Publications (12)65.23 Total impact
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Article: The role of SHIP in the development and activation of mouse mucosal and connective tissue mast cells.
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ABSTRACT: Although SHIP is a well-established suppressor of IgE plus Ag-induced degranulation and cytokine production in bone marrow-derived mast cells (BMMCs), little is known about its role in connective tissue (CTMCs) or mucosal (MMCs) mast cells. In this study, we compared SHIP's role in the development as well as the IgE plus Ag and TLR-induced activation of CTMCs, MMCs, and BMMCs and found that SHIP delays the maturation of all three mast cell subsets and, surprisingly, that it is a positive regulator of IgE-induced BMMC survival. We also found that SHIP represses IgE plus Ag-induced degranulation of all three mast cell subsets and that TLR agonists do not trigger their degranulation, whether SHIP is present or not, nor do they enhance IgE plus Ag-induced degranulation. In terms of cytokine production, we found that in MMCs and BMMCs, which are poor producers of TLR-induced cytokines, SHIP is a potent negative regulator of IgE plus Ag-induced IL-6 and TNF-α production. Surprisingly, however, in splenic or peritoneal derived CTMCs, which are poor producers of IgE plus Ag-induced cytokines, SHIP is a potent positive regulator of TLR-induced cytokine production. Lastly, cell signaling and cytokine production studies with and without LY294002, wortmannin, and PI3Kα inhibitor-2, as well as with PI3K p85α(-/-) BMMCs and CTMCs, are consistent with SHIP positively regulating TLR-induced cytokine production via an adaptor-mediated pathway while negatively regulating IgE plus Ag-induced cytokine production by repressing the PI3K pathway.The Journal of Immunology 03/2012; 188(8):3839-50. · 5.79 Impact Factor -
Chapter: SHIP and Tumour-Associated Macrophages
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ABSTRACT: The SH2-containing inositol-5′-phosphatase, SHIP (aka SHIP1) is a hematopoietic-restricted phosphoinositol phosphatase that translocates to the plasma membrane following extracellular stimulation and hydrolyses the phosphatidylinositol-3-kinase (PI3K)-generated second messenger PI-3,4,5-P3 (PIP3) to PI-3,4-P2. As a result, it often acts as a negative regulator of PI3K, reducing the sensitivity of blood cells and blood cell progenitors to extracellular stimulators of proliferation, survival, and activation. However, because SHIP generates the second messenger PI-3,4-P2 and can also act as an adaptor, via its many protein–protein interaction domains, its effects are very cell type and stimulus dependent. In this review, we focus on SHIP’s structure and binding partners, the regulation of its expression and its biological properties, especially in terms of its potential effects on the M1 versus M2 skewing of tumor-associated macrophages.12/2011: pages 135-151; -
Article: Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice.
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ABSTRACT: As more groups investigate the role of myeloid-derived suppressor cells (MDSCs) in promoting the growth of primary tumors and distant tumor metastases, it is imperative to ensure the accurate detection and quantification of MDSC immunosuppression ex vivo. MDSCs are defined by their ability to suppress immune responses. Although different in vitro culture conditions have been used to study MDSCs, the effect of different culture conditions on MDSC immunosuppression is unknown. We therefore isolated MDSCs from the lungs and spleens of 4T1 murine mammary tumor-bearing mice and assayed MDSC-mediated suppression of T cell responses under different culture conditions. We found that 4T1-induced MDSCs effectively suppressed T cell proliferation under serum-free conditions, but not when fetal calf serum (FCS) was present. FCS neither altered the immunosuppressive activities of other myeloid cell types (i.e., peritoneal or tumor-associated macrophages) nor modified the susceptibility of T cells to myeloid cell-mediated suppression, but instead acted directly on 4T1-induced MDSCs to significantly reduce their immunosuppressive function. Importantly, we found that bovine serum albumin was a major contributor to the antagonistic effects of FCS on 4T1-induced MDSC immunosuppression by inhibiting reactive oxygen species production from MDSCs. This work reveals that in vitro culture conditions influence the immunosuppressive properties of MDSCs and highlights the importance of testing different culture conditions on MDSC phenotype to ensure that MDSC immunosuppression is not being masked. These data have important implications for the accurate detection and identification of MDSCs, as well as for determining the influence of MDSC-mediated immunosuppression on primary and metastatic tumor growth.Cancer Immunology and Immunotherapy 10/2011; 61(5):643-54. · 3.70 Impact Factor -
Article: SHIP represses Th2 skewing by inhibiting IL-4 production from basophils.
