Differential role of reactive oxygen species in the activation of mitogen-activated protein kinases and Akt by key receptors on B-lymphocytes: CD40, the B cell antigen receptor, and CXCR4
Differential role of reactive oxygen species in the activation of mitogen-activated protein kinases and Akt by key receptors on B-lymphocytes: CD40, the B cell antigen receptor, and CXCR4
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DOI：
10.1007/s12079-007-0006-y
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Gold, Michael R.
中科院分区：
文献类型：
--
作者：
Lee, Rosaline L.;Westendorf, Jens;Gold, Michael R.
背景B淋巴细胞产生的抗体在宿主防御感染中起关键作用。B细胞的发育、存活和活化受多种受体调节，包括检测病原体存在的B细胞抗原受体（BCR）、结合活化T细胞上的共刺激分子的CD 40和在B细胞发育和运输中起关键作用的趋化因子如SDF-1（CXCL 12）。许多受体的信号传导导致活性氧物质（ROS）的产生，其通过调节氧化还原敏感性激酶和磷酸酶的活性而作为第二信使起作用。我们研究了活性氧在BCR、CD 40和CXCR 4（SDF-1受体）信号传导中的作用。我们专注于ERK，JNK，p38和Akt，激酶，调节多个过程，包括细胞存活，增殖和migration.Results使用抗氧化剂N-乙酰L-半胱氨酸（NAC）和依布硒啉耗尽细胞内的活性氧的激活，我们确定了一个不同的要求活性氧在ERK，JNK，p38和Akt的激活这些受体。我们发现，CD 40激活JNK，p38，和Akt通过氧化还原依赖性途径是敏感的ROS消耗NAC和依布硒。相反，BCR诱导的ERK、JNK、p38和Akt活化不受ROS耗竭的影响。结论BCR、CD 40和CXCR 4激活ERK、JNK、p38和Akt时对ROS的不同需求可能反映了这些激酶上游激活因子的多样性，其中只有一些可以以氧化还原依赖性方式调节。这些发现支持ROS是B细胞中重要的第二信使的观点，并表明氧化剂或抗氧化剂可用于调节B细胞活化。
Background Antibodies produced by B-lymphocytes play a key role in the host defense against infection. The development, survival, and activation of B cell is regulated by multiple receptors including the B cell antigen receptor (BCR), which detects the presence of pathogens, CD40, which binds costimulatory molecules on activated T cells, and chemokines such as SDF-1 (CXCL12) that play key roles in B cell development and trafficking. Signaling by many receptors results in the generation of reactive oxygen species (ROS) that function as second messengers by regulating the activity of redox-sensitive kinases and phosphatases. We investigated the role of ROS in signaling by the BCR, CD40, and CXCR4, the receptor for SDF-1. We focused on activation of ERK, JNK, p38, and Akt, kinases that regulate multiple processes including cell survival, proliferation, and migration.Results Using the anti-oxidants N-acetyl L-cysteine (NAC) and ebselen to deplete intracellular ROS, we identified a differential requirement for ROS in the activation of ERK, JNK, p38, and Akt by these receptors. We found that CD40 activated JNK, p38, and Akt via redox-dependent pathways that were sensitive to ROS depletion by NAC and ebselen. In contrast, BCR-induced activation of ERK, JNK, p38, and Akt was not affected by ROS depletion. We also found that CXCR4-induced Akt activation was ROS-dependent even though activation of the ERK, JNK, and p38 MAP kinases by CXCR4 occurred via ROS-independent pathways.Conclusion The differential requirement for ROS in the activation of ERK, JNK, p38, and Akt by the BCR, CD40, and CXCR4 likely reflects the multiplicity of upstream activators for each of these kinases, only some of which may be regulated in a redox-dependent manner. These findings support the idea that ROS are important second messengers in B cells and suggest that oxidants or antioxidants could be used to modulate B cell activation.