Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8
Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8
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DOI：
10.1073/pnas.1424626112
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发表时间：
2015-02-24
影响因子：
11.1
通讯作者：
Dinarello, Charles Anthony
中科院分区：
文献类型：
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作者：
Li, Suzhao;Neff, C. Preston;Dinarello, Charles Anthony
与IL-1 α和IL-33类似，IL-1家族成员IL-37b易位到细胞核，并与先天和适应性免疫的抑制有关。在这里，我们展示了IL-37前体的细胞外功能和加工形式。重组IL-37前体可使lps诱导的高炎性人血源性M1分化巨噬细胞中IL-6降低50% (P < 0.001)，但对M2巨噬细胞无效。与此相反，中和的单克隆抗il -37使lps诱导的IL-6、TNF α和IL-1 β升高（P < 0.01）。IL-37的抑制作用在低皮摩尔浓度下持续观察到，而不是在纳摩尔浓度下。lps诱导TNF α mRNA表达增加12倍，而IL-37预处理仅使TNF α mRNA表达减少3倍（P < 0.01）。在机制上，lps诱导的p38和pERK被IL-37降低。重组IL-37结合到IL-18受体的固定配体结合α链以及诱饵受体IL-1R8上。在M1巨噬细胞中，LPS增加了IL-1R8的表面表达。与人血液单核细胞相比，静息M1细胞表达更多的表面IL-1R8和总IL-1R8；IL-37预处理后，IL-1R8 mRNA水平增加16倍。IL-37在小鼠骨髓来源的树突状细胞中使lps诱导的TNF α和IL-6降低50-55%，但在il - 1r8缺陷小鼠来源的树突状细胞中则没有。在遭受全身性lps诱导炎症的小鼠中，预处理IL-37可降低循环和器官细胞因子水平。因此，除了具有核功能外，IL-37还通过与IL-18受体结合而利用IL-1R8发挥其抗炎特性，从而作为细胞外细胞因子。
Similar to IL-1 alpha and IL-33, IL-1 family member IL-37b translocates to the nucleus and is associated with suppression of innate and adaptive immunity. Here we demonstrate an extracellular function of the IL-37 precursor and a processed form. Recombinant IL-37 precursor reduced LPS-induced IL-6 by 50% (P < 0.001) in highly inflammatory human blood-derived M1 differentiated macrophages derived from selective subjects but not M2 macrophages. In contrast, a neutralizing monoclonal anti-IL-37 increased LPS-induced IL-6, TNF alpha and IL-1 beta (P < 0.01). The suppression by IL-37 was consistently observed at low picomolar but not nanomolar concentrations. Whereas LPS-induced a 12-fold increase in TNF alpha mRNA, IL-37 pretreatment decreased the expression to only 3-fold over background (P < 0.01). Mechanistically, LPS-induced p38 and pERK were reduced by IL-37. Recombinant IL-37 bound to the immobilized ligand binding alpha-chain of the IL-18 receptor as well as to the decoy receptor IL-1R8. In M1 macrophages, LPS increased the surface expression of IL-1R8. Compared with human blood monocytes, resting M1 cells express more surface IL-1R8 as well as total IL-1R8; there was a 16-fold increase in IL-1R8 mRNA levels when pretreated with IL-37. IL-37 reduced LPS-induced TNF alpha and IL-6 by 50-55% in mouse bone marrow-derived dendritic cells, but not in dendritic cells derived from IL-1R8-deficient mice. In mice subjected to systemic LPS-induced inflammation, pretreatment with IL-37 reduced circulating and organ cytokine levels. Thus, in addition to a nuclear function, IL-37 acts as an extracellular cytokine by binding to the IL-18 receptor but using the IL-1R8 for its anti-inflammatory properties.