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ABSTRACT: We report that SHIP(-/-) mice, compared to SHIP(+/+) mice, are Th2 skewed with elevated serum IgE and twice as many splenic CD4(+) Th2 cells that, when stimulated with anti-CD3, produce more IL-4 and less IFN-γ. Exploring the reason for this Th2 skewing, we found that freshly isolated SHIP(-/-) splenic and bone marrow basophils are present in elevated numbers and secrete far more IL-4 in response to IL-3 or to FcεRI stimulation than do WT basophils. These SHIP(-/-) basophils markedly skew wild-type macrophage colony stimulating factor-derived macrophages toward an M2 phenotype, stimulate OT-II CD4(+) Th cells to differentiate into Th2 cells, and trigger SHIP(+/+) B cells to become IgE-producing cells. All these effects are completely abrogated with neutralizing anti-IL-4 Ab. Exploring the cell signaling pathways responsible for hyperproduction of IL-4 by SHIP(-/-) basophils, we found that IL-3-induced activation of the PI3K pathway is significantly enhanced and that PI3K inhibitors, especially a p110α inhibitor, dramatically suppresses IL-4 production from these cells. In vivo studies, in which basophils were depleted from mast cell-deficient SHIP(+/+) and SHIP(-/-) mice, confirmed the central role that basophils play in the Th2 skewing of naive SHIP-deficient mice. Taken together, these studies demonstrate that SHIP is a potent negative regulator of IL-4 production from basophils and thus may be a novel therapeutic target for Th1- and Th2-related diseases.The Journal of Immunology 01/2011; 186(1):323-32. · 5.79 Impact Factor -
Article: Role of SHIP in cancer.
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ABSTRACT: The SH2-containing inositol-5'-phosphatase, SHIP (or SHIP1), is a hematopoietic-restricted phosphatidylinositide phosphatase that translocates to the plasma membrane after extracellular stimulation and hydrolyzes the phosphatidylinositol-3-kinase-generated second messenger PI-3,4,5-P(3) to PI-3,4-P(2). As a result, SHIP dampens down PI-3,4,5-P(3)-mediated signaling and represses the proliferation, differentiation, survival, activation, and migration of hematopoietic cells. There are multiple lines of evidence suggesting that SHIP may act as a tumor suppressor during leukemogenesis and lymphomagenesis. Because of its ability to skew macrophage progenitors toward M1 macrophages and naïve T cells toward T helper 1 and T helper 17 cells, SHIP may play a critical role in activating the immune system to eradicate solid tumors. In this review, we will discuss the role of SHIP in hematopoietic cells and its therapeutic potential in terms of suppressing leukemias and lymphomas and manipulating the immune system to combat cancer.Experimental hematology 11/2010; 39(1):2-13. · 3.11 Impact Factor -
Article: Tyrosine phosphorylation of SHIP promotes its proteasomal degradation.
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ABSTRACT: The activity of the SH2-containing-phosphatidylinositol-5'-phosphatase (SHIP, also known as SHIP1), a critical hematopoietic-restricted negative regulator of the PI3 kinase (PI3K) pathway, is regulated in large part via its protein levels. We sought to determine the mechanism(s) involved in its downregulation by BCR-ABL and by interleukin (IL)-4. We used Ba/F3(p210-tetOFF) cells to study the downregulation of SHIP by BCR-ABL and bone marrow-derived macrophages to study SHIP's downregulation by IL-4. We show herein that BCR-ABL downregulates SHIP, but not SHIP2 or PTEN, and this can be blocked with the Src kinase inhibitor PP2, which inhibits the tyrosine phosphorylation of SHIP, or with the proteasomal inhibitor MG-132. We also show, using anti-SHIP immunoprecipitates, that c-Cbl and Cbl-b are associated with SHIP and that BCR-ABL induces SHIP's polyubiquitination. This ubiquitination can be blocked with PP2, consistent with the tyrosine phosphorylation of SHIP acting as a signal for its ubiquitination. In bone marrow-derived macrophages, IL-4 also leads to the proteasomal degradation of SHIP but, unlike in Ba/F3(p210-tetOFF) cells, SHIP2 is also proteasomally degraded and the degradation of both inositol phosphatases can be prevented with PP2 or MG-132. Our results suggest that SHIP protein levels can be reduced via BCR-ABL and/or Src family member-induced tyrosine phosphorylation of SHIP because this triggers its polyubiquitination and degradation within the proteasome.Experimental hematology 03/2010; 38(5):392-402, 402.e1. · 3.11 Impact Factor -
Article: IgE-induced mast cell survival requires the prolonged generation of reactive oxygen species.
