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.
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.
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Xiaowan
X
Du
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Wei
W
Chen
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Yufeng
Y
Wang
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Chen
C
Chen
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Lei
L
Guo
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Rui
R
Ju
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Juan
J
Li
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China.
Dechang
D
Zhang
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China. Electronic address: leizhu2004@126.com.
Lei
L
Zhu
Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China. Electronic address: caiyingye@126.com.
Caiying
C
Ye
D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D007422:Intestines / Q000187:drug effects* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000627:therapeutic use*; D014302:Trinitrobenzenesulfonic Acid
D016207:Cytokines; D058847:Inflammasomes; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D014230:Triazoles; C062058:carboxyamido-triazole; D014302:Trinitrobenzenesulfonic Acid
Carboxyamidotriazole; Inflammatory bowel disease; NF-κB; NLRP3 inflammasome; TNBS rat colitis