INVOLVEMENT OF NF-KAPPA-B ACTIVATION IN THE INDUCTION OF TYPE-II NITRIC-OXIDE SYNTHASE IN HUMAN GLIOBLASTOMA CELLS

Nitric oxide (NO) produced by glial cells has been implicated in the p athogenesis of neurodegenerative diseases. In human glial cells, the t ranscriptional mechanism of inducible NO synthase (iNOS) remains to be understood. We examined the role of the transcription factor NF-xB in the induction of iNOS in a human glioblastoma cell line, A-172. Treat ment of A-172 cells with lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta) and interferon-gamma (IFN-gamma) induced iNOS mRNA and pro tein expression subsequent to the degradation of I Chi B, a protein th at inhibits NF-Chi B, and the DNA binding of NF-Chi B. Furthermore, th e antioxidant pyrroridine dithiocarbamate (PDTC), which is known to in hibit NF-Chi B activation, inhibited nitrite production in a dose-depe ndent manner. The inhibitory effect of PDTC correlated with the preven tion of I Chi B degradation. Another antioxidant, nordihydroguaiaretic acid (NDGA), also inhibited the nitrite formation and iNOS mRNA expre ssion through its preventive effect on NF-Chi B activation. These resu lts suggest the involvement of NF-Chi B activation in iNOS induction i n human glial cells.