SHIP negatively regulates IgE plus antigen-induced IL-6 production in mast cells by inhibiting NF-κB activity
SHIP negatively regulates IgE plus antigen-induced IL-6 production in mast cells by inhibiting NF-κB activity
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DOI：
10.4049/jimmunol.168.9.4737
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发表时间：
2002-05-01
影响因子：
4.4
通讯作者：
Krystal, G
中科院分区：
文献类型：
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作者：
Kalesnikoff, J;Baur, N;Krystal, G
我们在这项研究中证明，在含有 Src 同源 2 的肌醇 5'-磷酸酶 (SHIP)(-/-) 中，IgE + Ag 诱导的促炎细胞因子的产生明显高于 SHIP-/- 骨髓源性肥大细胞 (BMMC)。关注IL-6，我们发现SHIP+/+ BMMCs中IL-6 mRNA和蛋白质产生的抑制需要SHIP的酶活性，因为SHIP-/- BMMCs表达野生型，但不表达磷酸酶缺陷（D675G），SHIP将IgE + Ag诱导的IL-6 mRNA和蛋白质的增加恢复到SHIP+/+ BMMCs中看到的水平。比较各种信号通路的激活以确定哪些信号通路可能导致 SHIP-/- BMMC 中 IL-6 产量升高，我们发现磷脂酰肌醇 3-激酶/蛋白激酶 B (PKB)、细胞外信号相关激酶 (Erk)、p38、c-Jun N 端激酶和蛋白激酶 C (PKC) 通路在 SHIP-/- BMMC 中均升高。 IgE + Ag 诱导的 SHIP-/- 细胞。此外，抑制剂研究表明所有这些途径在 IL-6 的产生中都发挥着重要作用。向下游看，我们发现 IgE + Ag 诱导的 IL-6 产生依赖于 NF-kappaB 的活性，并且 SHIP-/- BMMC 中 IkappaB 磷酸化/降解和 NF-kappaB 易位、DNA 结合和反式激活要高得多。有趣的是，使用各种途径抑制剂，磷脂酰肌醇3激酶/PKB和PKC途径似乎至少部分通过增强IkappaB和NF-KB DNA结合的磷酸化来提高IL-6 mRNA合成，而Erk和p38途径通过增加NF-kappaB的反式激活潜力来增强IL-6 mRNA合成。综上所述，我们的数据与 SHIP 通过降低 IgE + Ag 诱导的磷脂酰肌醇-3,4,5-三磷酸水平，从而降低 PKB、PKC、Erk 和 p38 激活来负调节 NF-KB 活性和 IL-6 合成的模型一致。
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-kappaB and that IkappaB phosphorylation/degradation and NF-kappaB 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 IkappaB and NF-KB DNA binding while the Erk and p38 pathways enhance IL-6 mRNA synthesis by increasing the transactivation potential of NF-kappaB. Taken together, our data are consistent with a model in which SHIP negatively regulates NF-KB activity and IL-6 synthesis by reducing IgE + Ag-induced phosphatidylinositol-3,4,5-trisphosphate levels and thus PKB, PKC, Erk, and p38 activation.