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 defens e against bacterial and parasitic pathogens, but their relationship in inna te immunity is unknown. in the absence of NOS2 activity, IL-12 was unable t o prevent spreading of Leishmania parasites, did not stimulate natural kill er (NK) cells for cytotoxicity or interferon-gamma (IFN-gamma) release, and failed to activate Tyk2 kinase and to tyrosine phosphorylate Stat4 (the ce ntral signal transducer of IL-12) in NK cells. Activation of Tyk2 in NK cel ls by IFN-alpha/beta also required NOS2. Thus, NOS2-derived NO is a prerequ isite for cytokine signaling and function in innate immunity.