NOD-Like Receptor Family Pyrin Domain-Containing 3 Inflammasome Activation Exacerbates 5-Fluorouracil-Induced Small Intestinal Mucositis via Interleukin-1β Activation
| Autor: | Satoshi Kosaka, Tetsuya Tanigawa, Koji Otani, Shuhei Hosomi, Noriko Kamata, Koichi Taira, Yuji Nadatani, Yuji Matsumoto, Toshio Watanabe, Yasuaki Nagami, Akinobu Nakata, Akira Higashimori, Yasuhiro Fujiwara, Fumio Tanaka |
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| Rok vydání: | 2019 |
| Předmět: |
Mucositis
Inflammasomes medicine.medical_treatment Interleukin-1beta Intraperitoneal injection NLR Proteins Pharmacology Pyrin domain Mice 03 medical and health sciences 0302 clinical medicine NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Lamina propria Chemistry Caspase 1 Gastroenterology NOD-like receptor Pyrin Domain Inflammasome Small Intestinal Mucositis medicine.disease Small intestine Mice Inbred C57BL medicine.anatomical_structure 030220 oncology & carcinogenesis 030211 gastroenterology & hepatology Fluorouracil medicine.drug |
| Zdroj: | Digestion. 102:298-312 |
| ISSN: | 1421-9867 0012-2823 |
| DOI: | 10.1159/000504974 |
| Popis: | Background and Aim: 5-Fluorouracil (5-FU) is an anticancer agent that induces intestinal mucositis, which causes diarrhea and dehydration. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is responsible for inflammatory response activation via caspase-1 cleavage and subsequent interleukin-1β (IL-1β) and IL-18 activation and secretion. The objective of this study was to determine the role of the NLRP3 inflammasome in 5-FU-induced small intestinal mucositis. Methods: Small intestinal mucositis was induced in wild-type, NLRP3–/–, and caspase-1–/– mice by intraperitoneal injection of 5-FU. Some mice received intraperitoneal injection of a caspase-1 inhibitor, recombinant IL-1β or IL-18, or neutralizing antibody against IL-1β. Results: Mice treated with 5-FU developed small intestinal mucositis with diarrhea and body weight loss, characterized by a decrease in villus height and the villus height-to-crypt depth ratio. These histological changes peaked on day 3 and were accompanied by an increase in mRNA expression of NLRP3 and IL-1β and protein expression of cleaved caspase-1 and mature IL-1β. Mature IL-18 protein expression was not affected by 5-FU administration. NLRP3–/– mice exhibited less severe 5-FU-induced mucositis, and this phenotype was mimicked by genetic depletion or pharmacological inhibition of caspase-1. Small intestinal mucositis was aggravated by exogenous IL-1β and neutralized by IL-1β antibody treatment. Administration of exogenous IL-18 or anti-IL-18 antibody did not affect any parameters associated with mucositis. NLRP3, cleaved caspase-1, and IL-1β were expressed by inflammatory cells (mainly macrophages) in the lamina propria and damaged epithelial cells. Conclusions: NLRP3 inflammasome activation may exacerbate 5-FU-induced small intestinal mucositis via IL-1β maturation. |
| Databáze: | OpenAIRE |
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