LPS induction of I kappa B-alpha degradation and iNOS expression in a skindendritic cell line is prevented by the Janus kinase 2 inhibitor, tyrphostin B42

The Janus kinase (JAK) family of protein tyrosine kinases are activated in response to a wide variety of external stimuli, Here we have investigated w hether the janus kinase 2 (JAK2) is involved in the induction of nitric oxi de synthase type II (iNOS) expression in a mouse fetal skin dendritic cell line (FSDC). In FSDC the expression of iNOS protein and nitric oxide produc tion, in response to the lipopolysaccharide (LPS) stimulus (5 mug/ml), is i nhibited by the specific inhibitor of the JAK2, tyrphostin B42 with an half maximal inhibitory concentration (IC50) of 9.65 muM. The antioxidant compo und pyrrolidinedithiocarbamate (PDTC) inhibits both the nitrite production with an IC50 of 16.6 muM and the iNOS protein expression in FSDC, In additi on, LPS induces the activation of NF-kappaB, and tyrphostin B42 prevents th e degradation of the cytosolic factor I kappaB-alpha and blocks the translo cation of the NF-kappaB p65 protein subunit into the nucleus, These results indicate that the JAK family of protein kinases and the transcription fact or NF-kappaB are involved in the induction of iNOS protein expression in FS DC stimulated with LPS. (C) 2001 Academic Press.