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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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Submitted December 19, 2006
Accepted March 7, 2007
Regulation of Toll-like receptor-mediated inflammatory response by complement in vivo
Xinhua Zhang, Yuko Kimura, Chongyun Fang, Lin Zhou, Georgia Sfyroera, John D Lambris, Rick A Wetsel, Takashi Miwa, and Wen-Chao Song*
Institute for Translational Medicine & Therapeutics, and Dept of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA
Dept of Pathology and Laboratory Medicine, and Dept of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA
Research Center for Immunology and Autoimmune Diseases, University of Texas-Houston, Houston, TX
* Corresponding author; email: song{at}spirit.gcrc.upenn.edu.
Toll-like receptors (TLRs) and complement are two 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 two systems, when co-activated 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 IL-6, TNF- and IL-1 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 co-treated 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 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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C. Fang, T. Miwa, H. Shen, and W.-C. Song
Complement-Dependent Enhancement of CD8+ T Cell Immunity to Lymphocytic Choriomeningitis Virus Infection in Decay-Accelerating Factor-Deficient Mice
J. Immunol.,
September 1, 2007;
179(5):
3178 - 3186.
[Abstract]
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