Convergence of CpG DNA- and BCR-mediated signals at the c-Jun N-terminal kinase and NF-kappaB activation pathways: regulation by mitogen-activated protein kinases.
Convergence of CpG DNA- and BCR-mediated signals at the c-Jun N-terminal kinase and NF-kappaB activation pathways: regulation by mitogen-activated protein kinases.
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DOI：
10.1093/intimm/dxg058
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发表时间：
2003-05
影响因子：
4.4
通讯作者：
A. Yi;Jae-Geun Yoon;A. Krieg
中科院分区：
文献类型：
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作者：
A. Yi;Jae-Geun Yoon;A. Krieg
根据实验模型，细菌DNA或合成寡脱氧核苷酸（CpG DNA）中的未甲基化CpG基序可增强或拮抗B细胞中BCR诱导的信号。CpG DNA与BCR诱导的成熟B细胞增殖和IG产生协同作用，但阻断BCR介导的未成熟B细胞凋亡。在这里，我们使用小鼠B淋巴瘤细胞系WEHI-231（未成熟B淋巴细胞的模型）证明，CpG DNA增强了BCR介导的信号，用于激活促分裂原活化蛋白激酶（MAPK）激酶（MKK）3、MKK 4和MKK 6，以及它们随后的下游效应物c-Jun N-末端激酶（JNK）和p38，但不增强MEK 1/2或细胞外信号调节激酶（ERK）的活化。CpG DNA和BCR介导的信号也协同激活转录因子AP-1、NFAT和NF-κ B，但不协同激活cAMP反应元件结合因子。JNK和p38的协同激活有助于由CpG DNA和BCR介导的信号诱导的细胞因子的协同产生，但对CpG DNA保护WEHI-231细胞免于抗IgM诱导的生长停滞的能力几乎没有影响。相反，所有三种MAPK，JNK，ERK和p38，有助于CpG DNA和抗IgM协同诱导脾成熟B细胞增殖。这些结果表明，CpG DNA和BCR介导的信号在MKK、NF-κ B和NFAT活化水平上会聚，并且MAPK对CpG DNA介导的细胞因子产生与脾成熟B细胞和WEHI-231细胞中的细胞增殖具有不同的调节作用。
Depending on the experimental model, unmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (CpG DNA) either augment or antagonize BCR-induced signals in B cells. CpG DNA synergizes with BCR-induced proliferation and Ig production of mature B cells, but blocks BCR-mediated apoptosis of immature B cells. Here, we demonstrate using a murine B lymphoma cell line WEHI-231, which is a model for immature B lymphocytes, that CpG DNA augments BCR-mediated signals for the activation of mitogen-activated protein kinase (MAPK) kinase (MKK)3, MKK4 and MKK6, and their subsequent downstream effectors c-Jun N-terminal kinase (JNK) and p38, but does not enhance MEK1/2 or extracellular signal-regulated kinase (ERK) activation. CpG DNA- and BCR-mediated signals also synergize for the activation of transcription factors AP-1, NFAT and NF-kappaB, but not for cAMP-responsive elements binding factor. Synergistic activations of JNK and p38 contribute to the synergistic production of cytokines induced by CpG DNA- and BCR-mediated signals, but have little or no effect on the ability of CpG DNA to protect WEHI-231 cells from anti-IgM-induced growth arrest. In contrast, all three MAPK, JNK, ERK and p38, contribute to the synergistic induction of splenic mature B cell proliferation by CpG DNA and anti-IgM. These results indicate that CpG DNA- and BCR-mediated signals converge at the level of MKK, NF-kappaB and NFAT activation, and that MAPK have differential regulatory roles for CpG DNA-mediated cytokine production versus cell proliferation in splenic mature B cells and WEHI-231 cells.