Activity of SHIP, Which Prevents Expression of Interleukin-1β, is Reduced in Patients with Crohn's Disease.

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 PIK3CA 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.We collected intestines from SHIP-null mice, as well as Inpp5d+/+ mice (controls), and measured levels of cytokines of the interleukin-1 (IL1) family (IL1A, IL1B, IL1RA, and IL6) by ELISA. Macrophages were isolated from lamina propria cells of mice, IL1B production was measured, and mechanisms of increased IL1B production were investigated. Macrophages were incubated with pan-PI3K inhibitors or PIK3CA-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-naïve subjects with CD or without CD (controls), and measured SHIP levels and activity. PBMCs were incubated with lipopolysaccharide (LPS) and ATP, and levels of IL1B production were measured.Inflamed intestinal tissues and intestinal macrophages from SHIP-null mice produced higher levels of IL1B and IL18 than intestinal tissues from control mice. We found PIK3CA to be required for macrophage transcription of Il1b. 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 IL1B production by LPS and ATP (R2=.88).Macrophages from SHIP-deficient mice have increased PIK3CA-mediated transcription of Il1b, 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 IL1B production by LPS and ATP in PBMCs. Strategies to reduce IL1B might be developed to treat patients with CD found to have low SHIP activity.