CCR7-mediated c-Jun N-terminal kinase activation regulates cell migration in mature dendritic cells.
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.
Iijima
Norifumi
N
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-0815, Japan.
Yanagawa
Yoshiki
Y
Clingan
Jonathan M
JM
Onoé
Kazunori
K
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000276:immunology / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D004705:Endocytosis / Q000276:immunology; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology*; D019402:Macrophage Inflammatory Proteins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
C515479:Ccl21c protein, mouse; C095218:Ccl9 protein, mouse; C515371:Ccr7 protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D048031:JNK Mitogen-Activated Protein Kinases