Department of Medicine, University of Colorado Denver, Aurora, CO 80045.
Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4456-4461. doi: 10.1073/pnas.1821111116. Epub 2019 Feb 21.
The IL-1 family member IL-37 broadly suppresses innate inflammation and acquired immunity. Similar to IL-1α 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-1β, IL-6, TNFα and IFNγ 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 NFκB activation was also observed in macrophages from IL-37D20ATg mice. In vivo, levels of IL-1β, IL-6, and TNFα 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.
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 相似，IL-37 是一种双功能细胞因子，IL-37 可转位到细胞核，但也可通过细胞膜受体传递信号。这种细胞因子抑制先天炎症的能力，核内 IL-37 的作用尚不清楚。在这里，我们比较了表达天然人 IL-37 的转基因小鼠（IL-37Tg）与携带天冬氨酸（D）突变为丙氨酸（A）的 IL-37 （IL-37D20ATg）的转基因小鼠抑制先天炎症的能力。突变 D20A 阻止了半胱天冬酶-1 的切割，这是 IL-37 核转位所必需的一步。体外，IL-37Tg 小鼠的腹腔巨噬细胞减少了 LPS 诱导的 IL-1β、IL-6、TNFα 和 IFNγ 的产生，减少了 40-50%，而在 IL-37D20ATg 小鼠的巨噬细胞中则没有观察到这种抑制作用，这与核功能丧失一致。与 IL-37Tg 小鼠的巨噬细胞相比，在 IL-37D20ATg 小鼠的巨噬细胞中，也观察到 LPS 诱导的 MAP 激酶和 NFκB 激活的抑制作用明显减少或不存在。在体内，IL-37Tg 小鼠在脓毒症期间，肺和肝中的 IL-1β、IL-6 和 TNFα 水平明显降低，但在 IL-37D20ATg 小鼠中则没有观察到。然而，一旦细胞因子从细胞中释放出来并与受体结合，IL-37D20A 小鼠对先天炎症的抑制作用仍然完整。这些研究揭示了抑制先天炎症的核功能，并与 IL-37 的双重功能和半胱天冬酶-1 在限制炎症中的作用一致。
