DOP089 PTPN2 controls intestinal inflammation and promotes colitis-associated tumour formation via control of inflammasome activation and IL-1alpha release
Spalinger M.*1, Hering L.1, Manzini R.1, Riggs J.B.1, Gottier C.1, Atrott K.1, Fettelschoss A.2, Kündig T.2, Fried M.1,3, Rogler G.1,3, Scharl M.1,3
1University Hospital Zurich, Division of Gastroenterology and Hepatology, Zürich, Switzerland 2University Hospital Zürich, Clinic for Dermatology, Zürich, Switzerland 3University of Zurich, Zurich Center for Integrative Human Physiology, Zürich, Switzerland
Variants in the gene locus encoding protein tyrosine phosphatase non-receptor type 2 (PTPN2) are associated with Crohn's disease (CD) and ulcerative colitis (UC). We recently found that deletion of PTPN2 in macrophages promotes colitis severity, while protecting from colitis-associated tumours, but the molecular mechanisms underlying this phenotype are still elusive. IL-1α and IL-1β exert important, yet distinct, immune-modulatory function in the intestine, but their precise role during intestinal pathologies is still controversial. Here, we investigated whether IL-1α and/or IL-1β are involved in enhanced colitis and/or reduced tumour development observed in mice lacking PTPN2 in macrophages (PTPN2-LysMCre mice).
Colitis was induced in 10–12 week old PTPN2-LysMCre mice and their wild-type (WT) littermates by administration of 2% dextran-sodium sulfate (DSS) for 7 days (acute colitis), or by repeated treatment with 1.5% DSS for 7 days, followed by 10 days normal drinking water (four cycles in total, chronic colitis). For tumour induction, mice were injected with azoxymethan (AOM) at day one of each DSS cycle during chronic colitis induction. IL-1β and IL-1α were inhibited using a vaccine-based approach.
PTPN2 is a crucial regulator of inflammasome activation, and its loss in macrophages has important consequences for intestinal homeostasis. Further, our results demonstrate that the structurally related molecules IL-1α and IL-1β exert distinct roles during intestinal inflammation and tumorigenesis, and PTPN2 modulates secretion and surface expression of these two cytokines.