Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation
Bendamustine increases interleukin-10 secretion from B cells via p38 MAP kinase activation
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DOI：
10.1016/j.intimp.2016.07.033
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发表时间：
2016-10-01
影响因子：
5.6
通讯作者：
Takeuchi, Tsutomu
中科院分区：
文献类型：
--
作者：
Lu, Le;Yoshimoto, Keiko;Takeuchi, Tsutomu
我们研究了苯达莫司汀对B细胞功能的影响，并探讨了药物在自身免疫性疾病中的潜在临床应用。25-100 μ M苯达莫司汀以剂量依赖性方式显著抑制人B细胞系拉莫斯细胞的增殖。一致地，在这些浓度下，拉莫斯细胞的IgM分泌被显著抑制高达70%。然而，有趣的是，白细胞介素-10（IL-10）的产生和分泌在生长抑制浓度下被苯达莫司汀显著增加（至少> 10倍）。对IL-10产生的分子机制的探讨表明，苯达莫司汀增强了p38 MAP激酶的磷酸化。此外，Sp1被鉴定为下游转录因子，并且用它们的抑制剂抑制p38 MAP激酶和Sp1导致苯达莫司汀诱导的IL-10产生和Sp1的DNA结合的消除。重要的是，当来自健康供体的PBMC与浓度为30 μ M的苯达莫司汀一起培养时，在用抗IgM抗体、抗CD 40抗体、重组人IL-21（rhIL-21）和重组人可溶性BAFF（rhsBAFF）刺激下，外周血单个核细胞（PBMC）中的B细胞（CD 20 + CD 4-CD 8-CD 14-）产生IL-10的能力明显增强。这些结果共同表明，p38 MAP激酶-Sp1通路在苯达莫司汀诱导的B细胞产生IL-10中起着至关重要的作用。我们的研究结果表明，通过上调具有抗炎作用的IL-10来治疗自身免疫性疾病是一种新的可能性。(C)2016爱思唯尔B. V.保留所有权利。
We investigated the effects of bendamustine on B cell functions and explored potential clinical applications of the drugs to autoimmune diseases. Proliferation of Ramos cells, a human B cell line, was significantly inhibited by 25-100 mu M of bendamustine in a dose-dependent manner. Concordantly, IgM secretion from Ramos cells was significantly inhibited at these concentrations by up to 70%. Interestingly, however, the production and secretion of interleukin-10 (IL-10) were dramatically (at least > 10-fold) increased by bendamustine at growth inhibitory concentrations. Exploration of the molecular mechanism of IL-10 production revealed that bendamustine enhanced the phosphorylation of p38 MAP kinase. Further, Sp1 was identified as a downstream transcription factor, and the inhibition of p38 MAP kinase and Sp1 with their inhibitors led to the abrogation of bendamustine-induced IL-10 production and the DNA binding of Sp1. Importantly, when PBMC from healthy donors were cultured with bendamustine at the concentration of 30 mu M, under the stimulation with an anti-IgM antibody, an anti-CD40 antibody, recombinant human IL-21 (rhlL-21) and recombinant human soluble BAFF (rhsBAFF), IL-10 production by B cells (CD20+CD4-CD8-CD14-) among peripheral blood mononuclear cell (PBMC) was significantly enhanced by adding bendamustine. These results collectively suggest that the p38 MAP kinase-Sp1 pathway plays a crucial role in bendamustine-induced IL-10 production by B cells. Our findings suggest a novel therapeutic possibility for autoimmune diseases through the upregulation of IL-10 which has an anti-inflammatory effects. (C) 2016 Elsevier B.V. All rights reserved.