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ABSTRACT: We show in this study that the ability of five different monomeric IgEs to enhance murine bone marrow-derived mast cell (BMMC) survival correlates with their ability to stimulate extracellular calcium (Ca(2+)) entry. However, whereas IgE+Ag more potently stimulates Ca(2+) entry, it does not enhance survival under our conditions. Exploring this further, we found that whereas all five monomeric IgEs stimulate a less robust Ca(2+) entry than IgE+Ag initially, they all trigger a more prolonged Ca(2+) influx, generation of reactive oxygen species (ROS), and ERK phosphorylation. These prolonged signaling events correlate with their survival-enhancing ability and positively feedback on each other to generate the prosurvival cytokine, IL-3. Interestingly, the prolonged ERK phosphorylation induced by IgE appears to be regulated by a MAPK phosphatase rather than MEK. IgE-induced ROS generation, unlike that triggered by IgE+Ag, is not mediated by 5-lipoxygenase. Moreover, ROS inhibitors, which block both IgE-induced ROS production and Ca(2+) influx, convert the prolonged ERK phosphorylation induced by IgE into the abbreviated phosphorylation pattern observed with IgE+Ag and prevent IL-3 generation. In support of the essential role that IgE-induced ROS plays in IgE-enhanced BMMC survival, we found the addition of H(2)O(2) to IgE+Ag-stimulated BMMCs leads to IL-3 secretion.The Journal of Immunology 10/2008; 181(6):3850-60. · 5.79 Impact Factor -
Article: The role of SHIP in macrophages.
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ABSTRACT: The SH2-containing inositol-5'-phosphatase, SHIP, represses the proliferation, survival, and activation of hematopoietic cells, in large part by translocating to membranes following extracellular stimulation and hydrolysing the phosphatidylinositol-3-kinase (PI3K)-generated second messenger PI-3,4,5-P3 (PIP3) to PI-3,4-P2. SHIP-/- mice have, as a result, an increased number of monocyte/macrophages because their progenitors display enhanced survival and proliferation, as well as more rapid differentiation. Interestingly, SHIP-/- mice do not display lipopolysaccharide (LPS)- or CpG oligonucleotide-induced tolerance because this blunting of inflammatory mediator production is contingent upon LPS- and CpG-induced upregulation of SHIP in their macrophages and mast cells. This upregulation is mediated via the production of autocrine-acting TGFbeta which is induced via the MyD88-dependent pathway. The increased levels of SHIP then inhibit both MyD88-dependent and independent signaling. Intriguingly, SHIP-/- peritoneal and alveolar macrophages produce less nitric oxide (NO) than wild-type macrophages because they have constitutively high arginase I levels and this enzyme competes with inducible nitric oxide synthase (iNOS) for the substrate L-arginine. It is likely that, in the face of chronically elevated PIP3 levels in their myeloid progenitors, SHIP-/- mice display a skewed development away from M1 (killer) macrophages towards M2 (healing) macrophages. This suggests that SHIP plays a critical role in programming macrophages.Frontiers in Bioscience 02/2007; 12:2836-48. · 3.52 Impact Factor -
Article: SHIP represses the generation of alternatively activated macrophages.
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ABSTRACT: We recently reported that SHIP restrains LPS-induced classical (M1) activation of in vitro differentiated, bone marrow-derived macrophages (BMMPhis) and that SHIP upregulation is essential for endotoxin tolerance. Herein, we show that in vivo differentiated SHIP-/- peritoneal (PMPhis) and alveolar (AMPhis) macrophages, unlike their wild-type counterparts, are profoundly M2 skewed (alternatively activated), possessing constitutively high arginase I (ArgI) and Ym1 levels and impaired LPS-induced NO production. Consistent with this, SHIP-/- mice display M2-mediated lung pathology and enhanced tumor implant growth. Interestingly, BMMPhis from SHIP-/- mice do not display this M2 phenotype unless exposed to TGFbeta within normal mouse plasma (MP) during in vitro differentiation. Our results suggest that SHIP functions in vivo to repress M2 skewing and that macrophage polarization can occur during differentiation in response to TGFbeta if progenitors have elevated PIP3.Immunity 11/2005; 23(4):361-74. · 21.64 Impact Factor -
Article: IgE alone stimulates mast cell adhesion to fibronectin via pathways similar to those used by IgE + antigen but distinct from those used by Steel factor.
