Requirement for Type 2 NO Synthase for IL-12 Signaling in Innate Immunity

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 kill...

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Veröffentlicht in:	Science (American Association for the Advancement of Science) 1999-05, Vol.284 (5416), p.951-955
Hauptverfasser:	Diefenbach, Andreas, Schindler, Heike, Röllinghoff, Martin, Yokoyama, Wayne M., Bogdan, Christian
Format:	Artikel
Sprache:	eng
Schlagworte:	Analysis of the immune response. Humoral and cellular immunity Animals Biological and medical sciences Cell lines Cells, Cultured Cellular biology Cultured cells Cyclic GMP - metabolism Cytotoxicity, Immunologic DNA-Binding Proteins - metabolism Enzyme Activation Enzyme Inhibitors - pharmacology Fundamental and applied biological sciences. Psychology Fundamental immunology Immune system Immunity, Innate Immunobiology Infections Innate immunity Interferon-gamma - biosynthesis Interferon-gamma - genetics Interferons - pharmacology Interleukin-12 Interleukin-12 - pharmacology Interleukin-12 - physiology Janus Kinase 2 Killer Cells, Natural - immunology Killer Cells, Natural - metabolism Leishmania Leishmania major Leishmaniasis, Cutaneous - immunology Leishmaniasis, Cutaneous - metabolism Life cycle. Host-agent relationship. Pathogenesis Lymphokines, interleukins ( function, expression) Lysine - analogs & derivatives Lysine - pharmacology Messenger RNA Mice Mice, Inbred BALB C Mice, Inbred C57BL Microbiology Natural killer cells Nitric Oxide - metabolism Nitric Oxide Synthase - antagonists & inhibitors Nitric Oxide Synthase - metabolism Nitric Oxide Synthase Type II Parasites Pathogenic microorganisms Phosphorylation Protein-Tyrosine Kinases - metabolism Proteins - metabolism Proto-Oncogene Proteins Protozoa Regulatory factors and their cellular receptors Signal Transduction Sodium STAT4 Transcription Factor T lymphocytes Trans-Activators - metabolism TYK2 Kinase Up-Regulation
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Beschreibung
Zusammenfassung:	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-γ (IFN-γ) 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-α/β also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity.
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.284.5416.951