Activity of SHIP, Which Prevents Expression of Interleukin 1 beta, Is Reduced in Patients With Crohn's Disease

作者：Ngoh Eyler N; Weisser Shelley B; Lo Young; Kozicky Lisa K; Jen Roger; Brugger Hayley K; Menzies Susan C; McLarren Keith W; Nackiewicz Dominika; van Rooijen Nico; Jacobson Kevan; Ehses Jan A; Turvey Stuart E; Sly Laura M^*

来源：Gastroenterology, 2016, 150(2): 465-476.

DOI：10.1053/j.gastro.2015.09.049

• PI3Kp110 alpha
• Signal Transduction
• Inflammatory
• Phosphatidylinositol

BACKGROUND & AIMS: Crohn's disease (CD) is associated with a dysregulated immune response to commensal microorganisms in the intestine. Mice deficient in inositol polyphosphate 5'-phosphatase D (INPP5D, also known as SHIP) develop intestinal inflammation resembling that of patients with CD. SHIP is a negative regulator of PI3Kp110 alpha activity. We investigated mechanisms of intestinal inflammation in Inpp5d(-/-) mice (SHIP-null mice), and SHIP levels and activity in intestinal tissues of subjects with CD. METHODS: We collected intestines from SHIP-null mice, as well as Inpp5d(+/+) mice (controls), and measured levels of cytokines of the interleukin 1 (IL1) family (IL1 alpha, IL1 beta, IL1ra, and IL6) by enzyme-linked immunosorbent assay. Macrophages were isolated from lamina propria cells of mice, IL1 beta production was measured, and mechanisms of increased IL1 beta production were investigated. Macrophages were incubated with pan-phosphatidylinositol 3-kinase inhibitors or PI3Kp110 alpha-specific inhibitors. Some mice were given an antagonist of the IL1 receptor; macrophages were depleted from ilea of mice using clodronate-containing liposomes. We obtained ileal biopsies from sites of inflammation and peripheral blood mononuclear cells (PBMCs) from treatment-naive subjects with CD or without CD (controls), and measured SHIP levels and activity. PBMCs were incubated with lipopolysaccharide and adenosine triphosphate, and levels of IL1 beta production were measured. RESULTS: Inflamed intestinal tissues and intestinal macrophages from SHIP-null mice produced higher levels of IL1 beta and IL18 than intestinal tissues from control mice. We found PI3Kp110a to be required for macrophage transcription of Il1 beta. Macrophage depletion or injection of an IL1 receptor antagonist reduced ileal inflammation in SHIP-null mice. Inflamed ileal tissues and PBMCs from patients with CD had lower levels of SHIP protein than controls (P <.0001 and P <.0002, respectively). There was an inverse correlation between levels of SHIP activity in PBMCs and induction of IL1 beta production by lipopolysaccharide and adenosine triphosphate (R-2 = .88). CONCLUSIONS: Macrophages from SHIP-deficient mice have increased PI3Kp110 alpha-mediated transcription of Il1 beta, which contributes to spontaneous ileal inflammation. SHIP levels and activity are lower in intestinal tissues and peripheral blood samples from patients with CD than controls. There is an inverse correlation between SHIP activity and induction of IL1 beta production by lipopolysaccharide and adenosine triphosphate in PBMCs. Strategies to reduce IL1 beta might be developed to treat patients with CD found to have low SHIP activity.

• 出版日期2016-2