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B Activity1
* Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada;
Max Planck Institute for Experimental Endocrinology, Hannover, Germany; and
Department of Molecular Immunology, Biology III, University of Freiburg and Max Planck Institute for Immunobiology, Freiburg, Germany
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-
B and that IB
phosphorylation/degradation and NF-B 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 IB
and NF-B DNA binding while the Erk and p38 pathways enhance IL-6
mRNA synthesis by increasing the transactivation potential of NF-B.
Taken together, our data are consistent with a model in which SHIP
negatively regulates NF-B activity and IL-6 synthesis by reducing
IgE + Ag-induced phosphatidylinositol-3,4,5-trisphosphate levels and
thus PKB, PKC, Erk, and p38 activation.
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