Regulation of the immune response by SHIP

March, Michael; Ravichandran, Kodi S.

doi:10.1006/smim.2001.0340

Cited by 60 publications

(53 citation statements)

References 77 publications

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“…In this study, we demonstrate that two isoforms, Fc␥RIIA and Fc␥RIIB, are involved in recognition of immune complexes and of GXM, respectively. Fc␥RIIA is regarded as an activator of multiple intracellular pathways (45); in contrast Fc␥RIIB has inhibitory functions because of its ITIM, that activates the SHIP (46). Indeed, engagement of Fc␥RIIB by GXM leads to recruitment on macrophages of SHIP, a molecule considered a mediator of cellular activation/inhibition.…”

Section: Discussionmentioning

confidence: 99%

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

Monari

Kozel

Paganelli

et al. 2006

The Journal of Immunology

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A microbial polysaccharide (glucuronoxylomannan (GXM)) exerts potent immunosuppression by direct engagement to immunoinhibitory receptor FcγRIIB. Activation of FcγRIIB by GXM leads to the recruitment and phosphorylation of SHIP that prevents IκBα activation. The FcγRIIB blockade inhibits GXM-induced IL-10 production and induces TNF-α secretion. GXM quenches LPS-induced TNF-α release via FcγRIIB. The addition of mAb to GXM reverses GXM-induced immunosuppression by shifting recognition from FcγRIIB to FcγRIIA. These findings indicate a novel mechanism by which microbial products can impair immune function through direct stimulation of an inhibitory receptor. Furthermore, our observations provide a new mechanism for the ability of specific Ab to reverse the immune inhibitory effects of certain microbial products.

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Section: Discussionmentioning

confidence: 99%

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

Monari

Kozel

Paganelli

et al. 2006

The Journal of Immunology

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“…SHIP is recruited by engagement of the inhibitory Fc receptor in B cells and mast cells (5)(6)(7)(8) or by the engagement of FcRs (Fc RI and Fc␥RIII), cytokine [interleukin 3 (IL3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and TGF␤], and growth factor (steel factor and M-CSF) receptors in myeloid cells (2,9). Once SHIP is recruited to the membrane by the signaling complexes, its enzymatic activity depletes PI(3,4,5)P 3 and prevents membrane localization of PHdomain-containing factors such as Tec kinases, Akt, and PLC␥ (10)(11)(12)(13).…”

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confidence: 99%

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

Тарасенко

Kole

Anthony

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The 5 -phosphoinositol phosphatase SHIP negatively regulates signaling pathways triggered by antigen, cytokine and Fc receptors in both lymphocytes and myeloid cells. Mice with germ-line (null) deletion of SHIP develop a myeloproliferative-like syndrome that causes early lethality. Lymphocyte anomalies have been observed in SHIP-null mice, but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells, we have generated mice with T cell-specific deletion of SHIP. In the absence of SHIP, we found no differences in thymic selection or in the activation state and numbers of regulatory T cells in the periphery. In contrast, SHIP-deficient T cells do not skew efficiently to Th2 in vitro. Mice with T cell-specific deletion of SHIP show poor antibody responses on Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Th1-associated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8 ؉ cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in T cells SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity.cytotoxicity ͉ T-bet T he 5Ј-inositol phosphatase SHIP is a well characterized inhibitory molecule that regulates cell responses in lymphocytes and myeloid cells by its ability to hydrolyze the second messenger PI(3,4,5) trisphosphate (1-4). SHIP is recruited by engagement of the inhibitory Fc receptor in B cells and mast cells (5)(6)(7)(8) or by the engagement of FcRs (Fc RI and Fc␥RIII), cytokine [interleukin 3 (IL3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and TGF␤], and growth factor (steel factor and M-CSF) receptors in myeloid cells (2, 9). Once SHIP is recruited to the membrane by the signaling complexes, its enzymatic activity depletes PI(3,4,5)P 3 and prevents membrane localization of PHdomain-containing factors such as Tec kinases, Akt, and PLC␥ (10-13). This inhibitory effect ultimately leads to reduced calcium influx and prevents cellular activation (14).Germ-line deletion of SHIP in mice leads to early mortality from a myeloproliferative-like syndrome characterized by profound splenomegaly and massive myeloid infiltration of the lung (15). B cells develop abnormally in SHIP-null mice, with an activated phenotype and specifically lacking the marginal zone B cell population (16,17). The absence of marginal-zone B cells in SHIP-null mice has been explained not as a B cell primary defect, but as a consequence of macrophage dysregulation in the spleen of these animals (17). Macrophages from SHIP-null mice are skewed toward an M2-activated phenotype showing high levels of arginase I (ArgI) and Ym1. R...

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“…In response to M-CSF, the hemopoietic specific SHIP1 becomes tyrosine phosphorylated and associates with c-fms via the adaptor protein Shc, leading to generation of negative regulatory signals (9,10). SHIP1 contains an N-terminal Src homology 2, a central inositol-5-phosphatase, and a C-terminal proline-rich domain, within which are two phosphotyrosine binding sites (NPXY).…”

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confidence: 99%

SHIP1 Negatively Regulates Proliferation of Osteoclast Precursors via Akt-Dependent Alterations in D-Type Cyclins and p27

Zhou

Kitaura

Teitelbaum

et al. 2006

The Journal of Immunology

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Osteoclasts arise from macrophage progenitors in bone marrow (BMMs) as a consequence of signaling events elicited by M-CSF and receptor activator of NF-κB ligand, acting on their unique receptors, via c-Fms and receptor activator of NF-κB. Both receptors activate the PI3K and MAPK pathways, which promote cell proliferation and survival. SHIP1 is essential for normal bone homeostasis, as mice lacking the protein exhibit osteoporosis resulting from increased numbers of hyper-resorptive osteoclasts. In this study, we show that BMMs from SHIP1 null mice respond to M-CSF, but not receptor activator of NF-κB ligand, by increasing Akt activation. In consequence, there are up-regulation of D-type cyclins, down-regulation of the cyclin-dependent kinase inhibitor p27, and, therefore, increased phosphorylation of the retinoblastoma protein and cell proliferation. Surprisingly, cell survival of wild-type and knockout BMMs is unaltered. Finally, osteoclastogenesis and periarticular bone erosions are markedly increased in SHIP1−/− mice with inflammatory arthritis, a condition characterized by increased M-CSF expression. The SHIP1/Akt pathway therefore suppresses bone loss in pathological states associated with an excess of the cytokine.

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Regulation of the immune response by SHIP

Cited by 60 publications

References 77 publications

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

Microbial Immune Suppression Mediated by Direct Engagement of Inhibitory Fc Receptor

T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses

SHIP1 Negatively Regulates Proliferation of Osteoclast Precursors via Akt-Dependent Alterations in D-Type Cyclins and p27

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