Role of Src homology 2-containing-inositol 5′-phosphatase (SHIP) in mast cells and macrophages. (1st February 2003)

• Record Type: Journal Article
• Authors: Rauh, M.J.; Kalesnikoff, J.; Hughes, M.; Sly, L.; Lam, V.; Krystal, G.
• Is Part Of: Biochemical Society transactions. Volume 31:Number 1(2003)
• Page Start: 286
• Page End: 291
• Publication Date: 2003-02-01
• Subjects: arginase -- M1 and M2 macrophages -- phosphoinositide 3-kinase pathway; Biochemistry -- Congresses; 572
• DOI: 10.1042/bst0310286
• Languages: English
• ISSNs: 0300-5127

Abstract

Abstract : 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) P 3 (PI-3, 4, 5-P3 ) to PtdIns(3, 4) P 2 . 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.