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The terminal complement complex C5b‐9 stimulates interleukin‐6 production in human smooth‐muscle cells through activation of transcription factors NF‐κB 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‐κΒ (NF‐κB). 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‐κB 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 stress and the activation of the redox sensitive transcription factors NF‐κB and AP‐1. Our data support a new mechanism for the proatherogenic effect of the terminal complement complex.