The macroscopic appearance was analyzed considering the presence of induration, edema, thickness, and evidence of mucosal hemorrhage. Two days after the last TNBS administration, mice were killed and the colons were removed, examined, and divided for histology and RNA extraction.
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No differences in terms of mortality were observed among the TNBS-administered animals (≈20% of the C57BL/6 mice, irrespective of the FXR genetic background, and ≈40% of the BALB/c mice of the TNBS group as well as the TNBS plus INT-747 group). During the 8 wk of treatment, mice were examined weekly for weight loss, diarrhea, rectal bleeding and prolapse, piloerection, lethargy, and periorbital exudates. In both experiments, control mice received 30% ethanol alone ( n = 7). To test the efficacy of FXR activation to prevent the development of chronic colitis, BALB/c mice were administered TNBS ( n = 15) or TNBS plus INT-747 (5 mg/kg/day via intragastric catheter n = 15). To test the influence of FXR in the inflammatory and fibrotic response to the chronic administration of TNBS, chronic colitis was induced in C57BL/6 FXR wild-type (FXR +/+ n = 20) and FXR −/− ( n = 18). Briefly, 6- to 8-wk-old female mice were treated weekly for 8 wk with escalating doses (0.5 to 1.25 mg, with an 0.25 mg increase every 2 wk) of TNBS in 30% ethanol via an intrarectal catheter. The induction of chronic colitis was performed according the protocol proposed by Lawrance et al.
In aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis. FXR activation increased the colon expression of I-BABP, FXR, and SHP while reducing IL-1β, IL-2, IL-6, TNF-α, and IFN-γ mRNA expression and attenuating disease severity. In vivo treatment with INT-747 attenuates organ injury and immune cell activation. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR −/− mice ( p < 0.01). Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element on the IL-1β promoter. Exposure of LPS-activated macrophages to 6-ethyl chenodeoxycholic acid (6E-CDCA INT-747) a synthetic FXR ligand, results in a reciprocal regulation of NF-κB dependent-genes (TNF-α, IL-1β, IL-6, COX-1, COX-2, and iNOS) and induction of SHP, a FXR-regulated gene. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. Acute (7 days) and chronic (8 wk) colitis were induced in wild-type and FXR −/− mice by intrarectal administration of trinitrobenzensulfonic acid or by 7-day administration of 5% dextran sulfate in drinking water. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues.
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