Toll-like receptor–independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation (original) (raw)
Article| November 21 2005
1Department of Genetics, Osaka University Medical School
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1Department of Genetics, Osaka University Medical School
2Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences
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3Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871
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4Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
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1Department of Genetics, Osaka University Medical School
2Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences
5Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan
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Yasutaka Okabe
1Department of Genetics, Osaka University Medical School
Kohki Kawane
1Department of Genetics, Osaka University Medical School
2Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences
Shizuo Akira
3Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871
Tadatsugu Taniguchi
4Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
Shigekazu Nagata
1Department of Genetics, Osaka University Medical School
2Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences
5Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan
Abbreviations used: IRF3, IFN regulatory factor 3; MACS, magnetic-activated cell sorting; MEF, mouse embryonal fibroblast; TLR, Toll-like receptor; TRIF, Toll/IL-1 receptor domain-containing adaptor inducing IFN-β.
Received: August 16 2005
Accepted: October 05 2005
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2005
J Exp Med (2005) 202 (10): 1333–1339.
Deoxyribonuclease (DNase) II in macrophages cleaves the DNA of engulfed apoptotic cells and of nuclei expelled from erythroid precursor cells. _DNase II_–deficient mouse embryos accumulate undigested DNA in macrophages, and die in feto because of the activation of the interferon β (IFNβ) gene. Here, we found that the F4/80-positive macrophages in DNase II−/− fetal liver specifically produce a set of cytokines such as IFNβ, TNFα, and CXCL10. Whereas, IFN-inducible genes (2′5′-oligo(A) synthetase, IRF7, and ISG15) were expressed not only in macrophages but also in other F4/80-negative cells. When DNase II−/− macrophages or embryonal fibroblasts engulfed apoptotic cells, they expressed the IFNβ and CXCL10 genes. The ablation of Toll-like receptor (TLR) 3 and 9, or their adaptor molecules (MyD88 and TRIF), had no effect on the lethality of the DNase II−/− mice. These results indicate that there is a TLR-independent sensing mechanism to activate the innate immunity for the endogenous DNA escaping lysosomal degradation.
The Rockefeller University Press
2005
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