3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6-type cytokine actions by targeting the glycoprotein 130 subunit: potential clinical implications.
BACKGROUND
The multifunctional inflammatory cytokine IL-6 regulates the acute phase reaction and plays central roles in the pathogenesis of chronic inflammatory disorders.


OBJECTIVE
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.


CONCLUSIONS
TB-2-081 inhibits IL-6-type cytokine action by attenuating the function of the common receptor subunit glycoprotein 130.


CONCLUSIONS
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.
Kino
Tomoshige
T
Pediatric Endocrinology Section, Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, Clinical Research Center, Bethesda, MD 20892-1109, USA. kinot@mail.nih.gov
Boos
Terrence L
TL
Sulima
Agnieszka
A
Siegel
Elise M
EM
Gold
Philip W
PW
Rice
Kenner C
KC
Chrousos
George P
GP
D000818:Animals; D002018:Bufanolides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005340:Fibrinogen / Q000235:genetics; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D017370:Interleukin-11 / Q000494:pharmacology; D015850:Interleukin-6 / Q000008:administration & dosage / Q000494:pharmacology; D053683:Oncostatin M / Q000494:pharmacology; D009961:Orosomucoid / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000737:chemistry / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012995:Solubility; D000514:alpha 1-Antichymotrypsin / Q000235:genetics; D000511:alpha-Macroglobulins / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
D002018:Bufanolides; D005340:Fibrinogen; D006023:Glycoproteins; D017370:Interleukin-11; D015850:Interleukin-6; D053683:Oncostatin M; D009961:Orosomucoid; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; D000514:alpha 1-Antichymotrypsin; D000511:alpha-Macroglobulins; D000093242:Interleukin-6 Inhibitors; C466795:20,21-epoxyresibufogenin-3-formate; C480482:glycoprotein 130, human