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NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis.

ABSTRACT: The inflammasomes induce maturation of pro-interleukin-1? (IL-1?) and pro-IL-18. We investigated roles of the NLRP3 inflammasome in the pathogenesis of ulcerative colitis (UC). After induction of oxazolone-induced colitis, a mouse UC model, colonic tissues were assayed for inflammatory mediators. Histological studies were performed on inflamed colonic tissue from mice and UC patients. Histological severity of murine colitis peaked on day 1, accompanied by an increase in the expression of Th2 cytokines including IL-4 and IL-13. Oxazolone treatment stimulated maturation of pro-caspase-1 and pro-IL-1?, while it reduced IL-18 expression. Either exogenous IL-1? or IL-18 ameliorated the colitis with or without reduction in Th2 cytokine expression, respectively. Induction of colitis decreased MUC2 expression, which was reversed by administration of IL-18, but not IL-1?. Compared to wild-type mice, NLRP3^-/- mice exhibited higher sensitivity to oxazolone treatment with enhancement of Th2 cytokine expression and reduction of mature IL-1? and IL-18 production; this phenotype was rescued by exogenous IL-1? or IL-18. Immunofluorescent studies revealed positive correlation of NLRP3 expression with disease severity in UC patients, and localization of the inflammasome-associated molecules in macrophages. The NLRP3 inflammasome-derived IL-1? and IL-18 may play a protective role against UC through different mechanisms.

SUBMITTER: Itani S

PROVIDER: S-EPMC5155456 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis.

Itani Shigehiro S Watanabe Toshio T Nadatani Yuji Y Sugimura Naoki N Shimada Sunao S Takeda Shogo S Otani Koji K Hosomi Shuhei S Nagami Yasuaki Y Tanaka Fumio F Kamata Noriko N Yamagami Hirokazu H Tanigawa Tetsuya T Shiba Masatsugu M Tominaga Kazunari K Fujiwara Yasuhiro Y Arakawa Tetsuo T

Scientific reports 20161214

The inflammasomes induce maturation of pro-interleukin-1β (IL-1β) and pro-IL-18. We investigated roles of the NLRP3 inflammasome in the pathogenesis of ulcerative colitis (UC). After induction of oxazolone-induced colitis, a mouse UC model, colonic tissues were assayed for inflammatory mediators. Histological studies were performed on inflamed colonic tissue from mice and UC patients. Histological severity of murine colitis peaked on day 1, accompanied by an increase in the expression of Th2 cyt ...[more]

PMID: 27966619

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Project description:BackgroundUlcerative colitis is a gut inflammatory disorder due to altered immune response to gut microbiome, with interplay of environmental and genetic factors. TNF-? activates inflammatory response through a cascade of immune responses, augmenting pro-inflammatory mediators and proteases, activating chemotaxis, and infiltration of inflammatory cells, leading to ulceration and haemorrhage through cytotoxic reactive oxygen species. 6-Paradol, a dietary component in several plants belonging to the Zingiberaceae family, has shown anti-inflammatory and antioxidant activities. Current study evaluates the effect of 6-paradol in amelioration of ulcerative colitis in rats for the first time.Methods6-Paradol (95% purity) was obtained from seeds of Aframomum melegueta. Rats were divided randomly into six groups (n?=?8). Group one was administered normal saline; group two was treated with the vehicle only; group three, sulfasalazine 500?mg/kg; and groups four, five, and six, were given 6-paradol (50, 100, 200, respectively) mg/kg orally through gastric gavage for 7?days. Colitis was induced on 4th day by intrarectal administration of 2?ml acetic acid (3%), approximately 3?cm from anal verge. On 8th day, rats were sacrificed, and distal one-third of the colon extending proximally up to 4?cm from anal orifice was taken for biochemical and gross examination. Two centimetres of injured mucosal portion was taken for histopathological investigations. SPSS (ver.26) was used for statistical analysis.ResultsColonic and serum glutathione (GSH) levels decreased, while colonic and serum malondialdehyde (MDA), colonic myeloperoxidase (MPO) activity, serum interleukin-6 (IL-6), serum tumour necrosis factor-? (TNF-?) levels, and colon weight to length ratio were increased significantly in the colitis untreated group compared to normal control. Treatment with 6-paradol considerably improved all these parameters, especially at a dose of 200?mg/kg (p?<?0.001), revealing non-significant differences with sulfasalazine 500?mg/kg and normal control (p?=?0.998). Sulfasalazine and 6-paradol in a dose dependent manner also markedly reversed mucosal oedema, atrophy and inflammation, cryptic damage, haemorrhage, and ulceration. There were non-significant differences between low and medium doses and between medium and high doses of 6-paradol for IL-6 and serum MDA levels.Conclusion6-Paradol demonstrated protection against acetic acid-induced ulcerative colitis, probably by anti-inflammatory and antioxidant actions.

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NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis.

Publications

NLRP3 inflammasome has a protective effect against oxazolone-induced colitis: a possible role in ulcerative colitis.

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