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Molecular Pharmacology

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Research ArticleArticle

Inhibition of Tumor Necrosis Factor-α through Selective Blockade of Pre-mRNA Splicing by Shikonin

Shao-Chih Chiu and Ning-Sun Yang
Molecular Pharmacology June 2007, 71 (6) 1640-1645; DOI: https://doi.org/10.1124/mol.106.032821
Shao-Chih Chiu
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Ning-Sun Yang
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Abstract

We previously developed a gene-gun-based in vivo screening system and identified shikonin as a potent suppressor of tumor necrosis factor-α (TNF-α) gene expression. Here, we show that shikonin selectively inhibits the expression of TNF-α at the RNA splicing level. Treatment of lipopolysaccharide-stimulated human primary monocytes and THP-1 cells with shikonin resulted in normal transcriptional induction of TNF-α, but unspliced pre-mRNA accumulated at the expense of functional mRNA. This effect occurred with noncytotoxic doses of shikonin and was highly specific, because mRNA production of neither a housekeeping gene nor another inflammatory cytokine gene, interleukin-8 (IL-8), was affected. Moreover, cotreatment with lipopolysaccharide (LPS) and shikonin increased the endpoint protein production of IL-8, accompanied by suppressed activation of the double-stranded RNA-activated protein kinase (PKR) pathway. Because PKR inactivation has been shown to down-regulate the splicing process of TNF-α RNA and interfere with translation, our findings suggest that shikonin may achieve differential modulation of cytokine protein expression through inactivation of the PKR pathway and reveal that regulation of TNF-α pre-mRNA splicing may constitute a promising target for future anti-inflammatory application.

Footnotes

  • This work was supported by grant 94F002-1 from Academia Sinica, Taipei, Taiwan, Republic of China.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.106.032821.

  • ABBREVIATIONS: TNF-α, tumor necrosis factor-α; PKR, double-stranded RNA-activated protein kinase; 2-AP, 2-aminopurine; CHX, cycloheximide; LPS, lipopolysaccharide; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole; U0126, 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene; RT-PCR, reverse transcriptase-polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ELISA, enzyme-linked immunosorbent assay; PBST, phosphate-buffered saline/Tween 20; IL, interleukin; 2APRE, 2-AP responsive element; eIF2α, eukaryotic initiation factor-2α.

    • Received November 21, 2006.
    • Accepted March 12, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (6)
Molecular Pharmacology
Vol. 71, Issue 6
1 Jun 2007
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Research ArticleArticle

Inhibition of Tumor Necrosis Factor-α through Selective Blockade of Pre-mRNA Splicing by Shikonin

Shao-Chih Chiu and Ning-Sun Yang
Molecular Pharmacology June 1, 2007, 71 (6) 1640-1645; DOI: https://doi.org/10.1124/mol.106.032821

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Research ArticleArticle

Inhibition of Tumor Necrosis Factor-α through Selective Blockade of Pre-mRNA Splicing by Shikonin

Shao-Chih Chiu and Ning-Sun Yang
Molecular Pharmacology June 1, 2007, 71 (6) 1640-1645; DOI: https://doi.org/10.1124/mol.106.032821
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