|
|
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.
Previous Article | Table of Contents | Next Article 
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-1β, 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.

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]
|
 |
|
|
|