Sodium butyrate improves porcine host defense peptide expression and relieves the inflammatory response upon Toll-like receptor 2 activation and histone deacetylase inhibition in porcine kidney cells.
Sodium butyrate improves porcine host defense peptide expression and relieves the inflammatory response upon Toll-like receptor 2 activation and histone deacetylase inhibition in porcine kidney cells.
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丁酸钠改善猪宿主防御肽的表达并减轻猪肾细胞中 Toll 样受体 2 激活和组蛋白脱乙酰酶抑制时的炎症反应
DOI：
10.18632/oncotarget.15714
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发表时间：
2017-04-18
期刊：
影响因子：
--
通讯作者：
Shan A
中科院分区：
文献类型：
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作者：
Dou X;Han J;Song W;Dong N;Xu X;Zhang W;Shan A
宿主防御肽（HDP）是先天免疫系统的重要组成部分，具有直接的抗菌和免疫调节活性。 HDP 合成的饮食调节已成为对抗病原体感染的一种新型非抗生素方法。 HDPs 的调节和机制具有物种和组织依赖性特征。在本研究中，我们研究了组蛋白脱乙酰酶抑制剂 (HDACi) 丁酸钠 (NaB) 是否可以诱导 PK-15 细胞中 HDP 表达以及 NaB 调节 HDP 表达的机制。我们的结果显示，NaB 增强了 PK-15 细胞中的 HDP 表达，包括猪 β-防御素 3 (pBD3)、附睾蛋白 2 剪接变体 C (pEP2C)、pBD128、pBD123 和 pBD115，但没有发生炎症反应。与 NaB 和另一种 HDACi、曲古抑菌素 A (TSA) 相比，HDAC 活性的抑制不足以诱导 pBD3 和 pEP2C 的表达。同时，NF-κB 激活参与 NaB 诱导 HDP 表达。 MAPK 通路抑制也阻止了 NaB 诱导 pBD3 和 pEP2C。此外，在 Toll 样受体 2 (TLR2) 配体肽聚糖存在的情况下，NaB 仍然可以促进 pBD3 和 pEP2C 表达并抑制 IL-6 产生。此外，TLR2 可以被 NaB 和肽聚糖激活，并且阻断 TLR2 表达可以抑制 HDP 诱导。最后，我们进一步表明，增加pBD3可以减少细胞因子白细胞介素18（IL-18）并增加猪密蛋白15（pCLDN15）含量，表明pBD3具有免疫调节功能。总之，这项工作为使用 HDACi-NaB 诱导猪肾防御肽铺平了道路，同时限制了炎症反应的有害风险。
Host defense peptides (HDPs) are an important component of the innate immune system and possess direct antimicrobial and immunomodulatory activities. Dietary regulation of HDPs synthesis has emerged as a novel non-antibiotic approach to combat pathogen infection. There are species- and tissue-dependent characteristics of the regulation and mechanism of HDPs. In this study, we investigated whether the histone deacetylase inhibitor (HDACi) sodium butyrate (NaB) could induce HDP expression and the mechanism underlying NaB-regulated HDP expression in PK-15 cells. Our results revealed that NaB augmented HDP expression in PK-15 cells, including porcine β-defensin 3 (pBD3), epididymis protein 2 splicing variant C (pEP2C), pBD128, pBD123, and pBD115, but no inflammatory response occurred. Inhibition of HDAC activity was not sufficient to induce the expression of pBD3 and pEP2C in comparisons of NaB and another HDACi, trichostatin A (TSA). Concomitantly, NF-κB activation was involved in the induction of HDP expression by NaB. MAPK pathway inhibition also prevented pBD3 and pEP2C induction by NaB. Furthermore, NaB could still promote pBD3 and pEP2C expression and inhibit IL-6 production in the presence of the toll-like receptor 2 (TLR2) ligand peptidoglycan. Moreover, TLR2 could be activated by both NaB and peptidoglycan, and blocking TLR2 expression suppressed HDP induction. Finally, we further showed that increased pBD3 could decrease cytokine interleukin-18 (IL-18) and increase porcine claudin 15 (pCLDN15) contents, suggesting an immunoregulatory function of pBD3. In conclusion, this work paves the way for using HDACi-NaB to induce porcine kidney defense peptides while limiting the deleterious risk of an inflammatory response.