Abstract
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.
Highlights
The metalloproteinase ADAM17 contributes to inflammatory and proliferative responses by shedding of cell-surface molecules
In the endoplasmic reticulum (ER) immature ADAM17 interacts with iRhom[1] or 2 which are inactive members of the rhomboid family 25–28. This interaction is required for ADAM17 trafficking to the Golgi apparatus where the prodomain of the protease is proteolytically removed, before the mature protease is transported to the cell c urface[23]
We describe cytokine driven transcriptional pathways that lead to upregulation of iRhom[2] but not iRhom[1] in vitro, and we demonstrate the consequences of this upregulation for ADAM17 maturation, surface expression and shedding of epithelial surface molecules
Summary
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. Upregulation of iRhom[2] can be mimicked by iRhom[2] overexpression and is associated with enhanced maturation and surface expression of ADAM17 which results in increased cleavage of transforming growth factor (TGF) alpha and junctional adhesion molecule (JAM)-A. Key substrates for ADAM17 include the tumor necrosis factor (TNF) α11–13, the transforming growth factor (TGF) α14 and the junctional adhesion molecule (JAM)-A8 These mediators are critically implicated in inflammatory and repair functions in vivo. By contrast iRhom[1] has been linked to critical homeostatic functions[26,38,39,40]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call