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Dipotassium Glycyrrhizate Inhibits HMGB1-Dependent Inflammation and Ameliorates Colitis in Mice.

Vitali R, Palone F, Cucchiara S, Negroni A, Cavone L, Costanzo M, Aloi M, Dilillo A, Stronati L - PLoS ONE (2013)

Bottom Line: DPG significantly reduces in vitro the release of HMGB1 in the extracellular matrix as well as expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, by inhibiting HMGB1.Murine colonic samples show decreased mRNA levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, RAGE and TLR4.DPG exerts inhibitory effects against HMGB1 activity, significantly reducing intestinal inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiobiology and Human Health, ENEA, Rome, Italy.

ABSTRACT

Background: High mobility group box-1 (HMGB1) is a DNA-binding protein that is released from injured cells during inflammation. Advances in targeting HMGB1 represent a major challenge to improve the treatment of acute/chronic inflammation.

Aim: This study is aimed at verifying whether the inhibition of HMGB1 through dipotassium glycyrrhizate (DPG) is a good strategy to reduce intestinal inflammation.

Methods: Human colon adenocarcinoma cell line, HT29, human epithelial colorectal adenocarcinoma, Caco2, and murine macrophage cell line, RAW 264.7, were cultured to investigate the effect of DPG on the secretion of HMGB1. Acute colitis was induced in C57BL/6 mice through administration of 3% dextran sodium sulphate (DSS); a combined treatment with DSS and 3 or 8 mg/kg/day DPG was used to investigate the effects of DPG on intestinal inflammation. Animals were euthanized at seventh day and colonic samples underwent molecular and histological analyses.

Results: DPG significantly reduces in vitro the release of HMGB1 in the extracellular matrix as well as expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, by inhibiting HMGB1. Moreover, DPG significantly decreases the severity of DSS-induced colitis in mice. Murine colonic samples show decreased mRNA levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, RAGE and TLR4. Finally, HMGB1, abundantly present in the feces of mice with DSS-induced colitis, is strongly reduced by DPG.

Conclusions: HMGB1 is an early pro-inflammatory cytokine and an active protagonist of mucosal gut inflammation. DPG exerts inhibitory effects against HMGB1 activity, significantly reducing intestinal inflammation. Thus, we reason that DPG could represent an innovative tool for the management of human intestinal inflammation.

No MeSH data available.


Related in: MedlinePlus

DPG reduces mRNA expression of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, TLR4 and RAGE, in inflamed tissues of DSS-treated mice.Quantitative real-time PCR. Data represent the target gene expression normalized to the reference gene. Values are mean ± sd of three independent experiments. UN, untreated animals; DSS, dextran sulfate sodium; DPG, dipotassium glycyrrhizate. **p<0.001.
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pone-0066527-g005: DPG reduces mRNA expression of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, TLR4 and RAGE, in inflamed tissues of DSS-treated mice.Quantitative real-time PCR. Data represent the target gene expression normalized to the reference gene. Values are mean ± sd of three independent experiments. UN, untreated animals; DSS, dextran sulfate sodium; DPG, dipotassium glycyrrhizate. **p<0.001.

Mentions: Tissue samples taken from the large colon of mice with DSS-induced colitis and mice treated with DSS and DPG were analysed to assess the expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, and confirm previous in vitro results about the ability of DPG to break down the inflammatory response. Results showed a dramatic decrease of all cytokine mRNA levels in mice treated with DPG as compared to DSS-treated mice (p<0.001) (Fig. 5). Besides, as it has been suggested that HMGB1 itself can signal through several inflammatory receptors, principally RAGE (Receptor for Advanced Glycation End products) and TLR4 (Toll-Like Receptor 4), transcripts for these receptors were also analysed. Results showed a significant decrease of RAGE and TLR4 mRNA levels in mice treated with DPG as compared to DSS-treated mice (p<0.001) (Fig. 5).


Dipotassium Glycyrrhizate Inhibits HMGB1-Dependent Inflammation and Ameliorates Colitis in Mice.

