SHIP deficiency causes Crohn's disease-like ileitis

Kerr, William G; Park, Mi-Young; Maubert, Monique; Engelman, Robert W

The CD-like pathological findings described above are routinely observed in the ileum of both SHIP À/À strains 31 41 and the SHIP DIPDIP strain 47 that harbour different mutations of the SHIP1 gene indicating this is a highly penetrant phenotype. Moreover, because the phenotype occurs in the SHIP DIPDIP strain where only the inositol phosphatase domain encoding exons of SHIP are excised, we conclude that the phenotype is dependent on loss of SHIP enzymatic activity. SHIP through its 5 9 -inositol phosphatase domain hydrolyses the second messenger PI(3,4,5)P 3 and thus limits PI3K activation of key downstream survival and effector pathways promoted by Akt and NF-kB. 30 40 However, recent findings indicate that SHIP, via generation of PI(3,4)P 2 , can also promote cellular survival by increasing activation of Akt, 49 consistent with the demonstration that Akt binds to and is more effectively activated by the SHIP product, PI(3,4)P 2 , than by its substrate, PI(3,4,5)P 3 . 51 Tiwari et al found that SHIP can also promote immune effector function via synthesis of PI(3,4)P 2 . 52 It remains to be determined whether SHIP-deficiency is causing ileitis due to a lack of inhibitory or activating signalling in immune cells. This may be dependent on cellular context. For instance, one could envision that SHIP may be required for efficient mucosal trafficking and survival of T cells via generation of PI(3,4)P 2 , but by decreasing PI(3,4,5)P 3 in neutrophils SHIP is also limiting their numbers and function at this enteric site. Future lineage specific SHIP ablation studies using SHIP flox/flox mice and appropriate Cre transgenes combined with biochemical analysis PI3K effector pathways in these models may elucidate the molecular mechanism underlying SHIP's role in preserving normal immune function/regulation in the ileum.