Role for nuclear interleukin-37 in the suppression of innate immunity
Role for nuclear interleukin-37 in the suppression of innate immunity
复制标题
DOI：
10.1073/pnas.1821111116
复制
发表时间：
2019-03-05
影响因子：
11.1
通讯作者：
Dinarello, Charles A.
中科院分区：
文献类型：
--
作者：
Li, Suzhao;Amo-Aparicio, Jesus;Dinarello, Charles A.
IL-1家族成员IL-37广泛抑制先天炎症和获得性免疫。与IL-1α和IL-33类似，IL-37是一种双重功能的细胞因子，IL-37不仅可以转运到细胞核，还可以通过表膜受体传递信号。对于这种细胞因子抑制先天炎症的能力，核IL-37的作用尚不清楚。在这里，我们比较了表达天然人IL-37(IL-37Tg)的转基因小鼠和携带天冬氨酸(D)到丙氨酸(A)氨基酸20位突变(IL-37D20ATg)的转基因小鼠对先天炎症的抑制作用。突变D20A阻止了caspase-1的切割，这是IL-37核转位所需的步骤。在体外，IL-37Tg小鼠的巨噬细胞可使脂多糖诱导的IL-1β、IL-6、TNF-α和干扰素-γ降低40-50%，而IL-37D20ATg小鼠的巨噬细胞未观察到这种抑制作用，这与核功能的丧失一致。与IL-37Tg小鼠的巨噬细胞相比，IL-37D20ATg小鼠的巨噬细胞对脂多糖诱导的MAP激酶和核因子-kappaB活性的抑制作用也明显减弱或不受抑制。在体内，IL-37Tg小鼠内毒素血症时肺和肝脏中IL-1β、IL-6和TNFα水平显著降低，而IL-37D20ATg小鼠未见明显变化。然而，一旦细胞因子从细胞中释放并与其受体结合，在IL-37D20A小鼠中，对先天炎症的抑制仍然完好无损。这些研究揭示了核抑制先天炎症的功能，并与IL-37的双重功能和caspase-1在限制炎症中的作用是一致的。
The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1 alpha and IL-33, IL-37 is a dual-function cytokine in that IL-37 translocates to the nucleus but also transmits a signal via surface membrane receptors. The role of nuclear IL-37 remains unknown on the ability of this cytokine to inhibit innate inflammation. Here, we compared suppression of innate inflammation in transgenic mice expressing native human IL-37 (IL-37Tg) with those of transgenic mice carrying the mutation of aspartic acid (D) to alanine (A) at amino acid 20 (IL-37D20ATg). The mutation D20A prevents cleavage of caspase-1, a step required for IL-37 nuclear translocation. In vitro, peritoneal macrophages from IL-37Tg mice reduced LPS-induced IL-1 beta, IL-6, TNF alpha and IFN gamma by 40-50% whereas in macrophages from IL-37D20ATg mice this suppression was not observed, consistent with loss of nuclear function. Compared with macrophages from IL-37Tg mice, significantly less or no suppression of LPS-induced MAP kinase and NF kappa B activation was also observed in macrophages from IL-37D20ATg mice. In vivo, levels of IL-1 beta, IL-6, and TNF alpha in the lungs and liver were markedly reduced during endotoxemia in IL-37Tg mice but not observed in IL-37D20ATg mice. However, suppression of innate inflammation remains intact in the IL-37D20A mice once the cytokine is released from the cell and binds to its receptor. These studies reveal a nuclear function for suppression of innate inflammation and are consistent with the dual function of IL-37 and a role for caspase-1 in limiting inflammation.