Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells
Small-molecule screening identifies inhibition of salt-inducible kinases as a therapeutic strategy to enhance immunoregulatory functions of dendritic cells
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DOI：
10.1073/pnas.1412308111
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发表时间：
2014-08-26
影响因子：
11.1
通讯作者：
Shamji, Alykhan F.
中科院分区：
文献类型：
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作者：
Sundberg, Thomas B.;Choi, Hwan Geun;Shamji, Alykhan F.
降低免疫调节细胞因子IL-10功能的遗传改变有助于小鼠和人的结肠炎。骨髓细胞如巨噬细胞（M Phi s）和树突状细胞（dc）在决定肠道中IL-10相对于炎症细胞因子的相对丰度方面起着重要作用。因此，使用小分子来促进dc - mfs产生IL-10代表了一种有希望的方法来提高这种细胞因子水平，特别是在肠道组织中。为此，我们筛选了一个标记良好的激酶抑制剂文库，这些化合物可以通过酵母细胞壁制剂zymosan刺激小鼠骨髓来源的dc促进IL-10的产生。该方法确定了一些激酶抑制剂，这些激酶抑制剂可以有效地上调IL-10的产生，包括美国食品和药物管理局（FDA）批准的靶向ABL、src家族和许多其他激酶的药物达沙替尼、博舒替尼和萨拉卡替尼。将活性化合物的激酶选择性与它们对IL-10产生的影响相关联表明，盐诱导激酶（SIKs）的抑制介导了观察到的IL-10的增加。利用sik靶向抑制剂HG-9-91-01和一系列结构类似物证实了这一点。SIK抑制IL-10的刺激作用还与促炎细胞因子IL-1 β、IL-6、IL-12和tnf - α的产生减少有关，这些协同作用在人DCs-M Phi s和从小鼠肠道组织分离的抗炎CD11c(+) CX(3)CR1（hi）细胞中观察到。总的来说，这些研究表明，SIK抑制促进了活化髓细胞的抗炎表型，其标志是IL-10的强劲产生，并将这些作用确定为与几种fda批准的多激酶抑制剂相关的先前未确定的活性。
Genetic alterations that reduce the function of the immunoregulatory cytokine IL-10 contribute to colitis in mouse and man. Myeloid cells such as macrophages (M Phi s) and dendritic cells (DCs) play an essential role in determining the relative abundance of IL-10 versus inflammatory cytokines in the gut. As such, using small molecules to boost IL-10 production by DCs-MFs represents a promising approach to increase levels of this cytokine specifically in gut tissues. Toward this end, we screened a library of well-annotated kinase inhibitors for compounds that enhance production of IL-10 by murine bone-marrow-derived DCs stimulated with the yeast cell wall preparation zymosan. This approach identified a number of kinase inhibitors that robustly up-regulate IL-10 production including the Food and Drug Administration (FDA)approved drugs dasatinib, bosutinib, and saracatinib that target ABL, SRC-family, and numerous other kinases. Correlating the kinase selectivity profiles of the active compounds with their effect on IL-10 production suggests that inhibition of salt-inducible kinases (SIKs) mediates the observed IL-10 increase. This was confirmed using the SIK-targeting inhibitor HG-9-91-01 and a series of structural analogs. The stimulatory effect of SIK inhibition on IL-10 is also associated with decreased production of the proinflammatory cytokines IL-1 beta, IL-6, IL-12, and TNF-alpha, and these coordinated effects are observed in human DCs-M Phi s and anti-inflammatory CD11c(+) CX(3)CR1(hi) cells isolated from murine gut tissue. Collectively, these studies demonstrate that SIK inhibition promotes an anti-inflammatory phenotype in activated myeloid cells marked by robust IL-10 production and establish these effects as a previously unidentified activity associated with several FDA-approved multikinase inhibitors.