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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: 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.
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Does smad7 Knockdown restore Aryl Hydrocarbon Receptor-mediated Protective Signals in the Gut? Context: 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. 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. 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.
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The inverse correlation between Smad7 and AhR expression helps to propagate inflammatory signals in the gut. Final Decision: yes