Iijima Norifumi, Yanagawa Yoshiki, Clingan Jonathan M, Onoé Kazunori
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Int Immunol. 2005 Sep;17(9):1201-12. doi: 10.1093/intimm/dxh297. Epub 2005 Jul 18.
c-Jun N-terminal kinase (JNK) is generally thought to be involved in inflammation, proliferation and apoptosis. However, functional role(s) of this molecule in dendritic cells (DCs) has not been well understood. CCR7 ligands, CCL19 and CCL21, induce not only chemotaxis but also endocytosis in mature DCs. In the present study, we examined the role of JNK for inducing chemotaxis and endocytosis in murine mature DCs. CCL19 rapidly enhanced endocytosis of mature DCs within a few minutes, whereas significant migration of mature DCs to this chemokine was detected 30 min or more after incubation. CCL19 significantly activated JNK in mature DCs at 15 min. CCL19 also increased interaction between phospho-JNK and phospho-mitogen-activated protein kinase kinase (MKK) 4 but not phospho-MKK7 in mature DCs, suggesting that the JNK activation is mediated via MKK4. Blocking of this JNK activation significantly inhibited the CCL19-induced migration of mature DCs. Blocking of Rho-associated kinase also inhibited the CCL19-induced migration without affecting the JNK activation. On the other hand, the inhibition of either JNK or Rho-associated kinase showed no significant effects on CCL19-induced endocytosis by mature DCs. These findings suggest that CCL19 activates JNK via a Rho-independent pathway, thereby inducing migration of mature DCs, whereas the JNK activation is dispensable for the CCL19-induced endocytosis. It seems that at least two different pathways, JNK pathway and Rho-associated kinase pathway, are involved in the CCR7-mediated migration of mature DCs. Thus, we demonstrate herein a novel role of JNK for regulating chemokine-induced DC migration.
c-Jun氨基末端激酶（JNK）通常被认为参与炎症、增殖和凋亡过程。然而，该分子在树突状细胞（DCs）中的功能作用尚未得到充分了解。CCR7配体CCL19和CCL21不仅能诱导成熟DCs的趋化作用，还能诱导其胞吞作用。在本研究中，我们检测了JNK在诱导小鼠成熟DCs趋化和胞吞作用中的作用。CCL19在几分钟内迅速增强了成熟DCs的胞吞作用，而在孵育30分钟或更长时间后才检测到成熟DCs对这种趋化因子的显著迁移。CCL19在15分钟时显著激活了成熟DCs中的JNK。CCL19还增加了成熟DCs中磷酸化JNK与磷酸化丝裂原活化蛋白激酶激酶（MKK）4之间的相互作用，但未增加与磷酸化MKK7的相互作用，这表明JNK的激活是通过MKK4介导的。阻断这种JNK激活显著抑制了CCL19诱导的成熟DCs迁移。阻断Rho相关激酶也抑制了CCL19诱导的迁移，而不影响JNK激活。另一方面，抑制JNK或Rho相关激酶对CCL19诱导的成熟DCs胞吞作用均无显著影响。这些发现表明，CCL19通过Rho非依赖途径激活JNK，从而诱导成熟DCs迁移，而JNK激活对于CCL19诱导的胞吞作用是可有可无的。似乎至少有两条不同的途径，即JNK途径和Rho相关激酶途径，参与了CCR7介导的成熟DCs迁移。因此，我们在此证明了JNK在调节趋化因子诱导的DC迁移中的新作用。
