Inducible IL-33 expression by mast cells is regulated by a calcium-dependent pathway.
Inducible IL-33 expression by mast cells is regulated by a calcium-dependent pathway.
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DOI：
10.4049/jimmunol.1201224
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发表时间：
2012-10-01
期刊：
影响因子：
--
通讯作者：
Bryce PJ
中科院分区：
文献类型：
--
作者：
Hsu CL;Bryce PJ
白细胞介素（IL）-33是IL-1家族细胞因子，其显示双重功能：通过其受体T1/ST 2或细胞核内的染色质结合因子的细胞因子。在功能上，它通过增强几种细胞类型的活化和存活来促进Th 2相关免疫。然而，调控IL-33表达的途径仍不清楚。虽然几种细胞显示组成型表达IL-33，我们以前表明，肥大细胞表达低水平的IL-33组成型，但IL-33诱导IgE介导的激活。这是通过钙依赖性机制介导的。在这里，我们定义了这种诱导型IL-33的调节途径。重要的是，该途径不改变具有高组成性IL-33表达的细胞（如上皮细胞或成纤维细胞）中的表达。我们的数据表明，在钙离子上游，抑制PI 3 K和Sphk活性降低了诱导型IL-33表达IgE/抗原活化。此外，Sphk 1 shRNA的表达阻止了IL-33表达的上调。在钙的下游，NFAT活性是诱导型IL-33表达所必需和充分的。我们还证明了钙依赖性转录从两个区域的IL-33基因，含有假定的NFAT结合位点，一个上游的外显子1和一个上游的起始位点。有趣的是，我们发现阻断其他钙通道，包括IP 3 R或NF-κB抑制IgE驱动的IL-1β，另一种IL-1家族细胞因子，但对诱导型IL-33表达没有影响。总之，我们的数据证明了IL-33表达调控的细胞特异性差异，并确定了肥大细胞活化后表达诱导型IL-33的关键途径。
Interleukin (IL)-33 is an IL-1 family cytokine that displays dual function: a cytokine via its receptor, T1/ST2 or a chromatin-binding factor within the nucleus. Functionally, it promotes Th2-associated immunity by enhancing the activation and survival of several cell types. However, the pathways regulating IL-33 expression are still unclear. While several cells display constitutive expression of IL-33, we showed previously that mast cells expressed low levels of IL-33 constitutively but that IL-33 was induced upon IgE-mediated activation. This was mediated via a calcium-dependent mechanism. Here, we define the pathway through which this inducible IL-33 is regulated. Importantly, this pathway does not alter expression in cells with high constitutive IL-33 expression, like epithelial cells or fibroblasts. Our data shows that, upstream of calcium, inhibition of PI3K and Sphk activity decreases inducible IL-33 expression to IgE/antigen activation. In addition, expression of Sphk1 shRNA prevents upregulation of IL-33 expression. Downstream of calcium, NFAT activity is necessary and sufficient for inducible IL-33 expression. We also demonstrate calcium-dependent transcription from two regions of the IL-33 gene that contain putative NFAT-binding sites, one upstream of exon 1 and one upstream of the start site. Interestingly, we show that blocking other calcium pathways, including IP3R, or NF-κB inhibits IgE-driven IL-1β, another IL-1 family cytokine, but have no influence on inducible IL-33 expression. In summary, our data demonstrates cell-specific differences in the regulation of IL-33 expression and defines a pathway critical for the expression of inducible IL-33 by mast cells upon their activation.
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