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Requirement for type 2 NO synthase for IL-12 signaling in innate immunity
A Diefenbach1, H Schindler, M Röllinghoff
1Institut für Klinische Mikrobiologie, Immunologie und Hygiene, Universität Erlangen, Wasserturmstrasse 3, D-91054 Erlangen, Germany.
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.