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PI 3-Kinase in the Immune System

Role of Src homology 2-containing-inositol 5′-phosphatase (SHIP) in mast cells and macrophages

M.J. Rauh, J. Kalesnikoff, M. Hughes, L. Sly, V. Lam, G. Krystal
Biochemical Society Transactions Feb 01, 2003, 31 (1) 286-291; DOI: 10.1042/bst0310286
M.J. Rauh
The Terry Fox Laboratory, B.C. Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
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J. Kalesnikoff
The Terry Fox Laboratory, B.C. Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
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M. Hughes
The Terry Fox Laboratory, B.C. Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
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L. Sly
The Terry Fox Laboratory, B.C. Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
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V. Lam
The Terry Fox Laboratory, B.C. Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
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G. Krystal
The Terry Fox Laboratory, B.C. Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada
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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)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.

  • arginase
  • M1 and M2 macrophages
  • phosphoinositide 3-kinase pathway

Footnotes

  • PI 3-Kinase in the Immune System, a Biochemical Society Focused Meeting held at Novartis Horsham Research Centre, 9–10 September 2002

  • Abbreviations used: Ag, antigen; BMMC, bone-marrow-derived mast cell; IFN-γ, interferon-γ; IL, interleukin; iNOS, inducible NO synthase; IP4, Ins(1,3,4,5)P4; LPS, lipopolysaccharide; NFκB, nuclear factor κB; PH, pleckstrin homology; PI-3, 4-P2; PtdIns(3,4)P2; PI-3,4,5-P3, PtdIns(3,4,5)P3; PI-4,5-P2, PtdIns(4,5)P2; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue deleted on chromosome 10; SH2/SH3, Src homology 2/3; SHIP, SH2-containing-inositol 5´-phosphatase; SF, Steel Factor; sSHIP, stem cell SHIP.

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February 2003

Volume: 31 Issue: 1

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Role of Src homology 2-containing-inositol 5′-phosphatase (SHIP) in mast cells and macrophages
M.J. Rauh, J. Kalesnikoff, M. Hughes, L. Sly, V. Lam, G. Krystal
Biochemical Society Transactions Feb 2003, 31 (1) 286-291; DOI: 10.1042/bst0310286
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Role of Src homology 2-containing-inositol 5′-phosphatase (SHIP) in mast cells and macrophages
M.J. Rauh, J. Kalesnikoff, M. Hughes, L. Sly, V. Lam, G. Krystal
Biochemical Society Transactions Feb 2003, 31 (1) 286-291; DOI: 10.1042/bst0310286

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Keywords

arginase
M1 and M2 macrophages
phosphoinositide 3-kinase pathway

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