| First Author | Kuwabara T | Year | 2012 |
| Journal | J Leukoc Biol | Volume | 92 |
| Issue | 2 | Pages | 309-18 |
| PubMed ID | 22591694 | Mgi Jnum | J:186174 |
| Mgi Id | MGI:5431157 | Doi | 10.1189/jlb.0811415 |
| Citation | Kuwabara T, et al. (2012) CCR7 ligands up-regulate IL-23 through PI3-kinase and NF-kappaB pathway in dendritic cells. J Leukoc Biol 92(2):309-18 |
| abstractText | We reported previously that the production of IL-23 is impaired in DCs from mice that lack expression of the chemokines CCL19 and CCL21, which share the receptor CCR7, suggesting that these chemokines are required for IL-23 expression. However, the molecular mechanism of CCR7-mediated IL-23 production in DCs is unknown. We found that CCL19 and CCL21 stimulated DCs through CCR7 and induced transcription of IL-23p19 mRNA and IL-23 production in splenic and BMDC. Stimulation of DCs with CCR7 ligands induced phosphorylation of MAPK family members and of Akt, but only a specific PI3K inhibitor, LY294002, not inhibitors of ERK, JNK, or p38, decreased IL-23p19 transcription and IL-23 production. In DCs stimulated with CCL19 or CCL21, IkappaBalpha was degraded, and NF-kappaB was translocated into the nucleus. Prevention of NF-kappaB activation blocked chemokine-mediated IL-23p19 transcription. A PI3K inhibitor abolished NF-kappaB activation and IL-23 production. Based on these findings, we concluded that PI3K and NF-kappaB signaling pathways play a critical role in CCR7-mediated IL-23 production in murine DCs. As IL-23 contributes to Th17 cell generation, and Th17 cells are pathogenic in autoimmune diseases, precise elucidation of these mechanisms would contribute to the development of strategies to control autoimmune diseases. |
