CCR7 ligands up-regulate IL-23 through PI3-kinase and NF-κB pathway in dendritic cells
CCR7 ligands up-regulate IL-23 through PI3-kinase and NF-κB pathway in dendritic cells
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DOI：
10.1189/jlb.0811415
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发表时间：
2012-08-01
影响因子：
5.5
通讯作者：
Kakiuchi, Terutaka
中科院分区：
文献类型：
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作者：
Kuwabara, Taku;Tanaka, Yuriko;Kakiuchi, Terutaka
我们以前报道过，在缺乏趋化因子CCL 19和CCL 21表达的小鼠的DC中，IL-23的产生受损，这表明这些趋化因子是IL-23表达所必需的。然而，CCR 7介导的DC中IL-23产生的分子机制尚不清楚。我们发现，CCL 19和CCL 21通过CCR 7刺激DC，并诱导脾和BMDC中IL-23 p19 mRNA的转录和IL-23的产生。用CCR 7配体刺激DC诱导MAPK家族成员和Akt的磷酸化，但只有特异性PI 3 K抑制剂LY 294002，而不是ERK、JNK或p38抑制剂，降低IL-23 p19转录和IL-23产生。在用CCL 19或CCL 21刺激的DC中，I-κ B α被降解，NF-κ B易位到细胞核中。NF-κ B活化的预防阻断了趋化因子介导的IL-23 p19转录。PI 3 K抑制剂可阻断NF-κ B活化和IL-23产生。基于这些发现，我们得出结论，PI 3 K和NF-κ B信号通路在小鼠DC中CCR 7介导的IL-23产生中起关键作用。由于IL-23有助于Th 17细胞的产生，并且Th 17细胞在自身免疫性疾病中是致病性的，因此这些机制的精确阐明将有助于控制自身免疫性疾病的策略的发展。J. Leukoc. 92：309-318; 2012.
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 kappa B alpha was degraded, and NF-kappa B was translocated into the nucleus. Prevention of NF-kappa B activation blocked chemokine-mediated IL-23p19 transcription. A PI3K inhibitor abolished NF-kappa B activation and IL-23 production. Based on these findings, we concluded that PI3K and NF-kappa 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. J. Leukoc. Biol. 92: 309-318; 2012.