title: Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo.
abstract: 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.
authors.affiliation: Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Zhang
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kimura
authors.forename: Chongyun
authors.initials: C
authors.lastname: Fang
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Georgia
authors.initials: G
authors.lastname: Sfyroera
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.forename: Rick A
authors.initials: RA
authors.lastname: Wetsel
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
mesh_terms: 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*
chemical_list: D018958:CD55 Antigens; D016207:Cytokines; D008024:Ligands; D051193:Toll-Like Receptors; D018664:Interleukin-12; D003165:Complement System Proteins