In:
Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 92, No. 2 ( 2012-08-01), p. 309-318
Abstract:
CCR7 ligands activate PI3-kinase and NF-κB pathways in DC to induce the expression of IL-23p19. 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, IκBα was degraded, and NF-κB was translocated into the nucleus. Prevention of NF-κB activation blocked chemokine-mediated IL-23p19 transcription. A PI3K inhibitor abolished NF-κB activation and IL-23 production. Based on these findings, we concluded that PI3K and NF-κB 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.
Type of Medium:
Online Resource
ISSN:
1938-3673
,
0741-5400
Language:
English
Publisher:
Oxford University Press (OUP)
Publication Date:
2012
detail.hit.zdb_id:
2026833-6
SSG:
12
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