| First Author | Monteleone I | Year | 2016 |
| Journal | J Crohns Colitis | Volume | 10 |
| Issue | 6 | Pages | 670-7 |
| PubMed ID | 26818761 | Mgi Jnum | J:318319 |
| Mgi Id | MGI:6859195 | Doi | 10.1093/ecco-jcc/jjw030 |
| Citation | Monteleone I, et al. (2016) Smad7 Knockdown Restores Aryl Hydrocarbon Receptor-mediated Protective Signals in the Gut. J Crohns Colitis 10(6):670-7 |
| abstractText | 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-beta1] activity, and TGF-beta1 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-beta1 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-beta1. 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 naive or Smad7-overexpressing T cells. RESULTS: In normal LPMC, TGF-beta1 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-beta1 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. |
