Complement and dilated cardiomyopathy: a role of sublytic terminal complement complex-induced tumor necrosis factor-alpha synthesis in cardiac myocytes.
Dilated cardiomyopathy is a syndrome characterized by cardiac enlargement and impaired systolic function of the heart. Tumor necrosis factor (TNF)-alpha, a pleiotropic cytokine, seems to play a central role in the progression of dilated cardiomyopathy. Recent data suggest that ongoing inflammation in the myocardium may, in many cases, contribute to the development of disease. Chronic generation of autoantibodies to myocardial antigens or, in some cases, viral infection are pathobiologically involved. Although both antibodies and some viruses activate the complement system, the role of innate immunity in dilated cardiomyopathy has as yet not been investigated systematically. In this study we demonstrate by analysis of myocardial biopsies from 28 patients that C5b-9, the terminal membrane attack complex of complement, accumulates in human myocardium in dilated cardiomyopathy. C5b-9 significantly correlates with immunoglobulin deposition and myocardial expression of TNF-alpha. In vitro, C5b-9 attack on cardiac myocytes induces nuclear factor (NF)-kappaB activation as well as transcription, synthesis, and secretion of TNF-alpha. We conclude that chronic immunoglobulin-mediated complement activation in the myocardium may contribute in part to the progression of dilated cardiomyopathy via C5b-9-induced TNF-alpha expression in cardiac myocytes.
Zwaka
Thomas P
TP
Department of Internal Medicine II-Cardiology, University of Ulm, Ulm, Germany.
Manolov
Dimitar
D
Ozdemir
Cüneyt
C
Marx
Nikolaus
N
Kaya
Ziya
Z
Kochs
Matthias
M
Höher
Martin
M
Hombach
Vinzenz
V
Torzewski
Jan
J
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation / Q000276:immunology*; D015938:Complement Membrane Attack Complex / Q000276:immunology*; D006801:Humans; D008297:Male; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology*
D015938:Complement Membrane Attack Complex; D014409:Tumor Necrosis Factor-alpha