Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis
Sublytic C5b-9 Induces IL-23 and IL-36a Production by Glomerular Mesangial Cells via PCAF-Mediated KLF4 Acetylation in Rat Thy-1 Nephritis
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DOI：
10.4049/jimmunol.1800719
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发表时间：
2018-11
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通讯作者：
Jing Zhang;Mengxiao Xie;L. Xia;Tianyi Yu;Fengxia He;Chenhui Zhao;W. Qiu;Dan Zhao;Yu Liu;Yajuan Gong;Chunyan Yao;Longfei Liu;Yingwei Wang
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作者：
Jing Zhang;Mengxiao Xie;L. Xia;Tianyi Yu;Fengxia He;Chenhui Zhao;W. Qiu;Dan Zhao;Yu Liu;Yajuan Gong;Chunyan Yao;Longfei Liu;Yingwei Wang
大鼠Thy-1肾炎（Thy-1 N）是一种人系膜增生性肾小球肾炎模型，其肾小球系膜细胞亚溶C5 b-9的形成伴随着促炎细胞因子的产生，但亚溶C5 b-9与细胞因子合成的关系及其机制尚不清楚。为了探索上述问题，在这项研究中，我们首先检查了促炎IL的水平（例如，IL-23和IL-36 a）以及转录因子（KLF 4）和辅激活因子（PCAF）在Thy-1 N大鼠肾组织和肾小球系膜细胞系（HBZY-1）中的亚溶解性C5 b-9刺激。进一步研究了KLF 4和PCAF在亚溶解性C5 b-9诱导的IL-23和IL-36 a产生中的作用及其相关机制。结果显示，KLF 4、PCAF、IL-23、IL-36 a水平明显升高。机制研究表明，亚裂解C5 b-9刺激可以通过KLF 4和PCAF上调增加IL-23和IL-36 a的合成，并且KLF 4和PCAF可以形成复合物，以KLF 4依赖的方式与IL-23或IL-36 a启动子结合，引起基因转录。重要的是，通过PCAF的KLF 4乙酰化有助于亚裂解C5 b-9诱导的IL-23和IL-36 a转录。此外，还鉴定了IL-23或IL-36 a启动子上的KLF 4结合区和被PCAF乙酰化的KLF 4赖氨酸位点。抑制肾脏KLF 4或PCAF基因表达可明显抑制Thy-1 N大鼠IL-23或IL-36 a的分泌，抑制Thy-1 N大鼠肾脏组织损伤。总的来说，这些研究结果表明，KLF 4/PCAF相互作用和KLF 4乙酰化的PCAF发挥了关键作用，在sublytic C5 b-9介导的IL-23和IL-36 a的生产Thy-1 N大鼠。
Sublytic C5b-9 formation on glomerular mesangial cells in rat Thy-1 nephritis (Thy-1N), a model of human mesangioproliferative glomerulonephritis, is accompanied by the production of proinflammatory cytokines, but the relationship between sublytic C5b-9 and cytokine synthesis and the underlying mechanism remains unclear. To explore the problems mentioned above, in this study, we first examined the levels of proinflammatory ILs (e.g., IL-23 and IL-36a) as well as transcription factor (KLF4) and coactivator (PCAF) in the renal tissues of Thy-1N rats and in the glomerular mesangial cell line (HBZY-1) stimulated by sublytic C5b-9. Then, we further determined the role of KLF4 and PCAF in sublytic C5b-9–induced IL-23 and IL-36a production as well as the related mechanism. Our results showed that the levels of KLF4, PCAF, IL-23, and IL-36a were obviously elevated. Mechanistic investigation revealed that sublytic C5b-9 stimulation could increase IL-23 and IL-36a synthesis through KLF4 and PCAF upregulation, and KLF4 and PCAF could form a complex, binding to the IL-23 or IL-36a promoter in a KLF4-dependent manner, causing gene transcription. Importantly, KLF4 acetylation by PCAF contributed to sublytic C5b-9–induced IL-23 and IL-36a transcription. Besides, the KLF4 binding regions on IL-23 or IL-36a promoters and the KLF4 lysine site acetylated by PCAF were identified. Furthermore, silencing renal KLF4 or PCAF gene could significantly inhibit IL-23 or IL-36a secretion and tissue damage of Thy-1N rats. Collectively, these findings implicate that the KLF4/PCAF interaction and KLF4 acetylation by PCAF play a pivotal role in the sublytic C5b-9–mediated IL-23 and IL-36a production of Thy-1N rats.