12-o-retinoylphorbol-13-acetate and phorbolol-myristate-acetate

The effect of YS 51, a synthetic 1-(beta-naphtylmethyl)6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline alkaloid, on the expression of manganese-superoxide dismutase (Mn-SOD), an antioxidant enzyme, was examined in sheep pulmonary artery endothelial cells (SPAEC) and a human cervical carcinoma cell line (Hela). YS 51 alone or in combination with cytokines enhanced the expression of Mn-SOD mRNA in SPAEC and Hela cells. YS 51 also showed synergistic effects on the induction of Mn-SOD mRNA with phorbol-12-myristate-13-acetate (TPA) and/or tumor necrosis factor-alpha (TNF-alpha). In Hela cells, the induction of Mn-SOD mRNA by YS 51 was in a time- and dose-dependent manner and the expression of Mn-SOD mRNA was increased to a maximum of 4-fold in 9 h. Enhancement of Mn-SOD mRNA by YS 51 was completely abolished by actinomycin D but not cycloheximide, suggesting that the induction of Mn-SOD mRNA byYS 51 is independent of new protein synthesis. Pretreatment of curcumin, an inhibitor of c-jun N-terminal kinase (JNK), dose-dependently suppressed the induction of Mn-SOD mRNA by YS 51, but not by 2'-amino-3'-methoxyflavone (PD98059) and 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5-(4-pyridyl)imidazol (SB203580), inhibitors of mitogen-activated protein kinase. Also, YS 51 induced the phosphorylation activity of JNK in a time-dependent manner without affecting the phosphorylation activity of the extracellular signal-regulated kinase 1 (ERK1) and p38 MAP kinase. These results implicated that the JNK pathway appears to play a crucial role in mediating the YS 51-induced Mn-SOD gene expression, and that up-regulation of Mn-SOD would contribute to the anti-inflammatory actions mediated by YS 51.

Topics: Animals; Blotting, Northern; Curcumin; Cycloheximide; Dactinomycin; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Endothelial Cells; Endothelium, Vascular; Enzyme Induction; Flavonoids; Gene Expression Regulation, Enzymologic; HeLa Cells; Humans; Imidazoles; Indoles; JNK Mitogen-Activated Protein Kinases; Maleimides; Mitogen-Activated Protein Kinase 3; p38 Mitogen-Activated Protein Kinases; Phorbol Esters; Phosphorylation; Pulmonary Artery; Pyridines; RNA, Messenger; Sheep; Superoxide Dismutase; Tetradecanoylphorbol Acetate; Tetrahydroisoquinolines; Tumor Necrosis Factor-alpha