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SHIP Negatively Regulates IgE + Antigen-Induced IL-6 Production in Mast Cells by Inhibiting NF-κB Activity1

MPS-Authors

Kalesnikoff,  Janet
Max Planck Society;

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Baur,  Nicole
Department of Developmental Biology, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

Hughes,  Michael R.
Max Planck Society;

Damen,  Jacqueline E.
Max Planck Society;

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Huber,  Michael
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Krystal,  Gerald
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Kalesnikoff, J., Baur, N., Leitges, M., Hughes, M. R., Damen, J. E., Huber, M., et al. (2002). SHIP Negatively Regulates IgE + Antigen-Induced IL-6 Production in Mast Cells by Inhibiting NF-κB Activity1. Journal of Immunology, 168(9), 4737-4746.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-9647-6
Abstract
We demonstrate in this study that IgE + Ag-induced proinflammatory cytokine production is substantially higher in Src homology-2-containing inositol 5'-phosphatase (SHIP)-/- than in SHIP+/+ bone marrow-derived mast cells (BMMCs). Focusing on IL-6, we found that the repression of IL-6 mRNA and protein production in SHIP+/+ BMMCs requires the enzymatic activity of SHIP, because SHIP-/- BMMCs expressing wild-type, but not phosphatase-deficient (D675G), SHIP revert the IgE + Ag-induced increase in IL-6 mRNA and protein down to levels seen in SHIP+/+ BMMCs. Comparing the activation of various signaling pathways to determine which ones might be responsible for the elevated IL-6 production in SHIP-/- BMMCs, we found the phosphatidylinositol 3-kinase/protein kinase B (PKB), extracellular signal-related kinase (Erk), p38, c-Jun N-terminal kinase, and protein kinase C (PKC) pathways are all elevated in IgE + Ag-induced SHIP-/- cells. Moreover, inhibitor studies suggested that all these pathways play an essential role in IL-6 production. Looking downstream, we found that IgE + Ag-induced IL-6 production is dependent on the activity of NF-κB and that IκB phosphorylation/degradation and NF-κB translocation, DNA binding and transactivation are much higher in SHIP-/- BMMCs. Interestingly, using various pathway inhibitors, it appears that the phosphatidylinositol 3-kinase/PKB and PKC pathways elevate IL-6 mRNA synthesis, at least in part, by enhancing the phosphorylation of IκB and NF-κB DNA binding while the Erk and p38 pathways enhance IL-6 mRNA synthesis by increasing the transactivation potential of NF-κB. Taken together, our data are consistent with a model in which SHIP negatively regulates NF-κB activity and IL-6 synthesis by reducing IgE + Ag-induced phosphatidylinositol-3,4,5-trisphosphate levels and thus PKB, PKC, Erk, and p38 activation.