Uesugi Miyuki, Nakajima Kazuyuki, Tohyama Yoko, Kohsaka Shinichi, Kurihara Tadashi
Neurobiology Lab, Department of Bioinformatics, Faculty of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan.
Brain Res. 2006 Feb 16;1073-1074:48-59. doi: 10.1016/j.brainres.2005.12.043. Epub 2006 Feb 2.
The molecular mechanism of cytotoxic cytokine tumor necrosis factor alpha (TNFalpha) induction in microglia remains to be clarified. We have previously reported that p38 mitogen-activated protein kinase (p38MAPK) is an important signaling molecule for the induction of TNFalpha in lipopolysaccharide (LPS)-stimulated microglia. Recently, we have shown that c-Jun N-terminal kinase (JNK) is associated with the induction of TNFalpha. Furthermore, using an NFkappaB inhibitor (SN50), we discovered that activation of nuclear factor kappaB (NFkappaB) may also be linked to TNFalpha induction. We therefore examined the relationship between NFkappaB and the two MAPKs (p38MAPK and JNK) in the signaling cascade of TNFalpha induction in LPS-stimulated microglia. NFkappaB inhibitor SN50 decreased the induction of TNFalpha under the suppressed NFkappaB activation. However, SN50 was found to prevent the activation of MKK3/6-p38MAPK and MKK4-JNK pathways. On the other hand, the other NFkappaB inhibitor ammonium pyrrolidine dithiocarbamate (APDC) neither prevented the activation of p38MAPK and JNK nor inhibited TNFalpha induction in LPS-stimulated microglia, although it was confirmed to serve as an NFkappaB inhibitor. These results suggest that both MKK3/6-p38MAPK and MKK4-JNK pathways are important signaling cascades leading to the induction of TNFalpha in LPS-stimulated microglia, but that NFkappaB itself is not required for this induction.
小胶质细胞中细胞毒性细胞因子肿瘤坏死因子α（TNFα）诱导的分子机制仍有待阐明。我们之前报道过，p38丝裂原活化蛋白激酶（p38MAPK）是脂多糖（LPS）刺激的小胶质细胞中诱导TNFα的重要信号分子。最近，我们发现c-Jun氨基末端激酶（JNK）与TNFα的诱导有关。此外，使用NFκB抑制剂（SN50），我们发现核因子κB（NFκB）的激活也可能与TNFα的诱导有关。因此，我们研究了LPS刺激的小胶质细胞中TNFα诱导信号级联反应中NFκB与两种丝裂原活化蛋白激酶（p38MAPK和JNK）之间的关系。NFκB抑制剂SN50在NFκB激活受到抑制的情况下降低了TNFα的诱导。然而，发现SN50可阻止MKK3/6-p38MAPK和MKK4-JNK途径的激活。另一方面，另一种NFκB抑制剂吡咯烷二硫代氨基甲酸铵（APDC）既不能阻止p38MAPK和JNK的激活，也不能抑制LPS刺激的小胶质细胞中TNFα的诱导，尽管已证实它可作为NFκB抑制剂。这些结果表明，MKK3/6-p38MAPK和MKK4-JNK途径都是LPS刺激的小胶质细胞中导致TNFα诱导的重要信号级联反应，但NFκB本身并非这种诱导所必需。
