Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells
Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells
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DOI：
10.1189/jlb.3ma0616-287r
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发表时间：
2017-04-01
影响因子：
5.5
通讯作者：
Nold, Marcel F.
中科院分区：
文献类型：
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作者：
Rudloff, Ina;Cho, Steven X.;Nold, Marcel F.
白细胞介素（IL）-1家族成员IL-37是为数不多的抗炎细胞因子之一，它能够对抗广谱的促炎攻击。虽然已知白细胞是IL-37的主要来源，但关于特定免疫细胞类型中IL-37产生和分泌的知识仍然有限。因此，我们研究了人PBMC中IL-37 mRNA表达以及蛋白质产生和分泌。在用Toll样受体（TLR）1-6和9的激动剂刺激的PBMC中，IL 1F 7（IL-37编码基因）被诱导高达9倍，在6-8 h达到峰值，并在72 h恢复至稳态。LPS诱导的IL 1F 7表达包括亚型B和c，但不包括亚型a和e。流式细胞术显示，在IL-37（+）PBMC中，单核细胞占主导地位（81-91%），但T细胞（6-8%）和髓样树突状细胞（mDCs，1-2%）也对IL-37（+）白细胞池有贡献。单核细胞和mDC，但不是T细胞，能够分泌IL-37。单核细胞和mDC在LPS刺激后分泌IL-37，而只有mDC在稳态下也释放IL-37。在单核细胞亚群中，IL-37是LPS诱导的，仅在经典单核细胞中分泌，尽管不太明显，但在中间单核细胞中分泌;刺激后早在3小时就观察到分泌。总体而言，我们的数据表明，mDC的组成性IL-37分泌可能有助于维持稳态的抗炎环境，而IL-37储存在单核细胞中，可用于在炎症发生时快速释放，从而充当新型抗炎警报素。这些见解可能被证明是重要的，以推进临床使用的保护功能的一个最强大的抗炎介质迄今发现。
The interleukin (IL)-1 family member IL-37 is one of few anti-inflammatory cytokines, and it is capable of countering a broad spectrum of proinflammatory assaults. Although it is known that leukocytes are a major source of IL-37, knowledge on IL-37 production and secretion in specific immune cell types remains limited. Thus, we investigated IL-37 mRNA expression as well as protein production and secretion in human PBMCs. In PBMCs stimulated with agonists of Toll-like receptors (TLRs) 1-6 and 9, IL1F7 (the IL-37-encoding gene) was induced up to 9-fold, peaked at 6-8 h and returned to steady-state at 72 h. LPS-induced IL1F7 expression comprised isoforms b and c but not a and e. Flow cytometry revealed that among IL-37(+) PBMCs, monocytes predominated (81-91%), but T cells (6-8%) and myeloid dendritic cells (mDCs, 1-2%) also contributed to the IL-37(+) leukocyte pool. Monocytes and mDCs, but not T cells, were capable of secreting IL-37. Whereas monocytes and mDCs secreted IL-37 upon LPS stimulation, only mDCs also released IL-37 at steady-state. Among monocyte subsets, IL-37 was LPS inducible and secreted only in classical and, although less pronounced, in intermediate monocytes; secretion was observed as early as 3 h after stimulation. Overall, our data suggest that constitutive IL-37 secretion by mDCs may serve to maintain an anti-inflammatory milieu at steady state, whereas IL-37 is stored in monocytes to be available for rapid release upon inflammatory encounters, thus acting as a novel anti-inflammatory alarmin. These insights may prove important to advancing towards clinical use the protective functions of one of the most powerful anti-inflammatory mediators so far discovered.