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Inflammatory activation of surface molecule shedding by upregulation of the pseudoprotease iRhom2 in colon epithelial cells.
Giese, Anja Adelina; Babendreyer, Aaron; Krappen, Peter; Gross, Annika; Strnad, Pavel; Düsterhöft, Stefan; Ludwig, Andreas.
Afiliación
  • Giese AA; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
  • Babendreyer A; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
  • Krappen P; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
  • Gross A; Division of Gastroenterology and Hepatology, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
  • Strnad P; Division of Gastroenterology and Hepatology, Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
  • Düsterhöft S; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.
  • Ludwig A; Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany. aludwig@ukaachen.de.
Sci Rep ; 11(1): 24230, 2021 12 20.
Article en En | MEDLINE | ID: mdl-34930929
The metalloproteinase ADAM17 contributes to inflammatory and proliferative responses by shedding of cell-surface molecules. By this ADAM17 is implicated in inflammation, regeneration, and permeability regulation of epithelial cells in the colon. ADAM17 maturation and surface expression requires the adapter proteins iRhom1 or iRhom2. Here we report that expression of iRhom2 but not iRhom1 is upregulated in intestinal tissue of mice with acute colitis. Our analysis of public databases indicates elevated iRhom2 expression in mucosal tissue and epithelial cells from patients with inflammatory bowel disease (IBD). Consistently, expression of iRhom2 but not iRhom1 is upregulated in colon or intestinal epithelial cell lines after co-stimulation with tumor necrosis factor (TNF) and interferon gamma (IFNgamma). This upregulation can be reduced by inhibition of Janus kinases or transcription factors NF-kappaB or AP-1. Upregulation of iRhom2 can be mimicked by iRhom2 overexpression and is associated with enhanced maturation and surface expression of ADAM17 which then results in increased cleavage of transforming growth factor (TGF) alpha and junctional adhesion molecule (JAM)-A. Finally, the induction of these responses is suppressed by inhibition of iRhom2 transcription. Thus, inflammatory induction of iRhom2 may contribute to upregulated ADAM17-dependent mediator and adhesion molecule release in IBD. The development of iRhom2-dependent inhibitors may allow selective targeting of inflammatory ADAM17 activities.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Colon / Péptidos y Proteínas de Señalización Intracelular / Células Epiteliales Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Colon / Péptidos y Proteínas de Señalización Intracelular / Células Epiteliales Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Sci Rep Año: 2021 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido