skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone

Abstract

Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b{sup +} macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 asmore » well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation. - Highlights: • Fraxinellone, a lactone compound, alleviated DSS induced colitis. • The effects of fraxinellone were attributed to its inhibition on infiltrated macrophages. • It regulated cytokine profiles in mice with experimental colitis. • It suppressed NF-κB signaling and NLRP3 inflammasome activation in macrophages.« less

Authors:
; ; ; ; ; ; ; ;
Publication Date:
OSTI Identifier:
22439918
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 281; Journal Issue: 1; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ALKALINE PHOSPHATASE; CONCENTRATION RATIO; DEXTRAN; DIARRHEA; DISEASES; ETIOLOGY; GLUTATHIONE; IN VITRO; INFLAMMATION; LARGE INTESTINE; MACROPHAGES; MESSENGER-RNA; MICE; NITRIC OXIDE

Citation Formats

Wu, Xue-Feng, Ouyang, Zi-Jun, Feng, Li-Li, Chen, Gong, Guo, Wen-Jie, Shen, Yan, Wu, Xu-Dong, Sun, Yang, and Xu, Qiang. Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone. United States: N. p., 2014. Web. doi:10.1016/J.TAAP.2014.10.002.
Wu, Xue-Feng, Ouyang, Zi-Jun, Feng, Li-Li, Chen, Gong, Guo, Wen-Jie, Shen, Yan, Wu, Xu-Dong, Sun, Yang, & Xu, Qiang. Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone. United States. https://doi.org/10.1016/J.TAAP.2014.10.002
Wu, Xue-Feng, Ouyang, Zi-Jun, Feng, Li-Li, Chen, Gong, Guo, Wen-Jie, Shen, Yan, Wu, Xu-Dong, Sun, Yang, and Xu, Qiang. 2014. "Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone". United States. https://doi.org/10.1016/J.TAAP.2014.10.002.
@article{osti_22439918,
title = {Suppression of NF-κB signaling and NLRP3 inflammasome activation in macrophages is responsible for the amelioration of experimental murine colitis by the natural compound fraxinellone},
author = {Wu, Xue-Feng and Ouyang, Zi-Jun and Feng, Li-Li and Chen, Gong and Guo, Wen-Jie and Shen, Yan and Wu, Xu-Dong and Sun, Yang and Xu, Qiang},
abstractNote = {Inflammatory bowel disease (IBD) affects millions of people worldwide. Although the etiology of this disease is uncertain, accumulating evidence indicates a key role for the activated mucosal immune system. In the present study, we examined the effects of the natural compound fraxinellone on dextran sulfate sodium (DSS)-induced colitis in mice, an animal model that mimics IBD. Treatment with fraxinellone significantly reduced weight loss and diarrhea in mice and alleviated the macroscopic and microscopic signs of the disease. In addition, the activities of myeloperoxidase and alkaline phosphatase were markedly suppressed, while the levels of glutathione were increased in colitis tissues following fraxinellone treatment. This compound also decreased the colonic levels of interleukin (IL)-1β, IL-6, IL-18 and tumor necrosis factor (TNF)-α in a concentration-dependent manner. These effects of fraxinellone in mice with experimental colitis were attributed to its inhibition of CD11b{sup +} macrophage infiltration. The mRNA levels of macrophage-related molecules in the colon, including intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX2), were also markedly inhibited following fraxinellone treatment. The results from in vitro assays showed that fraxinellone significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide (NO), IL-1β and IL-18 as well as the activity of iNOS in both THP-1 cells and mouse primary peritoneal macrophages. The mechanisms responsible for these effects were attributed to the inhibitory role of fraxinellone in NF-κB signaling and NLRP3 inflammasome activation. Overall, our results support fraxinellone as a novel drug candidate in the treatment of colonic inflammation. - Highlights: • Fraxinellone, a lactone compound, alleviated DSS induced colitis. • The effects of fraxinellone were attributed to its inhibition on infiltrated macrophages. • It regulated cytokine profiles in mice with experimental colitis. • It suppressed NF-κB signaling and NLRP3 inflammasome activation in macrophages.},
doi = {10.1016/J.TAAP.2014.10.002},
url = {https://www.osti.gov/biblio/22439918}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 281,
place = {United States},
year = {Sat Nov 15 00:00:00 EST 2014},
month = {Sat Nov 15 00:00:00 EST 2014}
}