The haemopoietic-restricted Src homology 2-containing inositol 5´-phosphatase (SHIP) acts as a negative regulator of myeloid cell proliferation, survival and end-cell activation. It does so, at least in part, by hydrolysing the phosphoinositide 3-kinase (PI3K)-generated second messenger, PtdIns(3,4,5)P3 (PI-3,4,5-P3) to PtdIns(3,4)P2. As a result, the myeloid progenitors in SHIP-knockout mice display enhanced survival and proliferation and the mice have increased numbers of neutrophils and monocytes/macrophages. Interestingly, although SHIP is not required for mast cell or macrophage development, it restrains their differentiation since progenitors from SHIP−/− mice differentiate into mature mast cells and macrophages significantly faster than their wild-type counterparts. This could suggest that elevated PI-3,4,5-P3 levels accelerate myeloid differentiation. In bone-marrow-derived mast cells, SHIP prevents degranulation by IgE alone, restrains IgE–antigen-induced degranulation and limits the production of inflammatory cytokines. On the other hand, in peritoneal macrophages, SHIP is a positive regulator of NO production, since SHIP−/− peritoneal macrophages produce 5–10-fold less NO than their wild-type counterparts, even though they show greater lipopolysaccharide/interferon-γ-induced nuclear factor κB activation and more rapid inducible NO synthase (iNOS) generation. This is a result of 10-fold higher levels of arginase I in the SHIP−/− macrophages, which redirects the iNOS substrate, l-arginine, from NO to ornithine production. This suggests that the chronically elevated PI-3,4,5-P3 levels in SHIP−/− mice may convert M1 (killing) macrophages, which produce NO to kill micro-organisms and tumour cells, into M2 (healing) macrophages, which produce ornithine to promote host cell growth and fibrosis.
Role of Src homology 2-containing-inositol 5′-phosphatase (SHIP) in mast cells and macrophages
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M.J. Rauh, J. Kalesnikoff, M. Hughes, L. Sly, V. Lam, G. Krystal; Role of Src homology 2-containing-inositol 5′-phosphatase (SHIP) in mast cells and macrophages. Biochem Soc Trans 1 February 2003; 31 (1): 286–291. doi: https://doi.org/10.1042/bst0310286
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