Role of Calcium Ionophore A23187-Induced Activation of IkappaB Kinase 2 in Mast Cells
Role of Calcium Ionophore A23187-Induced Activation of IkappaB Kinase 2 in Mast Cells
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DOI：
10.1159/000350357
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发表时间：
2013-01-01
影响因子：
2.8
通讯作者：
Nakajima, Hiroshi
中科院分区：
文献类型：
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作者：
Hosokawa, Junichi;Suzuki, Kotaro;Nakajima, Hiroshi
背景：已知肥大细胞通过释放含有组胺和其他预先形成的化学介质的颗粒在过敏性疾病中发挥关键作用。肥大细胞上 IgE (Fc epsilon RI) 高亲和力受体的交联导致细胞内游离钙浓度 [Ca2+](i) 快速增加，并随后激活许多转录因子，包括 NFAT、NF-kB、JNK 和 CREB。 Ca2+ 信号传导对于肥大细胞的增殖、基因表达和脱粒等许多细胞活动至关重要。除了 Ca2+ 信号传导之外，之前的报道表明，IkappaB 激酶 2（IKK2 或 IKK beta）是介导 NF-kB 激活的 IKK 复合物的核心成分，在 Fc epsilon RI 介导的脱粒和细胞因子产生中也发挥着至关重要的作用。此外，已经证明，PKC beta（一种钙依赖性 PKC 同工型）的激活会导致许多细胞类型中 IKK2 的激活。然而，Ca 2+ 信号传导和 PKC beta 在肥大细胞中 IKK2 激活中的作用仍然很大程度上未知。方法：我们研究了 PKC 抑制剂 Go6976 对肥大细胞中钙离子载体 A23187 诱导的 IKK2 激活的影响。我们还通过使用 IKK2 缺陷 (IKK2(-/-)) 胎儿肝源性肥大细胞 (FLMC) 检测了 IKK2 在 A23187 诱导的 NF-kB 依赖性基因诱导、脱颗粒、促炎细胞因子产生以及细胞外信号调节激酶 1 和 2 (ERK1/2) 激活中的作用。结果：即使肥大细胞中存在 Go6976，A23187 也会激活 IKK2 和 NF-kB。与野生型 FLMC 相比，IKK2(-/-)FLMC 中 A23187 诱导的脱粒、细胞因子产生和 ERK1/2 激活均减少。结论：Ca2+-IKK2 信号传导通过独立于 PKC beta 的机制参与活化肥大细胞的脱粒和细胞因子产生。版权所有 (C) 2013 S. Karger AG，巴塞尔
Background: Mast cells are known to play a pivotal role in allergic diseases by releasing granules containing histamine and other preformed chemical mediators. Cross-linking of high-affinity receptors for IgE (Fc epsilon RI) on mast cells results in rapid increases in intracellular free calcium concentration [Ca2+](i) and consequent activation of many transcription factors, including NFAT, NF-kB, JNK and CREB. Ca2+ signaling is essential for many cellular activities such as proliferation, gene expression and degranulation in mast cells. In addition to Ca2+ signaling, previous reports have shown that IkappaB kinase 2 (IKK2 or IKK beta), a central component of the IKK complex mediating NF-kB activation, also plays a crucial role in Fc epsilon RI-mediated degranulation and cytokine production. Moreover, it has been demonstrated that activation of PKC beta, a calcium-dependent PKC isoform, leads to IKK2 activation in many cell types. However, the roles of Ca 2+ signaling and PKC beta in the activation of IKK2 in mast cells remain largely unknown. Methods: We investigated the effect of PKC inhibitor Go6976 on calcium ionophore A23187-induced activation of IKK2 in mast cells. We also examined the role of IKK2 in A23187-induced NF-kB-dependent gene induction, degranulation, proinflammatory cytokine production and extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation by using IKK2-deficient (IKK2(-/-)) fetal liver-derived mast cells (FLMCs). Results: A23187 activated IKK2 and NF-kB even in the presence of Go6976 in mast cells. A23187-induced degranulation, cytokine production and activation of ERK1/2 were diminished in IKK2(-/-)FLMCs compared to those in wild-type FLMCs. Conclusions: Ca2+-IKK2 signaling is involved in the degranulation and cytokine production in activated mast cells by a mechanism independent of PKC beta. Copyright (C) 2013 S. Karger AG, Basel