Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity
Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity
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DOI：
10.4049/jimmunol.176.9.5362
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发表时间：
2006-05-01
影响因子：
4.4
通讯作者：
Diaz-Guerra, Maria Jose M.
中科院分区：
文献类型：
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作者：
Monsalve, Eva;Perez, Miguel A.;Diaz-Guerra, Maria Jose M.
Notch信号传导已经广泛涉及免疫系统发育沿着的细胞命运决定。然而，Notch信号在完全分化的免疫细胞中的作用尚未明确。我们分析了Notch蛋白家族成员在巨噬细胞活化过程中的表达。静息巨噬细胞表达Notch-1、-2和-4，以及Notch配体Jagged-1和-2。用LPS和/或IFN-γ处理后，我们观察到Notch-1和Jagged-1 mRNA和蛋白水平的p38 MAPK依赖性增加。为了研究Notch信号在巨噬细胞活化中的作用，我们在Raw 264.7细胞中强制瞬时表达截短的活性细胞内Notch-1（Notch-IC）蛋白，并分析其对参与巨噬细胞活化的转录因子活性的影响。Notch-IC增加STAT-1依赖性转录。此外，Raw 264.7 Notch-IC稳定转染子响应于IFN-γ增加了STAT 1依赖性转录，导致IFN调节因子-1、细胞因子信号传导抑制因子-1、ICAM-1和MHC II类蛋白的更高表达。这种作用独立于STAT 1 Tyr或Ser磷酸化的增加。然而，诱导型NO合酶的表达和NO的产生在相同的条件下下降。我们的研究结果表明，Notch上调和随后的信号转导后，巨噬细胞活化调节基因表达模式，已知影响成熟巨噬细胞的功能。
Notch signaling has been extensively implicated in cell-fate determination along the development of the immune system. However, a role for Notch signaling in fully differentiated immune cells has not been clearly defined. We have analyzed the expression of Notch protein family members during macrophage activation. Resting macrophages express Notch-1, -2, and -4, as well as the Notch ligands Jagged-1 and -2. After treatment with LPS and/or IFN-y, we observed a p38 MAPK-dependent increase in Notch-1 and Jagged-1 mRNA and protein levels. To study the role of Notch signaling in macrophage activation, we forced the transient expression of truncated, active intracellular Notch-1 (Notch-IC) proteins in Raw 264.7 cells and analyzed their effects on the activity of transcription factors involved in macrophage activation. Notch-IC increased STAT-1-dependent transcription. Furthermore, Raw 264.7 Notch-IC stable transfectants increased STAT1-dependent transcription in response to IFN-gamma, leading to higher expression of IFN regulatory factor-1, suppressor of cytokine signaling-1, ICAM-1, and MHC class II proteins. This effect was independent from an increase of STAT1 Tyr or Ser phosphorylation. However, inducible NO synthase expression and NO production decreased under the same conditions. Our results show that Notch up-regulation and subsequent signaling following macrophage activation modulate gene expression patterns known to affect the function of mature macrophages.