Impaired bcl3 up-regulation leads to enhanced lipopolysaccharide-induced interleukin (IL)-23P19 gene expression in IL-10-/- mice
Impaired bcl3 up-regulation leads to enhanced lipopolysaccharide-induced interleukin (IL)-23P19 gene expression in IL-10-/- mice
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DOI：
10.1074/jbc.m709029200
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发表时间：
2008-05-23
影响因子：
4.8
通讯作者：
Jobin, Christian
中科院分区：
文献类型：
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作者：
Muehlbauer, Marcus;Chilton, Paula M.;Jobin, Christian
遗传和生化分析表明，IL-23p19 在介导白细胞介素 10 缺陷 (IL-10(-/-)) 小鼠细菌诱导的结肠炎中发挥着核心作用。对导致IL-10(-/-)小鼠中IL-23基因表达增强的先天宿主反应失调的分子机制知之甚少。在这项研究中，我们研究了 Bcl3 在控制从 IL-10(-/-) 小鼠分离的骨髓源性树突状细胞 (BMDC) 中 LPS 诱导的 IL-23p19 基因表达的作用。我们报告，与 WT 小鼠相比，从 IL-10(-/-) 分离的 LPS 刺激的 BMDC 中 IL-23p19 mRNA 积累和蛋白质分泌更高。与 WT BMDC 相比，IL-10(-/-) BMDC 中脂多糖 (LPS) 诱导的 B 细胞白血病 3 (Bcl3) 表达严重受损（降低 90%）。染色质免疫沉淀证明与WT BMDC相比，RelA与IL-10(-/-)中的IL-23p19启动子的结合增强。 Bcl3 过表达降低了 IL-10(-/-) BMDC 中 LPS 诱导的 IL-23p19 基因表达，这与增强的 NF-κ B p50 结合和降低的 RelA 与基因启动子的结合相关。相反，Bcl3 敲低增强了 WT BMDC 中 LPS 诱导的 IL-23p19 基因表达。此外，与WT BMDC相比，Bcl3(-/-) BMDC中LPS诱导的IL-23p19基因表达显着增强。总之，IL-10(-/-)小鼠中LPS诱导的IL-23p19基因表达增强是由于Bcl3表达受损导致p50减少和RelA向IL-23p19启动子的募集增强。
Genetic and biochemical analyses show that IL-23p19 plays a central role in mediating bacteria- induced colitis in interleukin-10-deficient (IL-10(-/-)) mice. The molecular mechanisms responsible for the dysregulated innate host response leading to enhanced IL- 23 gene expression in IL- 10(-/-) mice are poorly understood. In this study, we investigated the role of Bcl3 in controlling LPS-induced IL-23p19 gene expression in bone marrow-derived dendritic cells (BMDC) isolated from IL- 10(-/-) mice. We report higher IL-23p19 mRNA accumulation and protein secretion in LPS-stimulated BMDC isolated from IL- 10(-/-) compared with WT mice. Lipopolysaccharide ( LPS)-induced B cell leukemia 3 ( Bcl3) expression was strongly impaired ( 90% decrease) in IL- 10(-/-) BMDC compared with WT BMDC. Chromatin immunoprecipitation demonstrated enhanced RelA binding to the IL-23p19 promoter in IL- 10(-/-) compared with WT BMDC. Bcl3 overexpression decreased LPS-induced IL-23p19 gene expression in IL- 10(-/-) BMDC, which correlated with enhanced NF-kappa B p50 binding and decreased RelA binding to the gene promoter. Conversely, Bcl3 knockdown enhanced LPS-induced IL-23p19 gene expression in WT BMDC. Moreover, LPS-induced IL-23p19 gene expression was significantly enhanced in Bcl3(-/-) BMDC compared with WT BMDC. In conclusion, enhanced LPS-induced IL-23p19 gene expression in IL- 10(-/-) mice is due to impaired Bcl3 expression leading to diminished p50 and enhanced RelA recruitment to the IL-23p19 promoter.