Shimokawara Tatsuo, Yamada Eiji, Masui Katsuya, Mishima Kenji, Enomoto Yasunori, Inoue Kazuya, Sakaki Toshisuke, Ichijima Kunio
Department of Pathology, Nara Medical University, Kashihara, Japan.
Neuropathology. 2002 Dec;22(4):261-8. doi: 10.1046/j.1440-1789.2002.00463.x.
Mitogen-activated protein (MAP) kinase cascades are activated in response to various extracellular stimuli. P38 MAP kinase is one of the MAP kinase family and is activated by proinflammatory cytokines and environmental stresses. Activating transcription factor-2 (ATF-2) is one of the targets for p38 MAP kinase. To obtain information on the role of the p38 MAP kinase in the neurons and glial cells after axotomy, we investigated changes of expression of p38 MAP kinase, MAP kinase kinase (MKK) 3, MKK4, MKK6 and ATF-2 in the dorsal motor nucleus of the vagus nerve and the hypoglossal nucleus following axotomy in rats using in situ hybridization and immunohistochemical techniques. Expression of p38 MAP kinase mRNA was observed in the neurons in control rats and showed no remarkable changes after axotomy in both nuclei. On the other hand, expression of p38 MAP kinase mRNA was observed in the perineuronal microglias after axotomy. The expression of p38 MAP kinase, activated p38 MAP kinase, MKK3 and ATF-2 were immunohistochemically observed in neurons of control rats in both nuclei. After axotomy, the expression of p38 MAP kinase, active and inactive, and ATF-2 in neurons were reduced in both nuclei, while expression of mRNA of p38 MAP kinase showed no reduction in neurons. These findings indicate that p38 MAP kinase is functionally regulated not by synthesis but by phosphorylation and regulates the activation of ATF-2 in neurons, and this cascade plays some role in retrograde neuronal reactions. Moreover, perineuronal microglial cells showed strong expression of p38 MAP kinase, active and inactive, after axotomy in both nuclei. These findings suggest that p38 MAP kinase is related to microglial cell reactions after axotomy.
丝裂原活化蛋白（MAP）激酶级联反应在响应各种细胞外刺激时被激活。p38 MAP激酶是MAP激酶家族之一，可被促炎细胞因子和环境应激激活。活化转录因子-2（ATF-2）是p38 MAP激酶的靶标之一。为了获得有关p38 MAP激酶在轴突切断后神经元和神经胶质细胞中的作用的信息，我们使用原位杂交和免疫组织化学技术研究了大鼠轴突切断后迷走神经背运动核和舌下神经核中p38 MAP激酶、MAP激酶激酶（MKK）3、MKK4、MKK6和ATF-2的表达变化。在对照大鼠的神经元中观察到p38 MAP激酶mRNA的表达，并且在轴突切断后两个核中均未显示出明显变化。另一方面，轴突切断后在神经元周围的小胶质细胞中观察到p38 MAP激酶mRNA的表达。在对照大鼠的两个核的神经元中通过免疫组织化学观察到p38 MAP激酶、活化的p38 MAP激酶、MKK3和ATF-2的表达。轴突切断后，两个核中神经元中p38 MAP激酶（活性和非活性）和ATF-2的表达均降低，而神经元中p38 MAP激酶的mRNA表达未降低。这些发现表明，p38 MAP激酶在功能上不是通过合成而是通过磷酸化来调节的，并调节神经元中ATF-2的激活，并且该级联反应在逆行神经元反应中起一定作用。此外，轴突切断后两个核中神经元周围的小胶质细胞均显示出活性和非活性p38 MAP激酶的强表达。这些发现表明，p38 MAP激酶与轴突切断后的小胶质细胞反应有关。
