Therapeutic efficacy of carboxyamidotriazole on 2,4,6-trinitrobenzene sulfonic acid-induced colitis model is associated with the inhibition of NLRP3 inflammasome and NF-κB activation.

Abstract

Excess proinflammatory cytokines owing to the activation of NF-κB and NLRP3 inflammasome play the key role in inflammatory bowel disease (IBD). Previously, we reported the anti-inflammatory activity of carboxyamidotriazole (CAI) resulting from decreasing cytokines. Therefore, we investigated the therapeutic effects of CAI in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced rat colitis and the involvement of CAI action with NLRP3 inflammasome and NF-κB pathway. CAI was orally administered to TNBS-induced colitis rat. The severity of colitis was assessed, and NLRP3 inflammasome, NF-κB pathway and cytokines were determined. Our results showed that CAI significantly reduced weight loss and disease activity index (DAI) scores in colitis rats and alleviated the colonic macroscopic signs and pathological damage. In addition, the intestinal inflammatory markers and permeability index were markedly ameliorated by CAI treatment. The decreased levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-18 were also detected in the colon tissues of CAI-treated colitis rats. Moreover, the activation of NLRP3 inflammasome in inflamed colon was significantly suppressed by showing an obvious reduction in the NLRP3 and activated caspase-1 levels. Furthermore, CAI reduced NF-κB p65 expression and IκBα phosphorylation and degradation in colitis rats. Therefore, CAI attenuates TNBS-induced colitis, which may be attributed to its inhibition of NLRP3 inflammasome and NF-κB activation, and down-regulation of proinflammatory cytokines. These results provide further understanding of the intestinal anti-inflammatory effect of CAI and highlight it as a potential drug for the treatment of IBD.

• Authors: Xiaowan Du, Wei Chen, Yufeng Wang, Chen Chen, Lei Guo, Rui Ju, Juan Li, Dechang Zhang, Lei Zhu, Caiying Ye
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 45 Pg. 16-25 (Apr 2017) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 28152446 (Publication Type: Evaluation Study, Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• Inflammasomes
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Triazoles
• carboxyamido-triazole
• Trinitrobenzenesulfonic Acid

Topics

• Animals
• Cells, Cultured
• Colitis (chemically induced, drug therapy)
• Colon (drug effects, pathology)
• Cytokines (metabolism)
• Female
• Gene Expression Regulation (drug effects)
• Humans
• Inflammasomes (metabolism)
• Inflammatory Bowel Diseases (drug therapy)
• Intestines (drug effects, pathology)
• NF-kappa B (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Triazoles (therapeutic use)
• Trinitrobenzenesulfonic Acid