title: Smad7 Knockdown Restores Aryl Hydrocarbon Receptor-mediated Protective Signals in the Gut.
abstract: OBJECTIVE
  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.
authors.affiliation: Dipartimento di Medicina dei Sistemi, ivan.monteleone@uniroma2.it.
authors.forename: Ivan
authors.initials: I
authors.lastname: Monteleone
authors.affiliation: Dipartimento di Medicina dei Sistemi.
authors.forename: Irene
authors.initials: I
authors.lastname: Marafini
authors.affiliation: Dipartimento di Medicina dei Sistemi.
authors.forename: Francesca
authors.initials: F
authors.lastname: Zorzi
authors.affiliation: Dipartimento di Medicina dei Sistemi.
authors.forename: Davide
authors.initials: D
authors.lastname: Di Fusco
authors.affiliation: Dipartimento di Medicina dei Sistemi.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dinallo
authors.affiliation: Dipartimento di Medicina dei Sistemi.
authors.forename: Angela
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Dipartimento di Chirurgia, Cattedra di Gastroenterologia, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Pierpaolo
authors.initials: P
authors.lastname: Sileri
authors.affiliation: Dipartimento di Chirurgia, Cattedra di Gastroenterologia, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Sica
authors.affiliation: Dipartimento di Medicina dei Sistemi.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monteleone
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000276:immunology / Q000378:metabolism*; D002227:Carbazoles / Q000378:metabolism / Q000627:therapeutic use; D016022:Case-Control Studies; D003092:Colitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D003424:Crohn Disease / Q000276:immunology* / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D007082:Ileum / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018336:Receptors, Aryl Hydrocarbon / Q000276:immunology / Q000378:metabolism*; D051906:Smad7 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002227:Carbazoles; D007378:Interleukins; D018336:Receptors, Aryl Hydrocarbon; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D000097043:Interleukin-22; C111855:6-formylindolo(3,2-b)carbazole; C111235:AHR protein, human; C484722:Ahr protein, mouse; C497806:SMAD7 protein, human; C497807:Smad7 protein, mouse
keywords: Crohn’s disease; Ficz; TGF-β; colitis; inflammation; intestine