B-cell receptor- and phorbol ester-induced NF-κB and c-Jun N-terminal kinase activation in B cells requires novel protein kinase C's
B-cell receptor- and phorbol ester-induced NF-κB and c-Jun N-terminal kinase activation in B cells requires novel protein kinase C's
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DOI：
10.1128/mcb.21.19.6640-6650.2001
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发表时间：
2001-10-01
影响因子：
5.3
通讯作者：
Scheidereit, C
中科院分区：
文献类型：
--
作者：
Krappmann, D;Patke, A;Scheidereit, C
已知抗原受体信号传导可激活淋巴细胞中的 NF-κB。虽然 T 细胞受体诱导的 NF-kappaB 激活关键取决于新型蛋白激酶 C theta (PKC theta)，但新型 PKC 在 B 细胞刺激中的作用尚未阐明。在原代小鼠脾 B 细胞中，我们发现新型 PKC δ 和 epsilon 高表达，但 theta 亚型仅弱表达。 Rottlerin 在原代 B 细胞和 T 细胞中阻断佛波酯（佛波醇肉豆蔻酸酯 [PMA]）或 B 细胞受体 (BCR) 介导的 NF-kappaB 和 c-Jun N 末端激酶 (JNK) 激活，程度相似，表明新型 PKC 是造血细胞信号传导的正调节因子。小鼠 70Z/3 前 B 细胞已被广泛用作 B 细胞中 NF-kappaB 激活的模型。与脾 B 细胞中的情况类似，rottlerin 抑制 70Z/3 细胞中 NF-kappaB 的 BCR 和 PMA 刺激。 70Z/3 细胞的衍生细胞 1.3E2 细胞由于缺乏 I kappaB 激酶 (IKK gamma) 蛋白而在 NF-kappaB 激活方面存在缺陷。 IKK γ 的异位表达可以挽救脂多糖 (LPS) 和白介素 1 β (IL-1 β) 引起的 NF-κB 激活，但不能挽救 PMA 引起的 NF-κB 激活。此外，PMA 诱导的丝裂原激活蛋白激酶 JNK 的激活在 1.3E2 细胞中被阻断，表明这两条途径共有的上游成分缺失或突变。对各种 PKC 同工型的分析表明，1.3E2 细胞中完全不存在 PKC theta，而 70Z/3 细胞中则表达 PKC theta。在 1.3E2 IKK gamma 表达细胞中，新型 PKC theta 或 δ 的稳定表达（而非经典 PKC beta II）可挽救 NF-kappaB 和 JNK 信号传导的 PMA 激活，这表明新型 PKC 对于 B 细胞激活具有关键作用。
Antigen receptor signaling is known to activate NF-kappaB in lymphocytes. While T-cell-receptor-indticed NF-kappaB activation critically depends on novel protein kinase C theta (PKC theta), the role of novel PKCs in B-cell stimulation has not been elucidated. In primary murine splenic B cells, we found high expression of the novel PKCs delta and epsilon but only weak expression of the theta isoform. Rottlerin blocks phorbol ester (phorbol myristate acetate [PMA])or B-cell receptor (BCR)-mediated NF-kappaB and c-Jun N-terminal kinase (JNK) activation in primary B and T cells to a similar extent, suggesting that novel PKCs are positive regulators of signaling in hematopoietic cells. Mouse 70Z/3 pre-B cells have been widely used as a model for NF-kappaB activation in B cells. Similar to the situation in splenic B cells, rottlerin inhibits BCR and PMA stimulation of NF-kappaB in 70Z/3 cells. A derivative of 70Z/3 cells, 1.3E2 cells, are defective in NF-kappaB activation due to the lack of the I kappaB kinase (IKK gamma) protein. Ectopic expression of IKK gamma can rescue NF-kappaB activation in response to lipopolysaccharides (LPS) and interleukin-1 beta (IL-1 beta), but not to PMA. In addition, PMA-induced activation of the mitogen-activated protein kinase JNK is blocked in 1.3E2 cells, suggesting that an upstream component common to both pathways is either missing or mutated. Analysis of various PKC isoforms revealed that exclusively PKC theta was absent in 1.3E2 cells while it was expressed in 70Z/3 cells. Stable expression of either novel PKC theta or -delta but not classical PKC beta II in 1.3E2 IKK gamma -expressing cells rescues PMA activation of NF-kappaB and JNK signaling, demonstrating a critical role of novel PKCs for B-cell activation.