P020. Interleukin-17A but not interleukin-17E is profibrotic in the gut of patients with Crohn's disease
P. Biancheri1, A. Di Sabatino1, A. Pasini1, C. Ubezio1, L. Rovedatti1, A. Massari1, A. Quadrelli1, T.T. MacDonald2, G.R. Corazza1
1Fondazione IRCCS Policlinico S. Matteo, University of Pavia, First Department of Medicine, Italy; 2Blizard Institute, Barts And The London School Of Medicine And Dentistry, Centre for Immunology and Infectious Disease, London, United Kingdom
Background: While interleukin (IL)-17A is pro-inflammatory, IL‑17E (also known as IL‑25) has been shown to exert an anti-inflammatory action in Crohn's disease (CD). There are no studies investigating the role of IL‑17E in modulating extracellular matrix in the gut, while it is known that IL‑17A increases matrix metalloproteinase (MMP) production by intestinal myofibroblasts. Here we have studied the role of both IL‑17A and IL‑17E in CD fibrogenesis.
Methods: Colonic submucosal myofibroblasts were isolated from strictured and non-strictured areas of 10 CD patients, and from normal areas of 10 subjects undergoing colectomy for colon cancer. Submucosal tissue from the same patients was homogenised for immunoblotting analysis. The expression of IL‑17 receptor (IL‑17R), which is common to both IL‑17A and IL‑17E, was determined on tissue homogenates and myofibroblast lysates. Myofibroblasts were cultured for 24 hours with recombinant human IL‑17A and IL‑17E, then supernatants were used for detection of soluble collagen and tissue inhibitor of MMPs (TIMP‑1). Myofibroblast migration was assessed using the in vitro wound-healing scratch assay.
Results: IL‑17R was expressed on CD strictured, CD non-strictured and control tissue homogenates, with no significant differences between the three groups. A similar result was observed on myofibroblasts from the same patients. IL‑17A but not IL‑17E significantly increased collagen production and TIMP‑1 expression, mainly in the supernatants of CD strictured myofibroblasts. Migration of CD strictured, CD non-strictured and control myofibroblasts was significantly inhibited by IL‑17A but not IL‑17E, with no significant differences between the three cell populations.
Conclusions: Our results suggest that IL‑17A but not IL‑17E is profibrotic in CD. Further studies are needed to clarify the signaling pathways mediating the differential effects of these two cytokines in the gut of CD patients.