Moscatilin repressed lipopolysaccharide-induced HIF-1alpha accumulation and NF-kappaB activation in murine RAW264.7 cells.
In the present study, we investigated the signaling pathways involved in the inhibition of cyclooxygenase 2 (COX-2) and iNOS by moscatilin under LPS challenge in murine macrophage-derived cell line RAW264.7. The results showed that moscatilin (10-100 microM) had a significant inhibition in a concentration-dependent manner on proinflammatory enzymes (COX-2 and iNOS) expression and macrophage activation under LPS (100 ng/mL) treatment. Hypoxia-inducible factor 1 (HIF-1)alpha was reported to initiate inflammation under cytokine stimulation or hypoxic conditions. In addition, the increase in transcriptional activity and translation process of HIF-1alpha under LPS stimulation resulted in HIF-1alpha accumulation. Moscatilin, a purified compound from Chinese herbs, had a dominant repression on HIF-1alpha expression via down regulating HIF-1alpha mRNA without inhibition of cell viability, translation machinery, or proteasome-mediated degradation of HIF-1alpha. Moreover, the results showed that moscatilin suppressed nuclear translocation of nuclear factor (NF)-kappaB subunits, p65 and p50, and NF-kappaB activity by inhibiting phosphorylation of inhibitor of kappaBalpha. Taken together, we demonstrated that moscatilin inhibited both COX-2 and iNOS expressions after LPS treatment in RAW264.7. Furthermore, the inhibition of moscatilin seemed to be dependent on the repression of HIF-1alpha accumulation and NF-kappaB activation.
Liu
Yi-Nan
YN
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
Pan
Shiow-Lin
SL
Peng
Chieh-Yu
CY
Huang
Der-Yi
DY
Guh
Jih-Hwa
JH
Chen
Chien-Chih
CC
Shen
Chien-Chang
CC
Teng
Che-Ming
CM
D000818:Animals; D001593:Benzyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001593:Benzyl Compounds; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D016328:NF-kappa B; C071845:dendrophenol; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2