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ABSTRACT: We recently demonstrated that immunoglobulin E (IgE), in the absence of cross-linking agents, activates signaling pathways in healthy murine bone marrow-derived mast cells (BMMCs) and that this activation enhances BMMC survival, at least in part, via secretion of autocrine-acting cytokines. We report herein that IgE alone also triggers the adhesion of both BMMCs and connective tissue mast cells (CTMCs) to the connective tissue component, fibronectin (FN). This adhesion occurs to the same extent as that triggered by optimal levels of Steel factor (SF) or IgE + antigen (IgE + Ag) and is mediated by an increased avidity of the integrin very late antigen 5 (VLA-5). Moreover, this IgE-induced adhesion, which is prolonged compared with that elicited by SF or IgE + Ag, requires phosphatidylinositol 3-kinase (PI3K), phospholipase C gamma (PLCgamma), and extracellular calcium but not extracellular-regulated kinase (Erk) or p38. Interestingly, we found, using the calcium channel blocker, 2-APB (2-aminoethoxydiphenyl borate) and Lyn-/- BMMCs that both IgE- and IgE + Ag-induced adhesion to FN require extracellular calcium entry, whereas SF does not. Furthermore, our data suggest that FN acts synergistically with IgE to prolong intracellular phosphorylation events and to enhance IgE-induced inflammatory cytokine production and BMMC survival.Blood 09/2003; 102(4):1405-13. · 9.90 Impact Factor -
Article: SHIP represses mast cell activation and reveals that IgE alone triggers signaling pathways which enhance normal mast cell survival.
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ABSTRACT: The hemopoietic specific, Src homology 2-containing inositol 5' phosphatase (SHIP) hydrolyzes the phosphatidylinositol (PI)-3-kinase generated second messenger, PI-3,4,5-trisphosphate (PIP(3)), to PI-3,4-bisphosphate (PI-3,4-P(2)) in normal bone marrow derived mast cells (BMMCs). As a consequence, SHIP negatively regulates IgE+antigen (Ag)-induced degranulation as well as leukotriene and inflammatory cytokine production. Interestingly, in the absence of SHIP, BMMCs degranulate extensively with IgE alone, i.e. without Ag, suggesting that IgE alone is capable of stimulating signaling in normal BMMCs and that SHIP prevents this signaling from progressing to degranulation. To test this, we compared signaling events triggered by monomeric IgE versus IgE+Ag in normal BMMCs and found that multiple pathways are triggered by monomeric IgE alone and, while they are in general weaker than those stimulated by IgE+Ag, they are more prolonged. Moreover, while SHIP prevents this IgE-induced signalling from progressing to degranulation or leukotriene production it allows sufficient production of autocrine acting cytokines, in part by activation of NFkappaB, to enhance BMMC survival. Interestingly, the activation of NFkappaB and the level of cytokines produced are far higher with IgE than with IgE+Ag. Moreover, IgE alone maintains Bcl-X(L) levels and enhances the adhesion of BMMCs to fibronectin and this likely enhances their survival still further.Molecular Immunology 10/2002; 38(16-18):1201-6. · 2.90 Impact Factor -
Article: Ships ahoy
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ABSTRACT: In 1996 three groups independently cloned a hemopoietic specific, src homology 2-containing inositol 5′-phosphatase which, based on its structure, was called SHIP. More recently, a second more widely expressed SHIP-like protein has been cloned and called SHIP2. Both specifically hydrolyze phosphatidylinositol-3,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate in vitro. Moreover, SHIP has been shown in vivo to be the primary enzyme responsible for breaking down phosphatidylinositol-3,4,5-trisphosphate to phosphatidylinositol-3,4-bisphosphate in normal mast cells and, as a result, limits normal and prevents inappropriate mast cell degranulation. Because of their ability to break down phosphatidylinositol-3,4,5-trisphosphate, the SHIPs have the potential to regulate many, if not all, phosphatidylinositol-3-kinase induced events including, proliferation, differentiation, apoptosis, end cell activation, cell movement and adhesion and will thus likely be the subject of intensive research over the next few years.The International Journal of Biochemistry & Cell Biology.
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- The Journal of Immunology (3)
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Institutions
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2003–2011
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Terry Fox Laboratory
Vancouver, British Columbia, Canada
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