Butyrate increases IL-23 production by stimulated dendritic cells
Butyrate increases IL-23 production by stimulated dendritic cells
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DOI：
10.1152/ajpgi.00540.2011
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发表时间：
2012-12-01
影响因子：
4.5
通讯作者：
Kao, John Y.
中科院分区：
文献类型：
--
作者：
Berndt, Bradford E.;Zhang, Min;Kao, John Y.
伯恩特·贝，张明，欧阳锡，科尔·TS，王德伟，路德·J，维尼阿米诺娃·纳，Merchant JL，陈C，Huffnagle GB，高军勇。丁酸盐通过刺激树突状细胞增加IL-23的产生。Am J Physiol Gasterintest肝脏Physiol 303：G1384-G1392,2012。2012年10月18日首次出版；doi：10.1152/ajpgi.00540.2011。-肠道微生物区系对维持肠道免疫动态平衡至关重要，并负责将膳食纤维分解为短链脂肪酸(SCFA)。丁酸盐是肠道中含量最丰富的生物活性单链脂肪酸，是一种组蛋白去乙酰化酶抑制剂(HDACi)，是一类具有强大免疫调节特性的药物。丁酸的这一特性，加上我们之前的发现，传统的树突状细胞(DC)在实验性结肠炎的发展中是必需的，这使得我们推测丁酸可能调节DC的功能，以调节肠道粘膜的动态平衡。我们发现，丁酸盐除了抑制内毒素诱导的骨髓来源的DC成熟和抑制DC IL-12的产生外，还显著诱导IL-23的表达。IL-23p19亚基在翻译前水平的上调与HDACi在基因表达的表观遗传修饰中的作用一致。此外，IL-23p19上调的机制不依赖于STAT3和ZBP89。脾细胞与内毒素刺激的DC经丁酸或不加丁酸盐处理后进行共培养，结果显示显著诱导IL-17和IL-10的产生。我们用葡聚糖硫酸钠(DSS)诱导的小鼠结肠炎模型进一步证实了丁酸盐的体内作用，发现在小鼠饮用水中添加丁酸盐加重了DSS-结肠炎。这与每天给DSS治疗的小鼠注射丁酸盐形成对比，后者轻微地改善了疾病的严重程度。我们的研究强调了丁酸在上调活化的DC产生IL-23方面的新作用，并证明了宿主对丁酸口服和全身给药途径的反应不同。
Berndt BE, Zhang M, Owyang SY, Cole TS, Wang TW, Luther J, Veniaminova NA, Merchant JL, Chen C, Huffnagle GB, Kao JY. Butyrate increases IL-23 production by stimulated dendritic cells. Am J Physiol Gastrointest Liver Physiol 303: G1384-G1392, 2012. First published October 18, 2012; doi: 10.1152/ajpgi.00540.2011.-The gut microbiota is essential for the maintenance of intestinal immune homeostasis and is responsible for breaking down dietary fiber into short-chain fatty acids (SCFAs). Butyrate, the most abundant bioactive SCFA in the gut, is a histone deacetylase inhibitor (HDACi), a class of drug that has potent immunomodulatory properties. This characteristic of butyrate, along with our previous discovery that conventional dendritic cells (DCs) are required for the development of experimental colitis, led us to speculate that butyrate may modulate DC function to regulate gut mucosal homeostasis. We found that butyrate, in addition to suppressing LPS-induced bone marrow-derived DC maturation and inhibiting DC IL-12 production, significantly induced IL-23 expression. The upregulation of mRNA subunit IL-23p19 at the pretranslational level was consistent with the role of HDACi on the epigenetic modification of gene expression. Furthermore, the mechanism of IL-23p19 upregulation was independent of Stat3 and ZBP89. Coculture of splenocytes with LPS-stimulated DCs pretreated with or without butyrate was performed and showed a significant induction of IL-17 and IL-10. We demonstrated further the effect of butyrate in vivo using dextran sulfate sodium (DSS)-induced colitis and found that the addition of butyrate in the drinking water of mice worsened DSS-colitis. This is in contrast to the daily intraperitoneal butyrate injection of DSS-treated mice, which mildly improved disease severity. Our study highlights a novel effect of butyrate in upregulating IL-23 production of activated DCs and demonstrates a difference in the host response to the oral vs. systemic route of butyrate administration.