3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit: Potential clinical implications

Tomoshige Kino, Terrence L. Boos, Agnieszka Sulima, Elise M. Siegel, Philip W. Gold, Kenner C. Rice, George P. Chrousos

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: The multifunctional inflammatory cytokine IL-6 regulates the acute phase reaction and plays central roles in the pathogenesis of chronic inflammatory disorders. Objectives: Two small chemical compounds, 3-O-formyl-20R,21-epoxyresibufogenin (TB-2-081) and 3-O-formyl-20S,21-epoxyresibufogenin (TB-2-082), known isolates from the Chinese toad skin extract drug Ch'an Su, were synthesized and tested on the IL-6-induced hepatic acute-phase reaction. Methods: HepG2 cells or rat primary hepatocytes were incubated with the compounds, and the effects on IL-6-induced expression of acute-phase molecules were tested. Results: TB-2-081, and to a lesser extent TB-2-082, suppressed IL-6-induced α1-antichymotrypsin (AACT) mRNA expression in HepG2 cells, whereas TB-2-081 failed to influence the mRNA expression of the TNF-α-induced mRNA expression of the methionine adenosyltransferase 2A gene in these cells. TB-2-081 suppressed IL-6-induced mRNA expression of α1-acid glycoprotein, α2-macroglobulin, and β-fibrinogen in and secretion of the C-reactive protein by rat primary hepatocytes. TB-2-081 shifted the IL-6 dose-response curve of the AACT mRNA expression right and downward and inhibited IL-6-induced phosphorylation of signal transducer and activator of transcription 3. In addition to IL-6, TB-2-081 inhibited IL-11-stimulated and oncostatin M-stimulated AACT mRNA expression independently of the IL-6 receptor subunit. The soluble glycoprotein 130, but not the soluble IL-6 receptor, antagonized TB-2-081-induced suppression of IL-6-stimulated AACT mRNA expression. Conclusion: TB-2-081 inhibits IL-6-type cytokine action by attenuating the function of the common receptor subunit glycoprotein 130. Clinical implications: This class of compounds may be beneficial for the treatment of diseases in which excessive circulation/production/action of IL-6-type cytokines play pathologic roles.

Original languageEnglish
Pages (from-to)437-444
Number of pages8
JournalJournal of Allergy and Clinical Immunology
Volume120
Issue number2
DOIs
Publication statusPublished - 1 Aug 2007

    Fingerprint

Keywords

  • IL-6 receptor
  • glycoprotein 130
  • hepatic acute phase proteins
  • signal transducer and activator of transcription 3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this