Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway

Jingjing Zhang, Wei Dou, Eryun Zhang, Aning Sun, Lili Ding, Xiaohui Wei, Guixin Chou, Sridhar Mani, Zhengtao Wang

Research output: Contribution to journalArticle

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Abstract

Paeonia lactiflora Pall is one of the most well-known herbs in China, Korea, and Japan for more than 1,200 years. Paeoniflorin, the major bioactive component of peony root, has recently been reported to have anticolitic activity. However, the underlying molecular mechanism is unclear. The present study was to explore the possible mechanism of paeoniflorin in attenuating dextran sulfate sodium (DSS)-induced colitis. Pre- and coadministration of paeoniflorin significantly reduced the severity of colitis and resulted in downregulation of several inflammatory parameters in the colon, including the activity of myeloperoxidase (MPO), the levels of TNF-α and IL-6, and the mRNA expression of proinflammatory mediators (MCP-1, Cox2, IFN-γ, TNF-α, IL-6, and IL-17). The decline in the activation of NF-κB p65, ERK, JNK, and p38 MAPK correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) but not TLR2 or TLR5 expression. In accordance with the in vivo results, paeoniflorin downregulated TLR4 expression, blocked nuclear translocation of NF-κB p65, and reduced the production of IL-6 in LPS-stimulated mouse macrophage RAW264.7 cells. Transient transfection assay performed in LPS-stimulated human colon cancer HT-29 cells indicated that paeoniflorin inhibits NF-κB transcriptional activity in a dose-dependent manner. TLR4 knockdown and overexpression experiments demonstrated a requirement for TLR4 in paeoniflorin- mediated downregulation of inflammatory cytokines. Thus, for the first time, the present study indicates that paeoniflorin abrogates DSS-induced colitis via decreasing the expression of TLR4 and suppressing the activation of NF-κB and MAPK pathways.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume306
Issue number1
DOIs
StatePublished - Jan 1 2014

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Dextran Sulfate
Toll-Like Receptor 4
Colitis
Paeonia
Interleukin-6
Down-Regulation
HT29 Cells
Interleukin-17
p38 Mitogen-Activated Protein Kinases
Korea
peoniflorin
Colonic Neoplasms
Peroxidase
Transfection
China
Japan
Colon
Macrophages
Cytokines
Messenger RNA

Keywords

  • DSS-induced colitis
  • MAPK
  • NF-κB
  • Paeoniflorin
  • TLR4

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway. / Zhang, Jingjing; Dou, Wei; Zhang, Eryun; Sun, Aning; Ding, Lili; Wei, Xiaohui; Chou, Guixin; Mani, Sridhar; Wang, Zhengtao.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 306, No. 1, 01.01.2014.

Research output: Contribution to journalArticle

Zhang, Jingjing ; Dou, Wei ; Zhang, Eryun ; Sun, Aning ; Ding, Lili ; Wei, Xiaohui ; Chou, Guixin ; Mani, Sridhar ; Wang, Zhengtao. / Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2014 ; Vol. 306, No. 1.
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AB - Paeonia lactiflora Pall is one of the most well-known herbs in China, Korea, and Japan for more than 1,200 years. Paeoniflorin, the major bioactive component of peony root, has recently been reported to have anticolitic activity. However, the underlying molecular mechanism is unclear. The present study was to explore the possible mechanism of paeoniflorin in attenuating dextran sulfate sodium (DSS)-induced colitis. Pre- and coadministration of paeoniflorin significantly reduced the severity of colitis and resulted in downregulation of several inflammatory parameters in the colon, including the activity of myeloperoxidase (MPO), the levels of TNF-α and IL-6, and the mRNA expression of proinflammatory mediators (MCP-1, Cox2, IFN-γ, TNF-α, IL-6, and IL-17). The decline in the activation of NF-κB p65, ERK, JNK, and p38 MAPK correlated with a decrease in mucosal Toll-like receptor 4 (TLR4) but not TLR2 or TLR5 expression. In accordance with the in vivo results, paeoniflorin downregulated TLR4 expression, blocked nuclear translocation of NF-κB p65, and reduced the production of IL-6 in LPS-stimulated mouse macrophage RAW264.7 cells. Transient transfection assay performed in LPS-stimulated human colon cancer HT-29 cells indicated that paeoniflorin inhibits NF-κB transcriptional activity in a dose-dependent manner. TLR4 knockdown and overexpression experiments demonstrated a requirement for TLR4 in paeoniflorin- mediated downregulation of inflammatory cytokines. Thus, for the first time, the present study indicates that paeoniflorin abrogates DSS-induced colitis via decreasing the expression of TLR4 and suppressing the activation of NF-κB and MAPK pathways.

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