DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA

Wen Ming Chu; Xing Gong; Zhi Wei Li; Kenji Takabayashi; Hong Hai Ouyang; Yi Chen; Augusto Lois; David J. Chen; Gloria C. Li; Michael Karin; Eyal Raz

doi:10.1016/S0092-8674(00)00194-X

DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA

Wen Ming Chu, Xing Gong, Zhi Wei Li, Kenji Takabayashi, Hong Hai Ouyang, Yi Chen, Augusto Lois, David J. Chen, Gloria C. Li, Michael Karin, Eyal Raz

Research output: Contribution to journal › Article › peer-review

159 Scopus citations

Abstract

Bacterial DNA and related synthetic immunostimulatory oligodeoxyribonucleotides (ISS-ODN) stimulate innate immunity. However, the molecular recognition mechanism that initiates signaling in response to bacterial DNA and ISS-ODN has not been identified. Herein, we demonstrate that administration of bacterial DNA and ISS-ODN to mice lacking the catalytic subunit of DNA-PK (DNA-PKcs) and in vitro stimulation of BMDM from these mice result in defective induction of IL-6 and IL-12. Further analysis using BMDM of IKKβ(-/-) revealed that both DNA-PKcs and IKKβ are essential for normal cytokine production in response to ISS-ODN or bacterial DNA. ISS-ODN and bacterial DNA activate DNA-PK, which in turn contributes to activation of IKK and NF-κB. These results reveal a novel role of DNA-PKcs in innate immune responses and a link between DNA repair and innate immunity.

Original language	English (US)
Pages (from-to)	909-918
Number of pages	10
Journal	Cell
Volume	103
Issue number	6
DOIs	https://doi.org/10.1016/S0092-8674(00)00194-X
State	Published - 2000

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/S0092-8674(00)00194-X

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@article{2d48aebe242944dd928b3253e64aaa3e,

title = "DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA",

abstract = "Bacterial DNA and related synthetic immunostimulatory oligodeoxyribonucleotides (ISS-ODN) stimulate innate immunity. However, the molecular recognition mechanism that initiates signaling in response to bacterial DNA and ISS-ODN has not been identified. Herein, we demonstrate that administration of bacterial DNA and ISS-ODN to mice lacking the catalytic subunit of DNA-PK (DNA-PKcs) and in vitro stimulation of BMDM from these mice result in defective induction of IL-6 and IL-12. Further analysis using BMDM of IKKβ(-/-) revealed that both DNA-PKcs and IKKβ are essential for normal cytokine production in response to ISS-ODN or bacterial DNA. ISS-ODN and bacterial DNA activate DNA-PK, which in turn contributes to activation of IKK and NF-κB. These results reveal a novel role of DNA-PKcs in innate immune responses and a link between DNA repair and innate immunity.",

author = "Chu, {Wen Ming} and Xing Gong and Li, {Zhi Wei} and Kenji Takabayashi and Ouyang, {Hong Hai} and Yi Chen and Augusto Lois and Chen, {David J.} and Li, {Gloria C.} and Michael Karin and Eyal Raz",

note = "Funding Information: We thank Parag Bhatt, Nan Fang, Yinglin Hu, Samantha Kim, Tony Yoon, M.-D. Nguyen, Arash Ronaghy, Tomoko Hayashi, Akihiro Kuri-masa, and Lucinda Beck for their excellent assistance. We also thank Dr. Yang Xu for providing us with ATM−/− mice. This work was supported in part by Dynavax Technologies Corp; by National Institutes of Health Grants to E. R. (AI 40682), M. K. (AI 43477), G. C. L. (CA-59609 and 78497), and D. J. C. (CA-505159); Cancer Research Institute postdoctoral fellowship to Z. W. L., tobacco-related disease research program to W. M. C. (9KT-00567;) and by California Cancer Research program to M. K.",

year = "2000",

doi = "10.1016/S0092-8674(00)00194-X",

language = "English (US)",

volume = "103",

pages = "909--918",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

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T1 - DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA

AU - Chu, Wen Ming

AU - Gong, Xing

AU - Li, Zhi Wei

AU - Takabayashi, Kenji

AU - Ouyang, Hong Hai

AU - Chen, Yi

AU - Lois, Augusto

AU - Chen, David J.

AU - Li, Gloria C.

AU - Karin, Michael

AU - Raz, Eyal

N1 - Funding Information: We thank Parag Bhatt, Nan Fang, Yinglin Hu, Samantha Kim, Tony Yoon, M.-D. Nguyen, Arash Ronaghy, Tomoko Hayashi, Akihiro Kuri-masa, and Lucinda Beck for their excellent assistance. We also thank Dr. Yang Xu for providing us with ATM−/− mice. This work was supported in part by Dynavax Technologies Corp; by National Institutes of Health Grants to E. R. (AI 40682), M. K. (AI 43477), G. C. L. (CA-59609 and 78497), and D. J. C. (CA-505159); Cancer Research Institute postdoctoral fellowship to Z. W. L., tobacco-related disease research program to W. M. C. (9KT-00567;) and by California Cancer Research program to M. K.

PY - 2000

Y1 - 2000

N2 - Bacterial DNA and related synthetic immunostimulatory oligodeoxyribonucleotides (ISS-ODN) stimulate innate immunity. However, the molecular recognition mechanism that initiates signaling in response to bacterial DNA and ISS-ODN has not been identified. Herein, we demonstrate that administration of bacterial DNA and ISS-ODN to mice lacking the catalytic subunit of DNA-PK (DNA-PKcs) and in vitro stimulation of BMDM from these mice result in defective induction of IL-6 and IL-12. Further analysis using BMDM of IKKβ(-/-) revealed that both DNA-PKcs and IKKβ are essential for normal cytokine production in response to ISS-ODN or bacterial DNA. ISS-ODN and bacterial DNA activate DNA-PK, which in turn contributes to activation of IKK and NF-κB. These results reveal a novel role of DNA-PKcs in innate immune responses and a link between DNA repair and innate immunity.

AB - Bacterial DNA and related synthetic immunostimulatory oligodeoxyribonucleotides (ISS-ODN) stimulate innate immunity. However, the molecular recognition mechanism that initiates signaling in response to bacterial DNA and ISS-ODN has not been identified. Herein, we demonstrate that administration of bacterial DNA and ISS-ODN to mice lacking the catalytic subunit of DNA-PK (DNA-PKcs) and in vitro stimulation of BMDM from these mice result in defective induction of IL-6 and IL-12. Further analysis using BMDM of IKKβ(-/-) revealed that both DNA-PKcs and IKKβ are essential for normal cytokine production in response to ISS-ODN or bacterial DNA. ISS-ODN and bacterial DNA activate DNA-PK, which in turn contributes to activation of IKK and NF-κB. These results reveal a novel role of DNA-PKcs in innate immune responses and a link between DNA repair and innate immunity.

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JO - Cell

JF - Cell

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ER -

DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA

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