IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist
IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist
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DOI：
10.1073/pnas.1121534109
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发表时间：
2012-02-21
影响因子：
11.1
通讯作者：
Dinarello, Charles A.
中科院分区：
文献类型：
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作者：
van de Veerdonk, Frank L.;Stoeckman, Angela K.;Dinarello, Charles A.
IL-1家族成员10（最近更名为IL-38）的功能作用仍然未知。本研究旨在阐明IL-38的生物学功能并鉴定其受体。热灭活的白色念珠菌用于刺激来自健康受试者的新鲜获得的人外周血单核细胞中的记忆T淋巴细胞细胞因子产生。添加重组IL-38（152个氨基酸）抑制T细胞细胞因子IL-22（减少37%）和IL-17（减少39%）的产生。在相同的外周血单核细胞培养物中，IL-38引起的IL-22和IL-17的减少与天然存在的IL-36受体拮抗剂（IL-36 Ra）引起的减少相似。IL-36 γ诱导的IL-8产生被IL-38降低（降低42%），并且也被IL-36 Ra降低（降低73%）。当使用人血单核细胞衍生的树突状细胞时，IL-38以及IL-36 Ra使LPS诱导的IL-6增加两倍。我们筛选了IL-1受体家族每个成员的固定化细胞外结构域，包括IL-36受体（也称为“IL-1受体相关蛋白2”），并观察到IL-38仅结合IL-36受体，IL-36 Ra也是如此。IL-38和IL-36 Ra对阿那白菌素诱导的IL-22和IL-17的剂量-反应抑制作用与经典的IL-1受体拮抗剂（阿那白滞素）不同，因为低浓度对抑制IL-22的产生是最佳的，而高浓度则适度增加IL-22。这些数据提供了IL-38与IL-36 Ra结合的证据，并且IL-38和IL-36 Ra通过接合IL-36受体对免疫细胞具有相似的生物学作用。
The functional role of IL-1 family member 10, recently renamed IL-38, remains unknown. In the present study we aimed to elucidate the biological function of IL-38 and to identify its receptor. Heat-killed Candida albicans was used to stimulate memory T-lymphocyte cytokine production in freshly obtained human peripheral blood mononuclear cells from healthy subjects. The addition of recombinant IL-38 (152 amino acids) inhibited the production of T-cell cytokines IL-22 (37% decrease) and IL-17 (39% decrease). The reduction in IL-22 and IL-17 caused by IL-38 was similar to that caused by the naturally occurring IL-36 receptor antagonist (IL-36Ra) in the same peripheral blood mononuclear cells cultures. IL-8 production induced by IL-36 gamma was reduced by IL-38 (42% decrease) and also was reduced by IL-36Ra (73% decrease). When human blood monocyte-derived dendritic cells were used, IL-38 as well as IL-36Ra increased LPS-induced IL-6 by twofold. We screened immobilized extracellular domains of each member of the IL-1 receptor family, including the IL-36 receptor (also known as "IL-1 receptor-related protein 2") and observed that IL-38 bound only to the IL-36 receptor, as did IL-36Ra. The dose-response suppression of IL-38 as well as that of IL-36Ra of Candida-induced IL-22 and IL-17 was not that of the classic IL-1 receptor antagonist (anakinra), because low concentrations were optimal for inhibiting IL-22 production, whereas higher concentrations modestly increased IL-22. These data provide evidence that IL-38 binds to the IL-36R, as does IL-36Ra, and that IL-38 and IL-36Ra have similar biological effects on immune cells by engaging the IL-36 receptor.