title: CCR7 ligands up-regulate IL-23 through PI3-kinase and NF-κ B pathway in dendritic cells.
abstract: 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.
authors.affiliation: Department of Immunology, Toho University School of Medicine, Tokyo, Japan. kuwabara@med.toho-u.ac.jp
authors.forename: Taku
authors.initials: T
authors.lastname: Kuwabara
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Fumio
authors.initials: F
authors.lastname: Ishikawa
authors.forename: Motonari
authors.initials: M
authors.lastname: Kondo
authors.forename: Hideki
authors.initials: H
authors.lastname: Sekiya
authors.forename: Terutaka
authors.initials: T
authors.lastname: Kakiuchi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D005260:Female; D053760:Interleukin-23 Subunit p19 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D054400:Receptors, CCR7 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation
chemical_list: C515371:Ccr7 protein, mouse; C508841:Il23a protein, mouse; D053760:Interleukin-23 Subunit p19; D008024:Ligands; D016328:NF-kappa B; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019869:Phosphatidylinositol 3-Kinases