Janus kinase 3 inhibitor WHI-P154 in macrophages activated by bacterial endotoxin: differential effects on the expression of iNOS, COX-2 and TNF-alpha.

ABSTRACT

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.