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Blood, 1 July 2007, Vol. 110, No. 1, pp. 228-236.
Prepublished online as a Blood First Edition Paper on March 15, 2007; DOI 10.1182/blood-2006-12-063636.
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IMMUNOBIOLOGY
Regulation of Toll-like receptor–mediated inflammatory response by complement in vivo
Xinhua Zhang1,
Yuko Kimura1,
Chongyun Fang1,
Lin Zhou1,
Georgia Sfyroera2,
John D. Lambris2,
Rick A. Wetsel3,
Takashi Miwa1, and
Wen-Chao Song1
1 Institute for Translational Medicine and Therapeutics and Department of Pharmacology,
2 Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia;
3 Research Center for Immunology and Autoimmune Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas, Houston
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  (TNF-), and IL-1ß, 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- B 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.
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