A murine model of chronic inflammation-induced intestinal fibrosis down-regulated by antisense NF-κB

Lawrance, Ian C.; Wu, Feng; Leite, André Z.; Willis, Joseph E.; West, Gail; Fiocchi, Claudio; Chakravarti, Shukti

doi:10.1053/j.gastro.2003.08.027

Cited by 214 publications

(226 citation statements)

References 49 publications

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“…In epithelial cells, NF-B not only contributes to the pathogenesis of IBD by altering intestinal barrier function but also activates proinflammatory signaling, potentiating the production of other proinflammatory cytokines by epithelial cells and promoting the inflammatory process. Administration of NF-B antisense oligonucleotides were reported to improve the severity of colitis in two mouse models of intestinal inflammation (Neurath et al, 1996;Lawrance et al, 2003). Although this would indicate that NF-B is involved in proinflammatory responses, data from animal models in which NF-B signaling in intestinal epithelial cells is ablated suggest that complete absence of NF-B has deleterious effects.…”

Section: Discussionmentioning

confidence: 99%

Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin α3 Expression

Theiss

Jenkins

Okoro

et al. 2009

MBoC

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Section: Discussionmentioning

confidence: 99%

Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin α3 Expression

Theiss

Jenkins

Okoro

et al. 2009

MBoC

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“…The efficacy of INT-747 was tested in acute and chronic models of colon inflammation induced by trinitrobenzenesulfonic acid (TNBS) or dextran sulfate (DSS) (24,25). Lamina propria-derived CD11b ϩ cells were prepared as described previously using a MACS selection system and CD11b microbeads (Miltenyi Biotec) following the manufacturer's instructions.…”

Section: Colitis Induction Study Design and Isolation And Stimulatimentioning

confidence: 99%

“…The induction of chronic colitis was performed according the protocol proposed by Lawrance et al (25). 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.…”

Section: Colitis Induction Study Design and Isolation And Stimulatimentioning

confidence: 99%

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The Bile Acid Receptor FXR Is a Modulator of Intestinal Innate Immunity

Vavassori

Mencarelli²,

Renga³

et al. 2009

The Journal of Immunology

526

442

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The farnesoid X receptor (FXR) is a bile acid-regulated nuclear receptor expressed in enterohepatic tissues. In this study we investigated whether FXR is expressed by cells of innate immunity and regulates inflammation in animal models of colitis. 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. The results of this experiment demonstrate that FXR is expressed by and exerts counterregulatory effects on cells of innate immunity. 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. FXR activation stabilizes the nuclear corepressor NCoR on the NF-κB responsive element on the IL-1β promoter. Colon inflammation in Crohn’s disease patients and in rodent models of colitis is associated with a reduced expression of FXR mRNA. Using two rodent models of colon inflammation, we show that progression of these immune-mediated disorders is exacerbated in FXR−/− mice (p < 0.01). In vivo treatment with INT-747 attenuates organ injury and immune cell activation. 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 aggregate, these findings provide evidence that FXR is an essential component of a network of nuclear receptors that regulate intestinal innate immunity and homeostasis.

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“…Inhibition of IKK␤ suppresses the production and secretion of the prototypic proinflammatory cytokine TNF-␣ and attenuates disease in animal models of rheumatoid arthritis, inflammationinduced bone loss, and allergen-induced airway disease (6)(7)(8)(9). Furthermore, inhibition of NF-B by either antisense oligonucleotides directed against RelA/p65 or a small-molecule inhibitor of IKK␤ appeared to ameliorate disease in mouse models of intestinal inflammation (10)(11)(12), suggesting that NF-B-directed therapy could be a valuable novel strategy in IBD therapy. In sharp contrast, however, conditional ablation of IKK␤ in intestinal epithelial cells (IECs) caused increased inflammation in an acute, chemically induced colitis model (13) and loss of IKK␥ in IECs caused spontaneous colitis (14).…”

mentioning

confidence: 99%