Previous reports have documented a correlation between excessive production of the complement component C5a during the onset of sepsis and poor clinical outcome associated with compromised innate immunity. And blockade of either C5a or its receptor has beneficial effects in experimental models of sepsis. Peter Ward and colleagues have now added further detail to this model by looking directly at the effects of C5a on the production of cytokines by neutrophils.

Neutrophils are important for innate responses to invading bacteria and they are one of the main sources of the pro-inflammatory cytokine tumour-necrosis factor (TNF) in the serum during inflammatory responses — for example, to bacterial lipopolysaccharide (LPS).

In an in vitro assay, C5a inhibited LPS-induced TNF production by blood neutrophils from normal rats. In an in vivo model of sepsis — caecal ligation/puncture (CLP) of rats — TNF production in response to LPS by blood neutrophils isolated during the first 12 hours of sepsis was markedly reduced compared with control neutrophils. The authors showed that this was due to C5a production by blocking endogenous C5a in the rats during sepsis with a C5a-specific antibody injected intravenously at the start of CLP. This led to increased levels of serum TNF and an increased TNF response of isolated neutrophils stimulated with LPS.

How does C5a mediate this effect on neutrophils? The promoter region of the TNF gene contains a binding site for nuclear factor-κB (NF-κB), and when neutrophils were treated in vitro with an inhibitor of NF-κB activation, their production of TNF in response to LPS was completely prevented. So, neutrophil production of TNF depends on NF-κB, the nuclear translocation and activity of which is negatively regulated by inhibitor of NF-κB (IκB). Neutrophils exposed to C5a in vitro had increased levels of IκBα, as did neutrophils isolated from CLP-induced septic rats. However, C5a did not increase transcription of the gene encoding IκBα, indicating that the increased protein levels might be due to reduced degradation. Regardless of the mechanism, an increased level of IκBα in response to C5a would result in decreased NF-κB activity and, therefore, decreased TNF transcription.

This study provides one possible explanation for the poor outcome associated with high levels of C5a, by showing that this can inhibit some of the innate defences of neutrophils in response to bacteria. Therefore, C5a could be a new target for the treatment of sepsis.