Τίτλος:
3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit: Potential clinical implications
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2007 American Academy of Allergy, Asthma & Immunology.
Συγγραφείς:
Kino, T.
Boos, T.L.
Sulima, A.
Siegel, E.M.
Gold, P.W.
Rice, K.C.
Chrousos, G.P.
Περιοδικό:
Allergy: European Journal of Allergy and Clinical Immunology
Λέξεις-κλειδιά:
3 o formyl 21 epoxyresibufogenin; alpha 1 antichymotrypsin; alpha 2 macroglobulin; C reactive protein; Chinese drug; fibrinogen; fibrinogen b beta chain; glycoprotein; glycoprotein 130; interleukin 11; interleukin 6; interleukin 6 receptor; messenger RNA; methionine adenosyltransferase; methionine adenosyltransferase 2a; oncostatin M; orosomucoid; protein subunit; STAT3 protein; tb 2 081; tb 2 082; tumor necrosis factor alpha; unclassified drug, animal cell; article; cell strain HepG2; Chinese medicine; concentration response; controlled study; drug mechanism; drug synthesis; gene expression; human; human cell; liver cell; nonhuman; priority journal; protein expression; protein phosphorylation; protein secretion; protein targeting; rat, alpha 1-Antichymotrypsin; alpha-Macroglobulins; Animals; Bufanolides; Cells, Cultured; Dose-Response Relationship, Drug; Fibrinogen; Glycoproteins; Humans; Interleukin-11; Interleukin-6; Oncostatin M; Orosomucoid; Phosphorylation; Rats; Receptors, Interleukin-6; RNA, Messenger; Solubility; STAT3 Transcription Factor
DOI:
10.1016/j.jaci.2007.03.018
