Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo.
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.
Zhang
Xinhua
X
Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Kimura
Yuko
Y
Fang
Chongyun
C
Zhou
Lin
L
Sfyroera
Georgia
G
Lambris
John D
JD
Wetsel
Rick A
RA
Miwa
Takashi
T
Song
Wen-Chao
WC
D000818:Animals; D018958:CD55 Antigens / Q000032:analysis; D003165:Complement System Proteins / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology*; D018664:Interleukin-12 / Q000097:blood; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology*
D018958:CD55 Antigens; D016207:Cytokines; D008024:Ligands; D051193:Toll-Like Receptors; D018664:Interleukin-12; D003165:Complement System Proteins