Janus kinase 3 inhibitor WHI-P154 in macrophages activated by bacterial endotoxin: differential effects on the expression of iNOS, COX-2 and TNF-alpha.
Bacterial endotoxin is a potent inducer of inflammatory response, including the induction of inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) production, and the expression of cyclo-oxygenase (COX)-2 and tumor necrosis factor (TNF)-alpha in inflammatory cells. In the present study, we investigated the effects of pharmacological inhibition of Janus kinase (JAK) 3 on the production of these proinflammatory molecules in macrophages exposed to bacterial endotoxin (lipopolysaccharide; LPS). JAK3 inhibitors WHI-P154 (4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline) and its derivative WHI-P131 inhibited LPS-induced iNOS expression and NO production in a dose-dependent manner. WHI-P154 inhibited the activation of signal transducer and activator of transcription (STAT) 1 and the expression of iNOS mRNA but it had no effect on iNOS mRNA decay when determined by actinomycin D assay. The JAK3 inhibitor had no effect on COX-2 expression, and TNF-alpha production was slightly inhibited only at higher drug concentrations (30 microM). In addition, WHI-P154 inhibited iNOS expression and NO production also in human epithelial cells. Our results suggest that JAK3 inhibition modulates human and murine iNOS expression and NO production in response to inflammatory stimuli.
Sareila
Outi
O
The Immunopharmacology Research Group, Medical School, University of Tampere, and Research Unit, Tampere University Hospital, Tampere, Finland.
Korhonen
Riku
R
Kärpänniemi
Outi
O
Nieminen
Riina
R
Kankaanranta
Hannu
H
Moilanen
Eeva
E
D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000502:physiology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D050794:STAT1 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; C116180:WHI P131; C113888:WHI P154; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D053616:Janus Kinase 3