Beauvericin ameliorates experimental colitis by inhibiting activated T cells via downregulation of the PI3K/Akt signaling pathway.

Abstract

Crohn's disease is a common, chronic inflammatory bowel condition characterized by remission and relapse. Accumulating evidence indicates that activated T cells play an important role in this disease. In the present study, we aimed to examine the effect of beauvericin, a natural cyclic peptide, on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice, which mimics Crohn's disease. Beauvericin significantly reduced weight loss, diarrhea and mortality, accompanied with notable alleviation of macroscopic and microscopic signs. In addition, this compound decreased serum levels of tumor necrosis factor (TNF)-α and interferon (IFN)-γ in a concentration-dependent manner in mice with experimental colitis. These effects of beauvericin are attributed to its inhibition on activated T cells. Flow cytometry and immunoblot assay data showed that beauvericin suppressed T-cell proliferation, activation and IFN-γ-STAT1-T-bet signaling and subsequently led to apoptosis of activated T cells by suppressing Bcl-2 and phosphorylated Bad as well as increasing cleavage of caspase-3, -9, -12 and PARP. Furthermore, inhibition of PI3K/Akt signaling, which was an upstream regulator of cell activation and survival in activated T cells, contributed to the effect of beauvericin. Overall, these results supported beauvericin as a novel drug candidate for the treatment of colonic inflammation mainly by targeting PI3K/Akt in activated T cells.

• Authors: Xue-Feng Wu, Rui Xu, Zi-Jun Ouyang, Cheng Qian, Yan Shen, Xu-Dong Wu, Yan-Hong Gu, Qiang Xu, Yang Sun
• Journal: PloS one (PLoS One) Vol. 8 Issue 12 Pg. e83013 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24340073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Depsipeptides
• Tumor Necrosis Factor-alpha
• beauvericin
• Interferon-gamma
• Trinitrobenzenesulfonic Acid
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Apoptosis
• Cell Proliferation (drug effects)
• Colitis (chemically induced, drug therapy)
• Depsipeptides (therapeutic use)
• Disease Models, Animal
• Down-Regulation
• Female
• Flow Cytometry
• Gene Expression Regulation, Enzymologic
• Inflammation
• Interferon-gamma (metabolism)
• Lymphocyte Activation (drug effects)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Inbred BALB C
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• T-Lymphocytes (drug effects)
• Trinitrobenzenesulfonic Acid (chemistry)
• Tumor Necrosis Factor-alpha (metabolism)