Background and Aim: In Crohn's disease [CD], the pathological process is driven by an excessive immune response that is poorly counterbalanced by regulatory mechanisms. One such a mechanism involves aryl hydrocarbon receptor [AhR], a transcription factor that delivers protective signals in the gut. Expression of AhR is reduced in CD lamina propria mononuclear cells [LPMC] even though factors accounting for such a defect remain unknown. Since CD LPMC express elevated levels of Smad7, an inhibitor of transforming growth factor beta 1 [TGF-β1] activity, and TGF-β1 regulates AhR in other systems, we examined the link between AhR and Smad7 in the gut. Methods: AhR and interleukin [IL]-22 were evaluated in normal LPMC stimulated with TGF-β1 and 6-formylindolo[3,2-b]carbazole [Ficz], an activator of AhR, and in CD LPMC incubated with a Smad7 antisense oligonucleotide and then stimulated with Ficz and TGF-β1. AhR and IL-22 expression was evaluated in LPMC of Smad7-transgenic mice. Finally, we evaluated the protective effect of Ficz on colitis in RAG1 mice injected with naïve or Smad7-overexpressing T cells. Results: In normal LPMC, TGF-β1 induced AhR and this event was associated with increased production of IL-22 following stimulation with Ficz. Treatment of CD LPMC with Smad7 antisense oligonucleotide enabled TGF-β1 to enhance AhR expression. Consistently, AhR expression and Ficz-induced IL-22 production were markedly reduced in T cells of Smad7-transgenic mice. In RAG1 mice, Ficz ameliorated colitis induced by wild type T cells but did not affect colitis induced by transfer of Smad7-overexpressing T cells. Conclusions: The inverse correlation between Smad7 and AhR expression helps to propagate inflammatory signals in the gut.

Monteleone, I., Marafini, I., Zorzi, F., Di Fusco, D., Dinallo, V., Rizzo, A., et al. (2016). Smad7 knockdown restores aryl hydrocarbon receptor-mediated protective signals in the gut. JOURNAL OF CROHN'S AND COLITIS, 10(6), 670-677 [10.1093/ecco-jcc/jjw030].

Smad7 knockdown restores aryl hydrocarbon receptor-mediated protective signals in the gut

MONTELEONE, IVAN;MARAFINI, IRENE;DINALLO, VINCENZO;SILERI, PIERPAOLO;SICA, GIUSEPPE;MONTELEONE, GIOVANNI
2016

Abstract

Background and Aim: In Crohn's disease [CD], the pathological process is driven by an excessive immune response that is poorly counterbalanced by regulatory mechanisms. One such a mechanism involves aryl hydrocarbon receptor [AhR], a transcription factor that delivers protective signals in the gut. Expression of AhR is reduced in CD lamina propria mononuclear cells [LPMC] even though factors accounting for such a defect remain unknown. Since CD LPMC express elevated levels of Smad7, an inhibitor of transforming growth factor beta 1 [TGF-β1] activity, and TGF-β1 regulates AhR in other systems, we examined the link between AhR and Smad7 in the gut. Methods: AhR and interleukin [IL]-22 were evaluated in normal LPMC stimulated with TGF-β1 and 6-formylindolo[3,2-b]carbazole [Ficz], an activator of AhR, and in CD LPMC incubated with a Smad7 antisense oligonucleotide and then stimulated with Ficz and TGF-β1. AhR and IL-22 expression was evaluated in LPMC of Smad7-transgenic mice. Finally, we evaluated the protective effect of Ficz on colitis in RAG1 mice injected with naïve or Smad7-overexpressing T cells. Results: In normal LPMC, TGF-β1 induced AhR and this event was associated with increased production of IL-22 following stimulation with Ficz. Treatment of CD LPMC with Smad7 antisense oligonucleotide enabled TGF-β1 to enhance AhR expression. Consistently, AhR expression and Ficz-induced IL-22 production were markedly reduced in T cells of Smad7-transgenic mice. In RAG1 mice, Ficz ameliorated colitis induced by wild type T cells but did not affect colitis induced by transfer of Smad7-overexpressing T cells. Conclusions: The inverse correlation between Smad7 and AhR expression helps to propagate inflammatory signals in the gut.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/12 - Gastroenterologia
Settore MED/18 - Chirurgia Generale
eng
Con Impact Factor ISI
Colitis; Crohn's disease; Ficz; Inflammation; Intestine; TGF-β; Gastroenterology
Crohn’s disease; Ficz; TGF-β; colitis; inflammation; intestine; Adult; Aged; Animals; Basic Helix-Loop-Helix Transcription Factors; Carbazoles; Case-Control Studies; Colitis; Crohn Disease; Female; Gene Knockdown Techniques; Humans; Ileum; Interleukins; Intestinal Mucosa; Leukocytes, Mononuclear; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Receptors, Aryl Hydrocarbon; Smad7 Protein; T-Lymphocytes; Transforming Growth Factor beta1
http://ecco-jcc.oxfordjournals.org/
Monteleone, I., Marafini, I., Zorzi, F., Di Fusco, D., Dinallo, V., Rizzo, A., et al. (2016). Smad7 knockdown restores aryl hydrocarbon receptor-mediated protective signals in the gut. JOURNAL OF CROHN'S AND COLITIS, 10(6), 670-677 [10.1093/ecco-jcc/jjw030].
Monteleone, I; Marafini, I; Zorzi, F; Di Fusco, D; Dinallo, V; Rizzo, A; Sileri, P; Sica, G; Monteleone, G
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/171110
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