JAK inhibitors AG-490 and WHI-P154 decrease IFN-gamma-induced iNOS expression and NO production in macrophages.
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.
Sareila
Outi
O
The Immunopharmacology Research Group, Medical School, University of Tampere and Research Unit, Tampere University Hospital, 33014 Tampere, Finland.
Korhonen
Riku
R
Kärpänniemi
Outi
O
Nieminen
Riina
R
Kankaanranta
Hannu
H
Moilanen
Eeva
E
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*
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