DIFFERENTIAL SUPPRESSION OF GLIAL NITRIC-OXIDE SYNTHASE INDUCTION BY STRUCTURALLY RELATED TYROSINE KINASE INHIBITORS

Incubation of C6 astrocytoma cells with bacterial endotoxin (lipopolys accharide; LPS) plus interferon-gamma (IFN-gamma), or with a combinati on of cytokines (TNF-alpha, IL1-beta, and IFN-gamma) leads to high lev els of inducible nitric oxide synthase (iNOS) expression. Previous res ults demonstrated a requirement for tyrosine kinase (TK) activities fo r iNOS induction. In the present study, a set of structurally related TK inhibitors, the tyrphostins (TYRs), were used to characterize possi ble differences between LPS and cytokine iNOS induction. All TYRs test ed suppressed both types of induction. However, dose-response curves r evealed significant differences in the IC50 values obtained for some T YRs (T25 and T56), and significant differences in the IC50 potency ran k order when comparing inhibition of LPS versus cytokine-dependent iNO S induction. These results are consistent with differential TK utiliza tion by the LPS versus cytokine pathways of iNOS induction, and establ ish a basis for developing further selective inhibitors of iNOS expres sion.