Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells.
Manganese modulation of MAPK pathways: effects on upstream mitogen activated protein kinase kinases and mitogen activated kinase phosphatase-1 in microglial cells.
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DOI：
10.1002/jat.1552
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发表时间：
2011-01
影响因子：
3.3
通讯作者：
Filipov, Niko Lay M.
中科院分区：
文献类型：
--
作者：
Crittenden, Patrick L.;Filipov, Niko Lay M.
多项研究表明，锰（Mn）暴露增强炎症介质从激活的神经胶质细胞输出;这种增加的输出与增强的丝裂原活化蛋白激酶（MAPK：p38，ERK和JNK）活性相关。我们假设Mn通过激活MAPK上游的激酶，即，MKK-3/6、MKK-1/2和MKK-4（分别负责p38、ERK和JNK的活化），和/或通过抑制负责MAPK失活的主要磷酸酶MKP-1。将N9小胶质细胞暴露于Mn（250μM）、LPS（100 ng/ml）或Mn+LPS在1 h时增加MKK-3/6和MKK-4活性; Mn+LPS对MKK-4活化的影响大于其余。在4 h时，Mn、LPS和Mn+LPS增加MKK-3/6和MKK-1/2磷酸化，而MKK-4仅被Mn和Mn+LPS激活。除了通过Ser 257/Thr 261磷酸化激活MKK-4之外，Mn（4 h）阻止MKK-4在Ser 80上的磷酸化，其负调节MKK-4活性。暴露于Mn或Mn+LPS（1小时）降低MKP-1的mRNA和蛋白质表达，负MAPK调节剂。此外，我们观察到，在4小时，而不是在1小时，一个时间点，与MAPK活性增加相一致，Mn+LPS显着增加TNF-α，IL-6，和考克斯-2 mRNA，这表明一个延迟效应。MKK的所有三个主要组，MKK-1/2，MKK-3/6和MKK-4被Mn激活的事实表明Mn诱导的MAPK激活通过传统机制发生，这可能涉及最远上游的MAPK，MKKK（MAP 3 Ks）。此外，对于所有MKK，Mn诱导的活化持续至少4小时，表明长期效应。
Multiple studies demonstrate that manganese (Mn) exposure potentiates inflammatory mediator output from activated glia; this increased output is associated with enhanced mitogen activated protein kinase (MAPK: p38, ERK, and JNK) activity. We hypothesized that Mn activates MAPK by activating the kinases upstream of MAPK, i.e., MKK-3/6, MKK-1/2, and MKK-4 (responsible for activation of p38, ERK, and JNK, respectively), and/or by inhibiting a major phosphatase responsible for MAPK inactivation, MKP-1. Exposure of N9 microglia to Mn (250μM), LPS (100 ng/ml), or Mn+LPS increased MKK-3/6 and MKK-4 activity at 1 h; the effect of Mn+LPS on MKK-4 activation was greater than the rest. At 4 h, Mn, LPS, and Mn+LPS increased MKK-3/6 and MKK-1/2 phosphorylation, whereas MKK-4 was activated only by Mn and Mn+LPS. Besides activating MKK-4 via Ser257/Thr261 phosphorylation, Mn (4 h) prevented MKK-4’s phosphorylation on Ser80, which negatively regulates MKK-4 activity. Exposure to Mn or Mn+LPS (1 h) decreased both mRNA and protein expression of MKP-1, the negative MAPK regulator. In addition, we observed that at 4 h, but not at 1 h, a time point coinciding with increased MAPK activity, Mn+LPS markedly increased TNF-α , IL-6, and Cox-2 mRNA, suggesting a delayed effect. The fact that all three major groups of MKKs, MKK-1/2, MKK-3/6, and MKK-4 are activated by Mn suggests that Mn-induced activation of MAPK occurs via traditional mechanisms, which perhaps involve the MAPKs farthest upstream, MKKKs (MAP3Ks). In addition, for all MKKs, Mn-induced activation was persistent at least for 4 h, indicating a long-term effect.
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DOI：
10.1016/s0169-328x(00)00042-5
发表时间：
2000-04-14
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Heyen, JRR;Ye, SM;Johnson, RW
通讯作者：
Johnson, RW
DOI：
10.1084/jem.20051753
发表时间：
2006-01-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hammer M;Mages J;Dietrich H;Servatius A;Howells N;Cato AC;Lang R
通讯作者：
Lang R
影响因子：
4.2
作者：
Chen, CJ;Ou, YC;Chen, JH
通讯作者：
Chen, JH
影响因子：
4.8
作者：
Enslen, H;Raingeaud, J;Davis, RJ
通讯作者：
Davis, RJ
影响因子：
4.8
作者：
Fujishiro, M;Gotoh, Y;Asano, T
通讯作者：
Asano, T