3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit: potential clinical implications
- PMID: 17451794
- DOI: 10.1016/j.jaci.2007.03.018
3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit: potential clinical implications
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 alpha1-antichymotrypsin (AACT) mRNA expression in HepG2 cells, whereas TB-2-081 failed to influence the mRNA expression of the TNF-alpha-induced mRNA expression of the methionine adenosyltransferase 2A gene in these cells. TB-2-081 suppressed IL-6-induced mRNA expression of alpha1-acid glycoprotein, alpha2-macroglobulin, and beta-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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