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 - Aug 2007
Externally publishedYes

Fingerprint

Interleukin-6
Glycoproteins
Cytokines
Messenger RNA
Acute-Phase Reaction
Hep G2 Cells
Hepatocytes
Cytokine Receptor gp130
Methionine Adenosyltransferase
Oncostatin M
Interleukin-11
Interleukin-6 Receptors
20,21-epoxyresibufogenin-3-formate
STAT3 Transcription Factor
Macroglobulins
Anura
Fibrinogen
Phosphorylation
Skin
Acids

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit : Potential clinical implications. / Kino, Tomoshige; Boos, Terrence L.; Sulima, Agnieszka; Siegel, Elise M.; Gold, Philip W.; Rice, Kenner C.; Chrousos, George P.

In: Journal of Allergy and Clinical Immunology, Vol. 120, No. 2, 08.2007, p. 437-444.

Research output: Contribution to journalArticle

Kino, Tomoshige ; Boos, Terrence L. ; Sulima, Agnieszka ; Siegel, Elise M. ; Gold, Philip W. ; Rice, Kenner C. ; Chrousos, George P. / 3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit : Potential clinical implications. In: Journal of Allergy and Clinical Immunology. 2007 ; Vol. 120, No. 2. pp. 437-444.
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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.",
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author = "Tomoshige Kino and Boos, {Terrence L.} and Agnieszka Sulima and Siegel, {Elise M.} and Gold, {Philip W.} and Rice, {Kenner C.} and Chrousos, {George P.}",
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T1 - 3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit

T2 - Potential clinical implications

AU - Kino, Tomoshige

AU - Boos, Terrence L.

AU - Sulima, Agnieszka

AU - Siegel, Elise M.

AU - Gold, Philip W.

AU - Rice, Kenner C.

AU - Chrousos, George P.

PY - 2007/8

Y1 - 2007/8

N2 - 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.

AB - 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.

KW - glycoprotein 130

KW - hepatic acute phase proteins

KW - IL-6 receptor

KW - signal transducer and activator of transcription 3

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