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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. This Article Full Text (PDF) Erratum (v110,p3841) All Versions of this Article: blood-2006-12-063636v1 110/1/228    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhang, X. Articles by Song, W.-C. Search for Related Content PubMed PubMed Citation Articles by Zhang, X. Articles by Song, W.-C. Social Bookmarking                   What's this?  Previous Article  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Q. Peng, K. Li, N. Wang, Q. Li, E. Asgari, B. Lu, T. M. Woodruff, S. H. Sacks, and W. Zhou Dendritic Cell Function in Allostimulation Is Modulated by C5aR Signaling J. Immunol., November 15, 2009; 183(10): 6058 - 6068. [Abstract] [Full Text] [PDF] S. M. Mangsbo, J. Sanchez, K. Anger, J. D. Lambris, K. N. Ekdahl, A. S. Loskog, B. Nilsson, and T. H. Totterman Complement Activation by CpG in a Human Whole Blood Loop System: Mechanisms and Immunomodulatory Effects J. Immunol., November 15, 2009; 183(10): 6724 - 6732. [Abstract] [Full Text] [PDF] N. Mizutani, T. Nabe, and S. Yoshino Complement C3a Regulates Late Asthmatic Response and Airway Hyperresponsiveness in Mice J. Immunol., September 15, 2009; 183(6): 4039 - 4046. [Abstract] [Full Text] [PDF] C. Fang, X. Zhang, T. Miwa, and W.-C. Song Complement promotes the development of inflammatory T-helper 17 cells through synergistic interaction with Toll-like receptor signaling and interleukin-6 production Blood, July 30, 2009; 114(5): 1005 - 1015. [Abstract] [Full Text] [PDF] M. I. Fonseca, R. R. Ager, S.-H. Chu, O. Yazan, S. D. Sanderson, F. M. LaFerla, S. M. Taylor, T. M. Woodruff, and A. J. Tenner Treatment with a C5aR Antagonist Decreases Pathology and Enhances Behavioral Performance in Murine Models of Alzheimer's Disease J. Immunol., July 15, 2009; 183(2): 1375 - 1383. [Abstract] [Full Text] [PDF] T. Miwa, L. Zhou, Y. Kimura, D. Kim, A. Bhandoola, and W.-C. Song Complement-dependent T-cell lymphopenia caused by thymocyte deletion of the membrane complement regulator Crry Blood, March 19, 2009; 113(12): 2684 - 2694. [Abstract] [Full Text] [PDF] E. B. Thorgersen, A. Pharo, K. Haverson, A. K. Axelsen, P. Gaustad, G. J. Kotwal, G. Sfyroera, and T. E. Mollnes Inhibition of Complement and CD14 Attenuates the Escherichia coli-Induced Inflammatory Response in Porcine Whole Blood Infect. Immun., February 1, 2009; 77(2): 725 - 732. [Abstract] [Full Text] [PDF] K. Li, K. J. Anderson, Q. Peng, A. Noble, B. Lu, A. P. Kelly, N. Wang, S. H. Sacks, and W. Zhou Cyclic AMP plays a critical role in C3a-receptor-mediated regulation of dendritic cells in antigen uptake and T-cell stimulation Blood, December 15, 2008; 112(13): 5084 - 5094. [Abstract] [Full Text] [PDF] D. D. Kim, T. Miwa, Y. Kimura, R. A. Schwendener, M. van Lookeren Campagne, and W.-C. Song Deficiency of decay-accelerating factor and complement receptor 1-related gene/protein y on murine platelets leads to complement-dependent clearance by the macrophage phagocytic receptor CRIg Blood, August 15, 2008; 112(4): 1109 - 1119. [Abstract] [Full Text] [PDF] 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] [Full Text] [PDF]

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