DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA.
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 IKKbeta(-/-) revealed that both DNA-PKcs and IKKbeta 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-kappaB. These results reveal a novel role of DNA-PKcs in innate immune responses and a link between DNA repair and innate immunity.
Chu
W
W
The Sam and Rose Stein Institute for Research on Aging, University of California, San Diego 9500 Gilman Drive 92093, La Jolla, CA, USA. wmchu@ucsd.edu
Gong
X
X
Li
Z
Z
Takabayashi
K
K
Ouyang
H
H
Chen
Y
Y
Lois
A
A
Chen
D J
DJ
Li
G C
GC
Karin
M
M
Raz
E
E
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D004260:DNA Repair; D004269:DNA, Bacterial / Q000276:immunology* / Q000378:metabolism; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D051550:I-kappa B Kinase; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D004269:DNA, Bacterial; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D051550:I-kappa B Kinase; D018664:Interleukin-12; D015850:Interleukin-6; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D000077191:Wortmannin; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse