3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6–type cytokine actions by targeting the glycoprotein 130 subunit: Potential clinical implications

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3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6–type cytokine actions by targeting the glycoprotein 130 subunit: Potential clinical implications Tomoshige Kino, MD, PhD, Terrence L. Boos, PhD, Agnieszka Sulima, PhD, Elise M. Siegel, BS, Philip W. Gold, MD, Kenner C. Rice, PhD, George P. Chrousos, MD Journal of Allergy and Clinical Immunology Volume 120, Issue 2, Pages 437-444 (August 2007) DOI: 10.1016/j.jaci.2007.03.018 Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 TB-2-081 and TB-2-082 suppress IL-6–stimulated AACT mRNA expression in HepG2 cells. A, TB-2-081 and TB-2-082, but not TAS-3-124, suppressed IL-6–stimulated AACT mRNA expression. Cells were preincubated with increasing concentrations of TB-2-081, TB-2-082, or TSA-3-124, and 50 ng/mL IL-6 was added. Bars represent the means ± SEs. ∗P < .01; NS, not significant compared with baseline. B, TB-2-081 does not have a cytotoxic effect on HepG2 cells at the 10 μmol/L concentration. Cells were treated with indicated concentration of TB-2-081, and the cytotoxic effect was determined with the XTT assay. Circles indicate the mean ± SE values of % absorbance to that obtained in the absence of TB-2-081. C, TB-2-081 suppresses IL-6–induced AACT mRNA expression but not TNF-α–induced MTA2A mRNA expression. Cells were preincubated with TB-2-081, and 50 ng/mL IL-6 or 20 ng/mL TNF-α was added. Bars represent the mean ± SE values. ∗P < .01; NS, not significant compared with the baseline untreated with indicated cytokines. Journal of Allergy and Clinical Immunology 2007 120, 437-444DOI: (10.1016/j.jaci.2007.03.018) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TB-2-081 suppresses IL-6–stimulated mRNA expression in and protein secretion of acute-phase proteins by rat primary hepatocytes. A-C, TB-2-081 dose-dependently suppresses IL-6–stimulated mRNA expression of AGP, β-fibrinogen, and α2-macro. Cells were preincubated with TB-2-081, and 50 ng/mL IL-6 was added. Bars represent the mean ± SE values. ∗P < .01 compared with baseline. D, TB-2-081 downshifts the IL-6–induced titration curve of CRP secretion. Cells were preincubated with or without 10 μmol/L TB-2-081, and indicated concentrations of IL-6 were added. Circles represent the mean ± SE values. ∗P < .01 compared with the baseline untreated with TB-2-081. Journal of Allergy and Clinical Immunology 2007 120, 437-444DOI: (10.1016/j.jaci.2007.03.018) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TB-2-081 suppresses IL-6–induced AACT mRNA expression by inhibiting IL-6–induced signaling pathway in HepG2 cells. A, TB-2-081 shifts the dose-response curve of the IL-6 effect on AACT mRNA expression right and downward. Cells were preincubated with 10 μmol/L TB-2-081, and increasing concentrations of IL-6 were added. Circles represent the mean ± SE values. ED50s of IL-6 effect on AACT mRNA expression are indicated. B, TB-2-081 suppresses IL-6–induced phosphorylation (Y705) of STAT3 in Western blots. Cells were preincubated with TB-2-081, and 5 ng/mL IL-6 was added. The cells were incubated for the indicated periods in the top panel, and cultured for 10 minutes in the bottom panel. Journal of Allergy and Clinical Immunology 2007 120, 437-444DOI: (10.1016/j.jaci.2007.03.018) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TB-2-081 suppresses IL-6–type cytokine activities on AACT mRNA expression independently of the IL-6 receptor subunit in HepG2 cells. A, TB-2-081 suppresses the effects of IL-11 and OSM on AACT mRNA expression in addition to that of IL-6. Cells were preincubated with 10 μmol/L TB-2-081 or its vehicle (DMSO: control), and 50 ng/mL IL-6 or IL-11 or 25 ng/mL OSM was added. Bars represent the mean ± SE values. ∗P < .01; NS, not significant compared with the results obtained in the absence of TB-2-081. See this article's Table E2 in the Online Repository at www.jacionline.org for more detail. B, The IL-6 receptor subunit is not necessary for TB-2-081 to suppress IL-11–stimulated and OSM-stimulated AACT mRNA expression. Cells were transfected with the IL-6 receptor or the control siRNA, preincubated with 10 μmol/L TB-2-081 or the control DMSO, and exposed to 50 ng/mL IL-6 or IL-11 or 25 ng/mL OSM. Bars represent the mean ± SE values. ∗P < .01; NS, not significant. Please see text for details on the comparisons. Journal of Allergy and Clinical Immunology 2007 120, 437-444DOI: (10.1016/j.jaci.2007.03.018) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 The soluble gp130, but not the soluble IL-6 receptor, influences the inhibitory effect of TB-2-081 on IL-6–induced AACT mRNA expression in HepG2 cells. Cells were preincubated with TB-2-081 in the presence or absence of soluble gp130 (A) or the soluble IL-6 receptor (B). Subsequently, 50 ng/mL IL-6 was added. Bars represent the mean ± SE values. ∗P < .01; NS, not significant compared with the results obtained in the absence of TB-2-081. Journal of Allergy and Clinical Immunology 2007 120, 437-444DOI: (10.1016/j.jaci.2007.03.018) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions