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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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-1α (STAT-1α) Activation

Elisa Tedeschi, Marta Menegazzi, Daniela Margotto, Hisanori Suzuki, Ulrich Förstermann and Hartmut Kleinert
Journal of Pharmacology and Experimental Therapeutics October 2003, 307 (1) 254-261; DOI: https://doi.org/10.1124/jpet.103.054460
Elisa Tedeschi
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Marta Menegazzi
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Daniela Margotto
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Hisanori Suzuki
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Ulrich Förstermann
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Hartmut Kleinert
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Abstract

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-1α (STAT-1α), but not of nuclear factor-κB. This down-regulation of the STAT-1α DNA binding was shown to result from reduced tyrosine phosphorylation of the STAT-1α protein. The diminished STAT-1α 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.

Footnotes

  • This work was supported by Grant 8312-38 62 61/322a,b from the Innovation Foundation of the State of Rhineland-Palatinate (to H.K. and U.F.), by the Collaborative Research Center SFB 553 (Project A7 to H.K.), and Italian COFIN Grants 2000–2002 (to H.S.).

  • E.T. is supported by a doctoral fellowship in Biochemical Science from the University of Verona.

  • DOI: 10.1124/jpet.103.054460.

  • ABBREVIATIONS:: SJW, St. John's wort; NO, nitric oxide; NOS, NO synthase; iNOS, inducible NOS; eNOS, endothelial NOS; NF-κB, nuclear factor-κB; CM, cytokine mixture; IFN-γ, interferon-γ; IL-1β, interleukin-1β; JAK2, Janus kinase 2; STAT-1α, signal transducer and activator of transcription-1α; TNF-α, tumor necrosis factor-α; LPS, lipopolysaccharide; FCS, fetal calf serum; DMEM, Dulbecco's modified Eagle's medium; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; nt, nucleotide; kb, kilobase(s); PAGE, polyacrylamide gel electrophoresis; PVDF, polyvinylidene difluoride; ECL, enhanced chemiluminescence.

    • Received May 13, 2003.
    • Accepted June 20, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 307 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 307, Issue 1
1 Oct 2003
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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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-1α (STAT-1α) Activation

Elisa Tedeschi, Marta Menegazzi, Daniela Margotto, Hisanori Suzuki, Ulrich Förstermann and Hartmut Kleinert
Journal of Pharmacology and Experimental Therapeutics October 1, 2003, 307 (1) 254-261; DOI: https://doi.org/10.1124/jpet.103.054460

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Research ArticleINFLAMMATION AND IMMUNOPHARMACOLOGY

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-1α (STAT-1α) Activation

Elisa Tedeschi, Marta Menegazzi, Daniela Margotto, Hisanori Suzuki, Ulrich Förstermann and Hartmut Kleinert
Journal of Pharmacology and Experimental Therapeutics October 1, 2003, 307 (1) 254-261; DOI: https://doi.org/10.1124/jpet.103.054460
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