Involvement of Notch signaling pathway in regulating IL-12 expression via c-Rel in activated macrophages.
Involvement of Notch signaling pathway in regulating IL-12 expression via c-Rel in activated macrophages.
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DOI：
10.1016/j.molimm.2012.03.017
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发表时间：
2012-07
影响因子：
3.6
通讯作者：
Palaga T
中科院分区：
文献类型：
--
作者：
Boonyatecha N;Sangphech N;Wongchana W;Kueanjinda P;Palaga T
巨噬细胞在先天性和适应性免疫反应中发挥着重要作用。使用干扰素 (IFN) γ 与脂多糖 (LPS) 一起治疗可激活促炎巨噬细胞，巨噬细胞分泌各种促炎细胞因子，包括 IL-12。 IL-12 通过直接控制 CD4+ T 辅助细胞 1 细胞的分化来促进 Th1 型免疫反应。据报道，Notch 信号通路在活化的巨噬细胞中被激活，但该信号通路在 IL-12 表达中的参与尚未有记录。在本研究中，我们研究了 Notch 信号传导在调节 IL-12/IL-23 亚基 IL-12p40 表达中的作用。使用 γ 分泌酶抑制剂 (GSI) 抑制 Notch 信号传导，我们观察到 IFNγ/LPS 刺激后 il12p40 mRNA 水平和 IL-12p70 分泌显着降低。另一方面，在活化的RAW264.7巨噬细胞样细胞系中，活化形式的Notch1的过度表达显着增加了il12p40 mRNA的水平。 GSI 处理不影响 irf5 的表达，irf5 是巨噬细胞中 il12p40 转录的主要调节因子。对受这种抑制影响的信号级联的详细分析表明，GSI 处理会抑制 c-Rel 核转位，并且会损害 Erk1/2 的激活。在 GSI 存在的情况下，添加外源肿瘤坏死因子 (TNF) α 只能部分恢复 il12p40 的表达。出乎意料的是，使用显性失活（DN）Mastermind样（MAML）转录共激活剂抑制Notch信号传导，并不影响激活后的c-Rel核定位或il12p40 mRNA水平，这表明Notch信号传导的转录活性对于c-Rel的激活是可有可无的。这些结果强烈表明，激活的巨噬细胞中的 Notch 信号传导参与通过 c-Rel 直接调节 il12p40 的表达，并通过 TNFα 的产生间接调节 il12p40 的表达。
Macrophages play an important role both in innate and adaptive immune responses. Treatment with interferon (IFN) γ together with lipopolysaccharide (LPS) activates pro-inflammatory macrophages which secrete various pro-inflammatory cytokines including IL-12. IL-12 promotes a Th1 type immune response by directly controlling the differentiation of CD4+ T helper 1 cells. Activation of Notch signaling pathway was reported in activated macrophages but the involvement of this signaling pathway in IL-12 expression has not been documented. In this study, we investigated the role of Notch signaling in regulating expression of the IL-12/IL-23 subunit, IL-12p40. Using a gamma-secretase inhibitor (GSI) to inhibit Notch signaling, we observed a profound decrease in il12p40 mRNA levels and IL-12p70 secretion upon IFNγ/LPS stimulation. On the other hand, overexpression of activated form of Notch1 in activated RAW264.7 macrophage-like cell lines significantly increased the level of il12p40 mRNA. GSI treatment did not affect the expression of irf5, a master regulator of il12p40 transcription in macrophages. Detailed analysis of the signaling cascades that were affected by this inhibition showed that c-Rel nuclear translocation was inhibited and Erk1/2 activation was compromised by GSI treatment. Addition of exogenous tumor necrosis factor (TNF) α only partially rescued the expression of il12p40 in the presence of GSI. Unexpectedly, inhibition of Notch signaling using a dominant negative (DN) Mastermind-like (MAML) transcription co-activator, did not affect c-Rel nuclear localization upon activation or il12p40 mRNA levels, suggesting that the transcriptional activity of Notch signaling is dispensable for the activation of c-Rel. These results strongly suggest that Notch signaling in activated macrophages is involved in regulating the expression of il12p40 directly via c-Rel and indirectly via TNFα production.
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