Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A
Interleukin-23 production in dendritic cells is negatively regulated by protein phosphatase 2A
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DOI：
10.1073/pnas.0914703107
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发表时间：
2010-05-04
影响因子：
11.1
通讯作者：
Chang, Cheong-Hee
中科院分区：
文献类型：
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作者：
Chang, JiHoon;Voorhees, Timothy J.;Chang, Cheong-Hee
IL-12和IL-23由活化的抗原呈递细胞产生，但两者分别通过促进Th 1和Th 17细胞分化诱导不同的免疫应答。IL-23是由两个亚基组成的异二聚体细胞因子：与IL-12共享的p40和IL-23特有的p19。在这项研究中，我们发现，在树突状细胞（DC）中，蛋白磷酸酶2A（PP 2A）负调控IL-23的产生，而不是IL-12。PP 2A通过抑制IL-23 p19基因的表达来抑制IL-23的产生。用抑制PP 2A活性的冈田酸处理DC或用siRNA敲低PP 2A的催化亚基增强IL-23而不是IL-12的产生。与PP 2A不同，MAP激酶磷酸酶-1或CYLD对IL-23的产生没有影响，这支持了PP 2A的特异性。PP 2A介导的抑制需要一种新产生的蛋白质，该蛋白质可能负责在LPS刺激后将PP 2A和IKK β结合在一起，然后导致IKK磷酸化的终止。因此，我们的研究结果揭示了蛋白磷酸酶在调节IL-23产生中的重要作用，并将PP 2A鉴定为DC中IL-23 p19表达的先前未表征的抑制剂。
IL-12 and IL-23 are produced by activated antigen-presenting cells but the two induce distinct immune responses by promoting Th1 and Th17 cell differentiation, respectively. IL-23 is a heterodimeric cytokine consisting of two subunits: p40 that is shared with IL-12 and p19 unique to IL-23. In this study, we showed that the production of IL-23 but not IL-12 was negatively regulated by protein phosphatase 2A (PP2A) in dendritic cells (DC). PP2A inhibits IL-23 production by suppressing the expression of the IL-23p19 gene. Treating DC with okadaic acid that inhibits the PP2A activity or knocking down the catalytic subunit of PP2A with siRNA enhanced IL-23 but not IL-12 production. Unlike PP2A, MAP kinase phosphatase-1 or CYLD did not show an effect on IL-23 production supporting the specificity of PP2A. PP2A-mediated inhibition requires a newly made protein that is likely responsible for bringing PP2A and IKK beta together upon LPS stimulation, which then results in the termination of IKK phosphorylation. Thus, our results uncovered an important role of the protein phosphatase in the regulation of IL-23 production and identified PP2A as a previously uncharacterized inhibitor of IL-23p19 expression in DC.