The phosphodiesterase 4 inhibitor roflumilast augments the Th17-promoting capability of dendritic cells by enhancing IL-23 production, and impairs their T cell stimulatory activity due to elevated IL-10
The phosphodiesterase 4 inhibitor roflumilast augments the Th17-promoting capability of dendritic cells by enhancing IL-23 production, and impairs their T cell stimulatory activity due to elevated IL-10
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DOI：
10.1016/j.intimp.2016.03.025
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发表时间：
2016-06-01
影响因子：
5.6
通讯作者：
Reske-Kunz, Angelika B.
中科院分区：
文献类型：
--
作者：
Bros, Matthias;Montermann, Evelyn;Reske-Kunz, Angelika B.
磷酸二酯酶4（PDE 4）抑制剂用于防止细胞内第二信使cAMP的降解，从而对包括免疫细胞在内的不同细胞类型产生广泛的抗炎作用。通过激活腺苷酸环化酶来提高cAMP水平的试剂已显示在树突状细胞（DC）中印记Th 17促进能力。因此，我们研究了治疗相关PDE抑制剂诱导DC中显著Th 17偏斜能力的潜力。在此，我们显示，当在用LPS刺激的过程中用PDE 4抑制剂罗氟司特（ROF，商品名：Daxas）处理小鼠骨髓来源的（BM-）DC（ROF-DC）时，在共培养的同种异体T细胞中诱发升高的IL-17水平。此外，与对照组相比，IFN-γ水平保持不变，而Th 2细胞因子（IL-5，IL-10）的含量减少。ROF可增强BM-DCs中Th 17促进因子IL-23的表达。同样，当将IL-23或IL-6特异性中和抗体应用于Du细胞共培养物时，部分抑制了ROF-DCs的IL 17促进作用。此外，ROF-DCs显示出由于IL-10的产生增强而显著降低的同种异体T细胞刺激能力，这在将IL-10特异性中和抗体应用于DC/T细胞共培养物后得以恢复。BM-DCs的IL-17诱导和受损的T细胞刺激能力都被蛋白激酶A的特异性激活剂模拟，而EPAC（活化cAMP的交换蛋白）的刺激没有产生这样的效果。综上所述，我们的研究结果表明，PDE 4抑制剂除了其广泛的整体抗炎作用外，可能会增强DC中的Th 17极化能力，这是一种不必要的副作用。(C)2016爱思唯尔B. V.保留所有权利。
Phosphodiesterase 4 (PDE4) inhibitors serve to prevent degradation of the intracellular second messenger cAMP, resulting in broad anti-inflammatory effects on different cell types including immune cells. Agents that elevate cAMP levels via activation of adenylate cyclase have been shown to imprint a Th17-promoting capacity in dendritic cells (DCs). Therefore, we studied the potential of therapeutically relevant PDE inhibitors to induce a pronounced Th17-skewing capacity in DCs. Here we show that mouse bone marrow-derived (BM-) DCs when treated with the PDE4 inhibitor roflumilast (ROF, trade name: Daxas) in the course of stimulation with LPS (ROF-DCs) evoked elevated IL-17 levels in cocultured allogeneic T cells. In addition, as compared with control settings, levels of IFN-gamma remained unaltered, while contents of Th2 cytokines (IL-5, IL-10) were diminished. ROF enhanced expression of the Th17-promoting factor IL-23 in BM-DCs. In line, neutralizing antibodies specific for IL-23 or IL-6 when applied to Du cell cocultures partially inhibited the IL17-promoting effect of ROF-DCs. Furthermore, ROF-DCs displayed a markedly diminished allogeneic T cell stimulatory capacity due to enhanced production of IL-10, which was restored upon application of IL-10 specific neutralizing antibody to DC/T cell cocultures. Both the IL-17-inducing and impaired T cell stimulatory capacity of BM-DCs were mimicked by a specific activator of protein kinase A, while stimulation of EPACs (exchange proteins of activated cAMP) did not yield such effects. Taken together, our findings suggest that PDE4 inhibitors aside from their broad overall anti-inflammatory effects may enhance the Th17-polarizing capacity in DCs as an unwanted side effect. (C) 2016 Elsevier B.V. All rights reserved.