Vitali R, Palone F, Cucchiara S, Negroni A, Cavone L, Costanzo M, Aloi M, Dilillo A, Stronati L - PLoS ONE (2013)

DPG reduces mRNA expression of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, TLR4 and RAGE, in inflamed tissues of DSS-treated mice.Quantitative real-time PCR. Data represent the target gene expression normalized to the reference gene. Values are mean ± sd of three independent experiments. UN, untreated animals; DSS, dextran sulfate sodium; DPG, dipotassium glycyrrhizate. **p<0.001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3686690&req=5

pone-0066527-g005: DPG reduces mRNA expression of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, TLR4 and RAGE, in inflamed tissues of DSS-treated mice.Quantitative real-time PCR. Data represent the target gene expression normalized to the reference gene. Values are mean ± sd of three independent experiments. UN, untreated animals; DSS, dextran sulfate sodium; DPG, dipotassium glycyrrhizate. **p<0.001.
Mentions: Tissue samples taken from the large colon of mice with DSS-induced colitis and mice treated with DSS and DPG were analysed to assess the expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, and confirm previous in vitro results about the ability of DPG to break down the inflammatory response. Results showed a dramatic decrease of all cytokine mRNA levels in mice treated with DPG as compared to DSS-treated mice (p<0.001) (Fig. 5). Besides, as it has been suggested that HMGB1 itself can signal through several inflammatory receptors, principally RAGE (Receptor for Advanced Glycation End products) and TLR4 (Toll-Like Receptor 4), transcripts for these receptors were also analysed. Results showed a significant decrease of RAGE and TLR4 mRNA levels in mice treated with DPG as compared to DSS-treated mice (p<0.001) (Fig. 5).

Bottom Line: DPG significantly reduces in vitro the release of HMGB1 in the extracellular matrix as well as expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, by inhibiting HMGB1.Murine colonic samples show decreased mRNA levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, RAGE and TLR4.DPG exerts inhibitory effects against HMGB1 activity, significantly reducing intestinal inflammation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiobiology and Human Health, ENEA, Rome, Italy.

ABSTRACT

Background: High mobility group box-1 (HMGB1) is a DNA-binding protein that is released from injured cells during inflammation. Advances in targeting HMGB1 represent a major challenge to improve the treatment of acute/chronic inflammation.

Aim: This study is aimed at verifying whether the inhibition of HMGB1 through dipotassium glycyrrhizate (DPG) is a good strategy to reduce intestinal inflammation.

Methods: Human colon adenocarcinoma cell line, HT29, human epithelial colorectal adenocarcinoma, Caco2, and murine macrophage cell line, RAW 264.7, were cultured to investigate the effect of DPG on the secretion of HMGB1. Acute colitis was induced in C57BL/6 mice through administration of 3% dextran sodium sulphate (DSS); a combined treatment with DSS and 3 or 8 mg/kg/day DPG was used to investigate the effects of DPG on intestinal inflammation. Animals were euthanized at seventh day and colonic samples underwent molecular and histological analyses.

Results: DPG significantly reduces in vitro the release of HMGB1 in the extracellular matrix as well as expression levels of pro-inflammatory cytokines, TNF-alpha, IL-1beta and IL-6, by inhibiting HMGB1. Moreover, DPG significantly decreases the severity of DSS-induced colitis in mice. Murine colonic samples show decreased mRNA levels of pro-inflammatory cytokines TNF-alpha, IL-1beta and IL-6, as well as HMGB1 receptors, RAGE and TLR4. Finally, HMGB1, abundantly present in the feces of mice with DSS-induced colitis, is strongly reduced by DPG.

Conclusions: HMGB1 is an early pro-inflammatory cytokine and an active protagonist of mucosal gut inflammation. DPG exerts inhibitory effects against HMGB1 activity, significantly reducing intestinal inflammation. Thus, we reason that DPG could represent an innovative tool for the management of human intestinal inflammation.

No MeSH data available.


Related in: MedlinePlus