Paeoniflorin abrogates DSS-induced colitis via a TLR4-dependent pathway.
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.
1200 Cailun Rd., Rm. 5301, Shanghai Univ. of TCM, Shanghai 201203, China. vivi.dou@yahoo.com.
Jingjing
J
Zhang
Wei
W
Dou
Eryun
E
Zhang
Aning
A
Sun
Lili
L
Ding
Xiaohui
X
Wei
Guixin
G
Chou
Sridhar
S
Mani
Zhengtao
Z
Wang
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001565:Benzoates / Q000627:therapeutic use*; D001682:Biological Availability; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D016264:Dextran Sulfate / Q000494:pharmacology; D004365:Drugs, Chinese Herbal; D020869:Gene Expression Profiling; D005960:Glucosides / Q000627:therapeutic use*; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D023421:Models, Animal; D039821:Monoterpenes; D016328:NF-kappa B / Q000378:metabolism; D029596:Paeonia; D009195:Peroxidase / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D006027:Glycosides
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D001952:Bridged-Ring Compounds; D016264:Dextran Sulfate; D004365:Drugs, Chinese Herbal; D005960:Glucosides; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D039821:Monoterpenes; D016328:NF-kappa B; D009195:Peroxidase; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C495345:TLR4 protein, human; C015423:peoniflorin; D006027:Glycosides
DSS-induced colitis; MAPK; NF-κB; TLR4; paeoniflorin