Anti-inflammatory actions of St. John's wort: inhibition of human inducible nitric-oxide synthase expression by down-regulating signal transducer and activator of transcription-1alpha (STAT-1alpha) activation.
St. John's wort (SJW) has been described to show anti-inflammatory properties due to its inhibitory effects on the expression of pro-inflammatory genes like cyclooxygenase-2, interleukin-6, and inducible nitric-oxide synthase (iNOS). Since iNOS plays a critical role in chronic inflammatory diseases, we have focused our attention on the regulation of iNOS expression by SJW in two different human epithelial cell lines, alveolar A549/8 and colon DLD-1 cells. SJW extract concentration dependently inhibited human iNOS expression evaluated by measuring the amounts of iNOS mRNA, iNOS protein, and NO production in both cell lines. This inhibitory effect resulted from transcriptional inhibition as shown in reporter gene experiments. With electrophoretic mobility shift experiments, we found a SJW-mediated down-regulation of the DNA binding activity of the transcription factor signal transducer and activator of transcription-1alpha (STAT-1alpha), but not of nuclear factor-kappaB. This down-regulation of the STAT-1alpha DNA binding was shown to result from reduced tyrosine phosphorylation of the STAT-1alpha protein. The diminished STAT-1alpha tyrosine phosphorylation resulted from SJW-mediated reduction of Janus kinase 2 activity. These data suggest that extracts from SJW may be a promising anti-inflammatory principle in chronic inflammatory diseases.
Tedeschi
Elisa
E
Department of Neuroscience and Vision, University of Verona, Italy.
Menegazzi
Marta
M
Margotto
Daniela
D
Suzuki
Hisanori
H
Förstermann
Ulrich
U
Kleinert
Hartmut
H
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D020902:Hypericum / Q000737:chemistry*; D050832:Interferon-Stimulated Gene Factor 3; D016328:NF-kappa B / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000893:Anti-Inflammatory Agents; D050832:Interferon-Stimulated Gene Factor 3; D016328:NF-kappa B; D009573:Nitrites; D010936:Plant Extracts; D012333:RNA, Messenger; D014157:Transcription Factors; C079868:gamma interferon activation factor; D004247:DNA; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II