title: Colchicine prevents NSAID-induced small intestinal injury by inhibiting activation of the NLRP3 inflammasome.
abstract: 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.
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Koji
authors: K
authors: Otani
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Toshio
authors: T
authors: Watanabe
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Sunao
authors: S
authors: Shimada
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Shogo
authors: S
authors: Takeda
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Shigehiro
authors: S
authors: Itani
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Akira
authors: A
authors: Higashimori
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Yuji
authors: Y
authors: Nadatani
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Yasuaki
authors: Y
authors: Nagami
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Fumio
authors: F
authors: Tanaka
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Noriko
authors: N
authors: Kamata
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Hirokazu
authors: H
authors: Yamagami
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Tetsuya
authors: T
authors: Tanigawa
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Masatsugu
authors: M
authors: Shiba
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Kazunari
authors: K
authors: Tominaga
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Yasuhiro
authors: Y
authors: Fujiwara
authors: Department of Gastroenterology, Osaka City University Graduate School of Medicine 1-4-3 Asahimachi, Abeno-ku, Osaka, Japan.
authors: Tetsuo
authors: T
authors: Arakawa
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D020170:Caspase 1 / Q000378:metabolism; D003078:Colchicine / Q000494:pharmacology*; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000201:enzymology / Q000293:injuries* / Q000473:pathology; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020170:Caspase 1; D003078:Colchicine; D007213:Indomethacin