title: JAK inhibitors AG-490 and WHI-P154 decrease IFN-gamma-induced iNOS expression and NO production in macrophages.
abstract: In inflammation, inducible nitric oxide synthase (iNOS) produces nitric oxide (NO), which modulates inflammatory processes. We investigated the effects of Janus kinase (JAK) inhibitors, AG-490 and WHI-P154, on iNOS expression and NO production in J774 murine macrophages stimulated with interferon-gamma (IFN-gamma). JAK inhibitors AG-490 and WHI-P154 decreased IFN-gamma-induced nuclear levels of signal transducer and activator of transcription 1alpha (STAT1alpha). JAK inhibitors AG-490 and WHI-P154 decreased also iNOS protein and mRNA expression and NO production in a concentration-dependent manner. Neither of the JAK inhibitors affected the decay of iNOS mRNA when determined by actinomycin D assay. Our results suggest that the inhibition of JAK-STAT1-pathway by AG-490 or WHI-P154 leads to the attenuation of iNOS expression and NO production in IFN-gamma-stimulated macrophages.
authors.affiliation: The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, 33014 Tampere, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Sareila
authors.forename: Riku
authors.initials: R
authors.lastname: Korhonen
authors.forename: Outi
authors.initials: O
authors.lastname: Kärpänniemi
authors.forename: Riina
authors.initials: R
authors.lastname: Nieminen
authors.forename: Hannu
authors.initials: H
authors.lastname: Kankaanranta
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D011799:Quinazolines / Q000494:pharmacology*; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D050832:Interferon-Stimulated Gene Factor 3; D009573:Nitrites; D011799:Quinazolines; D020032:Tyrphostins; C113888:WHI P154; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C079868:gamma interferon activation factor; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D053613:Janus Kinase 1