Combined Inhibition of Complement and CD14 Attenuates Bacteria-Induced Inflammation in Human Whole Blood More Efficiently Than Antagonizing the Toll-like Receptor 4-MD2 Complex

J Infect Dis. 2016 Jul 1;214(1):140-50. doi: 10.1093/infdis/jiw100. Epub 2016 Mar 14.


Background: Single inhibition of the Toll-like receptor 4 (TLR4)-MD2 complex failed in treatment of sepsis. CD14 is a coreceptor for several TLRs, including TLR4 and TLR2. The aim of this study was to investigate the effect of single TLR4-MD2 inhibition by using eritoran, compared with the effect of CD14 inhibition alone and combined with the C3 complement inhibitor compstatin (Cp40), on the bacteria-induced inflammatory response in human whole blood.

Methods: Cytokines were measured by multiplex technology, and leukocyte activation markers CD11b and CD35 were measured by flow cytometry.

Results: Lipopolysaccharide (LPS)-induced inflammatory markers were efficiently abolished by both anti-CD14 and eritoran. Anti-CD14 was significantly more effective than eritoran in inhibiting LPS-binding to HEK-293E cells transfected with CD14 and Escherichia coli-induced upregulation of monocyte activation markers (P < .01). Combining Cp40 with anti-CD14 was significantly more effective than combining Cp40 with eritoran in reducing E. coli-induced interleukin 6 (P < .05) and monocyte activation markers induced by both E. coli (P < .001) and Staphylococcus aureus (P < .01). Combining CP40 with anti-CD14 was more efficient than eritoran alone for 18 of 20 bacteria-induced inflammatory responses (mean P < .0001).

Conclusions: Whole bacteria-induced inflammation was inhibited more efficiently by anti-CD14 than by eritoran, particularly when combined with complement inhibition. Combined CD14 and complement inhibition may prove a promising treatment strategy for bacterial sepsis.

Keywords: CD14; TLR; complement; eritoran; sepsis; treatment.

MeSH terms

  • Anti-Bacterial Agents / therapeutic use*
  • Cytokines / blood
  • Escherichia coli / drug effects
  • Humans
  • Inflammation / blood
  • Inflammation / drug therapy*
  • Inflammation / etiology*
  • Inflammation / microbiology*
  • Lipopolysaccharide Receptors / blood
  • Lipopolysaccharide Receptors / drug effects
  • Sepsis / drug therapy*
  • Sepsis / microbiology
  • Staphylococcal Infections / complications*
  • Staphylococcal Infections / drug therapy*
  • Staphylococcus aureus / drug effects
  • Toll-Like Receptor 4 / drug effects


  • Anti-Bacterial Agents
  • Cytokines
  • Lipopolysaccharide Receptors
  • Toll-Like Receptor 4