The terminal complement complex C5b-9 stimulates interleukin-6 production in human smooth muscle cells through activation of transcription factors NF-kappa B and AP-1.
Activation of the complement system plays an important role in the pathogenesis of atherosclerosis. The proinflammatory cytokine interleukin (IL)-6 is potentially involved in the progression of the disease. We therefore investigated whether the terminal complement complex C5b-9 affects IL-6 production from vascular smooth-muscle cells (VSMC) and set out to determine the underlying signal transduction pathway. Stimulation of human VSMC with C5b-9 resulted in an increase of IL-6 transcript and production of IL-6 protein. Pretreatment with pertussis toxin or pyrrolidine dithiocarbamate inhibited complement-dependent IL-6 mRNA expression and IL-6 release, suggesting the involvement of Gi-proteins and nuclear factor-kB (NF-kB). C5b-9 also induced formation of reactive oxygen species, which, along with IL-6 release, was inhibited by the antioxidant N-acetylcysteine. C5b-9 activated the redox-sensitive transcription factors NF-kB and activator protein-1 (AP-1), which were both involved in the induction of IL-6 by C5b-9, as demonstrated by cis element double-stranded (decoy) oligonucleotides (ODN). The results demonstrate that activation of the complement system induces IL-6 release from human VSMC by a Gi-dependent pathway involving the generation of oxidative stressand the activation of the redox sensitive transcription factors NF-kB and AP-1. Our data support a new mechanism for the proatherogenic effect of the terminal complement complex.
Viedt
C
C
Innere Medizin III, Universität Heidelberg, Germany.
Hänsch
G M
GM
Brandes
R P
RP
Kübler
W
W
Kreuzer
J
J
D000111:Acetylcysteine / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D015938:Complement Membrane Attack Complex / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008957:Models, Genetic; D009131:Muscle, Smooth, Vascular / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism*; D009841:Oligonucleotides / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D000975:Antioxidants; D015938:Complement Membrane Attack Complex; D015850:Interleukin-6; D016328:NF-kappa B; D009841:Oligonucleotides; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D000111:Acetylcysteine