Requirement for type 2 NO synthase for IL-12 signaling in innate immunity

Science. 1999 May 7;284(5416):951-5. doi: 10.1126/science.284.5416.951.

Abstract

Interleukin-12 (IL-12) and type 2 NO synthase (NOS2) are crucial for defense against bacterial and parasitic pathogens, but their relationship in innate immunity is unknown. In the absence of NOS2 activity, IL-12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer (NK) cells for cytotoxicity or interferon-gamma (IFN-gamma) release, and failed to activate Tyk2 kinase and to tyrosine phosphorylate Stat4 (the central signal transducer of IL-12) in NK cells. Activation of Tyk2 in NK cells by IFN-alpha/beta also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic GMP / metabolism
  • Cytotoxicity, Immunologic
  • DNA-Binding Proteins / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Immunity, Innate
  • Interferon-gamma / biosynthesis
  • Interferon-gamma / genetics
  • Interferons / pharmacology
  • Interleukin-12 / pharmacology
  • Interleukin-12 / physiology*
  • Janus Kinase 2
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Leishmania major*
  • Leishmaniasis, Cutaneous / immunology*
  • Leishmaniasis, Cutaneous / metabolism
  • Lysine / analogs & derivatives
  • Lysine / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Nitric Oxide Synthase / metabolism*
  • Nitric Oxide Synthase Type II
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism
  • Proteins / metabolism
  • Proto-Oncogene Proteins*
  • STAT4 Transcription Factor
  • Signal Transduction*
  • TYK2 Kinase
  • Trans-Activators / metabolism
  • Up-Regulation

Substances

  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • N(6)-(1-iminoethyl)lysine
  • Proteins
  • Proto-Oncogene Proteins
  • STAT4 Transcription Factor
  • Stat4 protein, mouse
  • Trans-Activators
  • Interleukin-12
  • Nitric Oxide
  • Interferon-gamma
  • Interferons
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Protein-Tyrosine Kinases
  • Jak2 protein, mouse
  • Janus Kinase 2
  • TYK2 Kinase
  • Tyk2 protein, mouse
  • Cyclic GMP
  • Lysine