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Inhibition of lethal inflammatory responses through the targeting of membrane-associated Toll-like receptor 4 signaling complexes with a Smad6-derived peptide.

Lee YS, Park JS, Jung SM, Kim SD, Kim JH, Lee JY, Jung KC, Mamura M, Lee S, Kim SJ, Bae YS, Park SH - EMBO Mol Med (2015)

Bottom Line: Here, we developed Smaducin-6, a novel membrane-tethered palmitic acid-conjugated Smad6-derived peptide composed of amino acids 422-441 of Smad6.Smaducin-6 interacted with Pellino-1, located in the inner membrane, thereby disrupting the formation of IRAK1-, RIP1-, IKKε-mediated TLR4 signaling complexes.Our findings provide clues to develop new peptide-based drugs to target Pellino-1 protein in TLR4 signaling pathway for the treatment of sepsis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.

No MeSH data available.


Related in: MedlinePlus

Smaducin-6 reduces systemic pro-inflammatory cytokines in CLP-induced sepsis miceA–I Smaducin-6 treatment decreased the concentration of IL-6, TNF-α, IFN-γ, and IL-1β in the blood of CLP mice (A–D), but not IL-4, IL-10, TGF-β1, IL-12, or IL-17A (E–I). Cytokine concentrations were analyzed by ELISA. n = 10 mice per group per experiment. Data were statistically analyzed by the Dunnett's multiple comparison test (one-way ANOVA). ***P < 0.001, **P < 0.005, *P < 0.05 compared to sham or vehicle control (CLP + Pal-Scram #1).J Expression of the IL-6 protein is reduced in the spleen and liver of Smaducin-6-treated CLP mice. Each lane represents independent mice.Source data are available online for this figure.
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fig05: Smaducin-6 reduces systemic pro-inflammatory cytokines in CLP-induced sepsis miceA–I Smaducin-6 treatment decreased the concentration of IL-6, TNF-α, IFN-γ, and IL-1β in the blood of CLP mice (A–D), but not IL-4, IL-10, TGF-β1, IL-12, or IL-17A (E–I). Cytokine concentrations were analyzed by ELISA. n = 10 mice per group per experiment. Data were statistically analyzed by the Dunnett's multiple comparison test (one-way ANOVA). ***P < 0.001, **P < 0.005, *P < 0.05 compared to sham or vehicle control (CLP + Pal-Scram #1).J Expression of the IL-6 protein is reduced in the spleen and liver of Smaducin-6-treated CLP mice. Each lane represents independent mice.Source data are available online for this figure.

Mentions: Cytokine storm is an important characteristic of sepsis, which results in multiple organ failure (Cavaillon et al, 2003). Treatment with Smaducin-6 significantly decreased the concentration of pro-inflammatory cytokines such as IL-6, IFN-γ, TNF-α, and IL-1β in both peripheral blood and peritoneal fluid of CLP mice after 18 h (Fig5A–D; Supplementary Figs S11A–D and S12). In contrast, the concentrations of IL-4, IL-10, TGF-β1, IL-12, and IL-17A did not show significant changes (Fig5E–I; Supplementary Fig S11E–I). Expression of IL-6 protein in the spleen and liver of Smaducin-6-treated CLP mice was significantly decreased compared with the control groups treated with PBS only or Pal-scram #1 (Fig5J). Reduction in pro-inflammatory cytokine levels in peripheral blood and peritoneal fluid explains the protective effect of Smaducin-6 on sepsis. Treatment with Smaducin-6 also reduced the level of CXCL2 chemokine, one of the hallmarks of sepsis (Supplementary Fig S11J).


Inhibition of lethal inflammatory responses through the targeting of membrane-associated Toll-like receptor 4 signaling complexes with a Smad6-derived peptide.

Lee YS, Park JS, Jung SM, Kim SD, Kim JH, Lee JY, Jung KC, Mamura M, Lee S, Kim SJ, Bae YS, Park SH - EMBO Mol Med (2015)

Smaducin-6 reduces systemic pro-inflammatory cytokines in CLP-induced sepsis miceA–I Smaducin-6 treatment decreased the concentration of IL-6, TNF-α, IFN-γ, and IL-1β in the blood of CLP mice (A–D), but not IL-4, IL-10, TGF-β1, IL-12, or IL-17A (E–I). Cytokine concentrations were analyzed by ELISA. n = 10 mice per group per experiment. Data were statistically analyzed by the Dunnett's multiple comparison test (one-way ANOVA). ***P < 0.001, **P < 0.005, *P < 0.05 compared to sham or vehicle control (CLP + Pal-Scram #1).J Expression of the IL-6 protein is reduced in the spleen and liver of Smaducin-6-treated CLP mice. Each lane represents independent mice.Source data are available online for this figure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492818&req=5

fig05: Smaducin-6 reduces systemic pro-inflammatory cytokines in CLP-induced sepsis miceA–I Smaducin-6 treatment decreased the concentration of IL-6, TNF-α, IFN-γ, and IL-1β in the blood of CLP mice (A–D), but not IL-4, IL-10, TGF-β1, IL-12, or IL-17A (E–I). Cytokine concentrations were analyzed by ELISA. n = 10 mice per group per experiment. Data were statistically analyzed by the Dunnett's multiple comparison test (one-way ANOVA). ***P < 0.001, **P < 0.005, *P < 0.05 compared to sham or vehicle control (CLP + Pal-Scram #1).J Expression of the IL-6 protein is reduced in the spleen and liver of Smaducin-6-treated CLP mice. Each lane represents independent mice.Source data are available online for this figure.
Mentions: Cytokine storm is an important characteristic of sepsis, which results in multiple organ failure (Cavaillon et al, 2003). Treatment with Smaducin-6 significantly decreased the concentration of pro-inflammatory cytokines such as IL-6, IFN-γ, TNF-α, and IL-1β in both peripheral blood and peritoneal fluid of CLP mice after 18 h (Fig5A–D; Supplementary Figs S11A–D and S12). In contrast, the concentrations of IL-4, IL-10, TGF-β1, IL-12, and IL-17A did not show significant changes (Fig5E–I; Supplementary Fig S11E–I). Expression of IL-6 protein in the spleen and liver of Smaducin-6-treated CLP mice was significantly decreased compared with the control groups treated with PBS only or Pal-scram #1 (Fig5J). Reduction in pro-inflammatory cytokine levels in peripheral blood and peritoneal fluid explains the protective effect of Smaducin-6 on sepsis. Treatment with Smaducin-6 also reduced the level of CXCL2 chemokine, one of the hallmarks of sepsis (Supplementary Fig S11J).

Bottom Line: Here, we developed Smaducin-6, a novel membrane-tethered palmitic acid-conjugated Smad6-derived peptide composed of amino acids 422-441 of Smad6.Smaducin-6 interacted with Pellino-1, located in the inner membrane, thereby disrupting the formation of IRAK1-, RIP1-, IKKε-mediated TLR4 signaling complexes.Our findings provide clues to develop new peptide-based drugs to target Pellino-1 protein in TLR4 signaling pathway for the treatment of sepsis.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Korea.

No MeSH data available.


Related in: MedlinePlus