Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo

Blood. 2007 Jul 1;110(1):228-36. doi: 10.1182/blood-2006-12-063636. Epub 2007 Mar 15.


Toll-like receptors (TLRs) and complement are 2 components of innate immunity that are critical for first-line host defense and elicitation of adaptive immune responses. Many pathogen-associated molecular patterns activate both TLR and complement, but whether and how these 2 systems, when coactivated in vivo, interact with each other has not been well studied. We demonstrate here a widespread regulation of TLR signaling by complement in vivo. The TLR ligands lipopolysacharride (TLR4), zymosan (TLR2/6), and CpG oligonucleotide (TLR9) caused, in a complement-dependent manner, strikingly elevated plasma interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and IL-1beta, and/or decreased plasma IL-12 levels in mice deficient in the membrane complement inhibitor decay-accelerating factor (DAF). A similar outcome was observed in wild-type mice cotreated with the TLR ligands and cobra venom factor, a potent complement activator. The regulatory effect of complement on TLR-induced cytokine production in vivo was mediated by the anaphylatoxin receptors C5aR and C3aR. Additionally, changes in lipopolysaccharide (LPS)-induced cytokine production in DAF-deficient mice correlated with increased mitogen-activated protein kinase and nuclear factor-kappaB activation in the spleen. These results reveal a strong interaction between complement and TLR signaling in vivo and suggest a novel mechanism by which complement promotes inflammation and modulates adaptive immunity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD55 Antigens / analysis
  • Complement System Proteins / immunology*
  • Cytokines / biosynthesis
  • Inflammation / immunology*
  • Interleukin-12 / blood
  • Ligands
  • Mice
  • Mice, Knockout
  • Signal Transduction
  • Toll-Like Receptors / immunology*


  • CD55 Antigens
  • Cytokines
  • Ligands
  • Toll-Like Receptors
  • Interleukin-12
  • Complement System Proteins