The multifunctional inflammatory cytokine IL-6 regulates the acute phase reaction and plays central roles in the pathogenesis of chronic inflammatory disorders.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.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.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.TB-2-081 inhibits IL-6–type cytokine action by attenuating the function of the common receptor subunit glycoprotein 130.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.