally, plasma IL-18 levels were significantly elevated in patients with heart failure and were higher in those who died at follow-up than in survivors. The results suggest a potential role for the immunoinflammatory IL-18 signaling pathway in the pathophysiology of heart failure and identify novel therapeutic targets for future testing.
Mallat
Ziad
Z
Institut Fédératif de Recherche Paris VII, INSERM U541, Hôpital Lariboisière, 41 Blvd. de la Chapelle, 75475 Paris Cedex 10, France. ziad.mallat@larib.inserm.fr
Heymes
Christophe
C
Corbaz
Anne
A
Logeart
Damien
D
Alouani
Sami
S
Cohen-Solal
Alain
A
Seidler
Tim
T
Hasenfuss
Gerd
G
Chvatchko
Yolande
Y
Shah
Ajay M
AM
Tedgui
Alain
A
D002303:Cardiac Output, Low / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D053727:Interleukin-18 Receptor alpha Subunit; D017202:Myocardial Ischemia / Q000235:genetics / Q000276:immunology; D009206:Myocardium / Q000737:chemistry / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D053724:Receptors, Interleukin-18; D015854:Up-Regulation
D006023:Glycoproteins; C508572:IL18R1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; C118370:interleukin-18 binding protein