Abstract
The SHIP converts phosphatidylinositol 3,4,5 triphosphate to phosphatidyl 3,4 biphosphate. SHIP has negative regulatory functions on PI3K-dependent signaling pathways, which occupy important roles in modulating neutrophil functions. We used neutrophils from transgenic SHIP(-/-) and SHIP(+/+) mice that were stimulated with peptidoglycan (PGN) to examine the role of SHIP in TLR2-induced neutrophil activation. SHIP(-/-) neutrophils demonstrated significantly increased activation of the PI3K-dependent kinase Akt after exposure to PGN. Release of cytokines and chemokines, including TNF-alpha, IL-1beta, IL-6, IL-10, and MIP-2, was also increased in SHIP(-/-) compared with SHIP(+/+) neutrophils. There was no difference in the nuclear translocation of the transcriptional factor NF-kappaB between PGN-stimulated SHIP(-/-) and SHIP(+/+) neutrophils. However, phosphorylation of the p65 subunit of NF-kappaB, an event essential for optimal transcriptional activity of NF-kappaB, was increased in TLR2-activated SHIP(-/-) neutrophils. SHIP(-/-) neutrophils demonstrated greater activation of ERK1/2 and p38 MAPKs than did SHIP(+/+) neutrophils after exposure to PGN. The severity of acute lung injury induced by PGN was greater in SHIP(-/-) as compared with SHIP(+/+) mice. These results demonstrate that SHIP has a negative regulatory role in TLR2-induced neutrophil activation and in the development of related in vivo neutrophil-dependent inflammatory processes, such as acute lung injury.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cells, Cultured
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Down-Regulation / genetics
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Down-Regulation / immunology
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Enzyme Activation / immunology
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Lung / enzymology*
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Lung / immunology
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Lung / pathology*
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Mice
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Mice, Transgenic
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / metabolism
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NF-kappa B / metabolism
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Neutrophil Activation* / genetics
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Neutrophil Activation* / immunology
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Neutrophils / enzymology
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Neutrophils / immunology
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Neutrophils / pathology
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Peptidoglycan / toxicity
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Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
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Phosphoric Monoester Hydrolases / deficiency
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology*
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptors, Immunologic / antagonists & inhibitors
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Receptors, Immunologic / physiology*
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Severity of Illness Index
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Toll-Like Receptor 2
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Transcription Factor RelA
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Up-Regulation / genetics
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Up-Regulation / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism
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src Homology Domains / genetics
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src Homology Domains / immunology
Substances
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NF-kappa B
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Peptidoglycan
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Proto-Oncogene Proteins
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Receptors, Immunologic
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Tlr2 protein, mouse
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Toll-Like Receptor 2
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Transcription Factor RelA
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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Phosphoric Monoester Hydrolases
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INPPL1 protein, human
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Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases