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CCR7 ligands up-regulate IL-23 through PI3-kinase and NF- B pathway in dendritic cells

Kuwabara, T;Tanaka, Y;Ishikawa, F;Kondo, M;Sekiya, H;Kakiuchi, T;

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, I B was degraded, and NF- B was translocated into the nucleus. Prevention of NF- B activation blocked chemokine-mediated IL-23p19 transcription. A PI3K inhibitor abolished NF- B activation and IL-23 production. Based on these findings, we concluded that PI3K and NF- B 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.