E. Galea et al., DIFFERENTIAL SUPPRESSION OF GLIAL NITRIC-OXIDE SYNTHASE INDUCTION BY STRUCTURALLY RELATED TYROSINE KINASE INHIBITORS, Neuroscience letters, 200(3), 1995, pp. 195-198
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.