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

Cell. 2000 Dec 8;103(6):909-18. doi: 10.1016/s0092-8674(00)00194-x.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Retracted Publication

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / metabolism
  • DNA Repair
  • DNA, Bacterial / immunology*
  • DNA, Bacterial / metabolism
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Enzyme Inhibitors / pharmacology
  • Enzyme-Linked Immunosorbent Assay
  • I-kappa B Kinase
  • Immunity, Innate*
  • Interleukin-12 / biosynthesis
  • Interleukin-12 / genetics
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Oligodeoxyribonucleotides / genetics
  • Oligodeoxyribonucleotides / immunology*
  • Oligodeoxyribonucleotides / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Wortmannin

Substances

  • Androstadienes
  • DNA, Bacterial
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Interleukin-6
  • NF-kappa B
  • Oligodeoxyribonucleotides
  • Phosphoinositide-3 Kinase Inhibitors
  • RNA, Messenger
  • Interleukin-12
  • DNA-Activated Protein Kinase
  • Protein Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse
  • Wortmannin