Anti-inflammatory mechanisms of phenanthroindolizidine alkaloids.
The molecular mechanisms for the anti-inflammatory activity of phenanthroindolizidine alkaloids were examined in an in vitro system mimicking acute inflammation by studying the suppression of lipopolysaccharide (LPS)/interferon-gamma (IFNgamma)-induced nitric oxide production in RAW264.7 cells. Two of the phenanthroindolizidine alkaloids, NSTP0G01 (tylophorine) and NSTP0G07 (ficuseptine-A), exhibited potent suppression of nitric oxide production and did not show significant cytotoxicity to the LPS/IFNgamma-stimulated RAW264.7 cells, in contrast to their respective cytotoxic effects on cancer cells. Tylophorine was studied further to investigate the responsible mechanisms. It was found to inhibit the induced protein levels of tumor necrosis factor-alpha, inducible nitric-oxide synthase (iNOS), and cyclooxygenase (COX)-II. It also inhibited the activation of murine iNOS and COX-II promoter activity. However, of the two common responsive elements of iNOS and COX-II promoters, nuclear factor-kappaB (NF-kappaB) and adaptor protein (AP)1, only AP1 activation was inhibited by tylophorine in the LPS/IFNgamma-stimulated RAW264.7 cells. Further studies showed that the tylophorine enhanced the phosphorylation of Akt and thus decreased the expression and phosphorylation levels of c-Jun protein, thereby causing the subsequent inhibition of AP1 activity. Furthermore, the tylophorine was able to block mitogen-activated protein/extracellular signal-regulated kinase kinase 1 activity and its downstream signaling activation of NF-kappaB and AP1. Thus, NSTP0G01 exerts its anti-inflammatory effects by inhibiting expression of the proinflammatory factors and related signaling pathways.
Yang
Cheng-Wei
CW
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taipei, Taiwan, Republic of China.
Chen
Wei-Liang
WL
Wu
Pei-Lin
PL
Tseng
Huan-Yi
HY
Lee
Shiow-Ju
SJ
D033961:Adaptor Protein Complex 1 / Q000037:antagonists & inhibitors; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D030681:Ficus / Q000737:chemistry*; D007212:Indolizines / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics; D010616:Phenanthrenes / Q000494:pharmacology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D033961:Adaptor Protein Complex 1; D000470:Alkaloids; D000893:Anti-Inflammatory Agents; D002867:Chromones; D052246:Cyclooxygenase 2 Inhibitors; D007212:Indolizines; D008070:Lipopolysaccharides; D009025:Morpholines; D016328:NF-kappa B; D010616:Phenanthrenes; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3; C004218:tylophorine