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

J Leukoc Biol. 2012 Aug;92(2):309-18. doi: 10.1189/jlb.0811415. Epub 2012 May 16.


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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Female
  • Interleukin-23 Subunit p19 / biosynthesis*
  • Interleukin-23 Subunit p19 / genetics
  • Interleukin-23 Subunit p19 / physiology
  • Ligands
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • NF-kappa B / physiology*
  • Phosphatidylinositol 3-Kinases / physiology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, CCR7 / genetics
  • Receptors, CCR7 / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Up-Regulation


  • Ccr7 protein, mouse
  • Il23a protein, mouse
  • Interleukin-23 Subunit p19
  • Ligands
  • NF-kappa B
  • RNA, Messenger
  • Receptors, CCR7
  • Phosphatidylinositol 3-Kinases