Open AccessColchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome
Author(s) -
Koji Otani,
Toshio Watanabe,
Sunao Shimada,
Shogo Takeda,
Shigehiro Itani,
Akira Higashimori,
Yuji Nadatani,
Yasuaki Nagami,
Fumio Tanaka,
Noriko Kamata,
Hirokazu Yamagami,
Tetsuya Tanigawa,
Masatsugu Shiba,
Kazunari Tominaga,
Yasuhiro Fujiwara,
Tetsuo Arakawa
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep32587
Subject(s) - inflammasome , colchicine , pyrin domain , caspase 1 , pharmacology , chemistry , apoptosis , receptor , recombinant dna , medicine , biochemistry , gene
The inflammasome is a large, multiprotein complex that consists of a nucleotide-binding oligomerization domain-like receptor (NLR), an apoptosis-associated speck-like protein containing a caspase recruitment domain, and pro-caspase-1. Activation of the inflammasome results in cleavage of pro-caspase-1 into cleaved caspase-1, which promotes the processing of pro-interleukin (IL)-1β into mature IL-1β. We investigated the effects of colchicine on non-steroidal anti-inflammatory drug (NSAID)-induced small intestinal injury and activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. Colchicine treatment inhibited indomethacin-induced small intestinal injury by 86% (1 mg/kg) and 94% (3 mg/kg) as indicated by the lesion index 24 h after indomethacin administration. Colchicine inhibited the protein expression of cleaved caspase-1 and mature IL-1β, without affecting the mRNA expression of NLRP3 and IL-1β. Although treatment with recombinant IL-1β (0.1 μg/kg) did not change the severity of small intestinal damage, the preventive effects of colchicine were abolished by supplementation with the same dose of recombinant IL-1β. Indomethacin-induced small intestinal damage was reduced by 77%, as determined by the lesion index in NLRP3 −/− mice, and colchicine treatment failed to inhibit small intestinal damage in NLRP3 −/− mice. These results demonstrate that colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome.