The SHIP1 (SH2-containing inositol-5′-phosphatase 1) acts as a negative regulator of proliferation, survival and end cell activation in haemopoietic cells. It does so, at least in part, by translocating to membranes after extracellular stimulation and hydrolysing the phosphoinositide 3-kinase-generated second messenger, PtdIns(3,4,5)P3 to PtdIns(3,4)P2. SHIP1−/− mice have, as a result, an increased number of neutrophils and monocyte/macrophages because their progenitors display enhanced survival and proliferation. These mice also suffer from osteoporosis because of an increased number of hyperactive osteoclasts and a significant neutrophil infiltration of the lungs. Interestingly, SHIP1−/− mice do not display endotoxin tolerance and we have found that lipopolysaccharide-induced endotoxin tolerance is contingent on up-regulating SHIP1, through the production of autocrine-acting transforming growth factor-β, in bone-marrow-derived macrophages and mast cells. Intriguingly, unlike bone-marrow-derived macrophages, SHIP1−/− peritoneal and alveolar macrophages produce 10-fold less NO than wild-type macrophages because these in vivo-generated macrophages have very high arginase I levels and this enzyme competes with inducible nitric oxide synthase for the substrate L-arginine. It is probable that, in the face of chronically increased PtdIns(3,4,5)P3 levels in their myeloid progenitors, SHIP1−/− mice display a skewed development away from M1 (killer) macrophages (which have high inducible nitric oxide synthase levels and produce NO to kill microorganisms and tumour cells), towards M2 (healing) macrophages (which have high arginase levels and produce ornithine to promote host-cell growth and collagen formation). This skewing probably occurs to avoid septic shock and suggests that the phosphoinositide 3-kinase pathway plays a critical role in programming macrophages.
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November 2004
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Conference Article|
October 26 2004
The role of SHIP1 in macrophage programming and activation
M.J. Rauh;
M.J. Rauh
1
1The Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, BC, Canada
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L.M. Sly;
L.M. Sly
1
1The Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, BC, Canada
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J. Kalesnikoff;
J. Kalesnikoff
1The Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, BC, Canada
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M.R. Hughes;
M.R. Hughes
1The Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, BC, Canada
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L.-P. Cao;
L.-P. Cao
1The Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, BC, Canada
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V. Lam;
V. Lam
1The Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, BC, Canada
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G. Krystal
G. Krystal
2
2To whom correspondence should be addressed (email gkrystal@bccrc.ca).
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Publisher: Portland Press Ltd
Received:
June 21 2004
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2004 The Biochemical Society
2004
Biochem Soc Trans (2004) 32 (5): 785–788.
Article history
Received:
June 21 2004
Citation
M.J. Rauh, L.M. Sly, J. Kalesnikoff, M.R. Hughes, L.-P. Cao, V. Lam, G. Krystal; The role of SHIP1 in macrophage programming and activation. Biochem Soc Trans 1 November 2004; 32 (5): 785–788. doi: https://doi.org/10.1042/BST0320785
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