164 : The serine protease plasmin induces expression of the CC-chemokine ligand 20 in human monocyte-derived dendritic cells
164 : The serine protease plasmin induces expression of the CC-chemokine ligand 20 in human monocyte-derived dendritic cells
复制标题
164：丝氨酸蛋白酶纤溶酶诱导人单核细胞衍生的树突状细胞中 CC 趋化因子配体 20 的表达
DOI：
10.1016/j.cyto.2013.06.167
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发表时间：
2013
期刊：
影响因子：
3.8
通讯作者：
Simmet T.
中科院分区：
文献类型：
--
作者：
Syrovets T;Simmet T.
IL-1 家族成员 IL-37 可减少先天性炎症和获得性免疫反应。我们发表的研究表明，原代细胞系或转染细胞系培养物中 IL-37 的过度表达可抑制 Toll 样受体配体、IL-1b 或 TNFa 诱导的促炎细胞因子的产生。抑制人单核细胞中的内源性 IL-37 会增加 IL-1b 的产生。与 IL-1 家族成员 IL-1a 和 IL-33 类似，IL-37 迁移到细胞核并影响转录。因此，尚不清楚 IL-37 是否通过细胞内或细胞外机制抑制先天反应。在本研究中，我们检查了重组 IL-37 蛋白的功能。重组 IL-37，无论是前体还是成熟形式，都与 IL-18 受体的 α 链结合，但仍然抑制 LPS 诱导的细胞因子。重组 IL-37 可减少 PBMC 中 LPS 诱导的细胞因子，而 IL-37 在人单核细胞来源的 M1 和树突状细胞 (DC) 中尤其能有效减少 (60–70%) LPS 诱导的细胞因子，并且始终处于低皮摩尔浓度。相反，微摩尔或高纳摩尔浓度不会抑制 LPS 诱导的细胞因子；因此，IL-37 不具有 IL-18 受体拮抗剂的功能。 LPS 诱导的 MAPK 激酶（例如磷酸化 p38 和 ERK）被重组 IL-37 下调。在 M1 巨噬细胞中，暴露于 IL-37 会增加 SIGIRR 的 mRNA 水平，并下调 TNF-a 等细胞因子的基因表达。低皮摩尔浓度的 IL-37 还可减少小鼠骨髓来源的 DC 中 LPS 诱导的细胞因子 (70-80%)，但 SIGIRR 缺陷小鼠来源的 DC 的减少明显较少。腹膜内注射重组 IL-37 还可减少注射 LPS 的小鼠的循环和细胞因子的产生。这项研究表明，除了核功能外，皮摩尔浓度的重组 IL-37 通过首先与 IL-18 受体结合，作为细胞外细胞因子具有活性。此外，重组 IL-37 的抗炎作用会降低 MAPK 活性，并且需要 SIGIRR 的存在。
IL-1 family member IL-37 reduces innate inflammation and acquired immune responses. Our published studies demonstrated that over expression of IL-37 in either primary or transfected cell line cultures suppress the production of pro-inflammatory cytokines induced by Toll-like receptor ligands, IL-1b or TNFa. Inhibition of endogenous IL-37 in human monocytes increases IL-1b production. Similar to IL-1 family member IL-1a and IL-33, IL-37 migrates to the nucleus where it affects transcription. Therefore, it remains unclear if IL-37 functions to inhibit innate responses by an intracellular or extracellular mechanism. In the present study, we examined the function of recombinant IL-37 proteins. Recombinant IL-37, either the precursor or mature forms, binds to the alpha chain of the IL-18 receptor, but nevertheless inhibits LPS-induced cytokines. Whereas recombinant IL-37 reduces LPS-induced cytokines in PBMC, IL-37 is particularly effective in reducing (60–70%) LPS-induced cytokines in human monocyte-derived M1 and dendritic cells (DC) and consistently at low picomolar concentrations. In contrast, micromolar or high nanomolar concentrations do not inhibit LPS induced cytokines; hence, IL-37 does not function as an IL-18 receptor antagonist. LPS induced MAPK kinases such as phospho-p38 and ERK are down-regulated by recombinant IL-37. In M1 macrophages, exposure to IL-37 increases mRNA levels of SIGIRR, and down-regulates gene expression of cytokines such as TNF-a. Low picomolar concentrations of IL-37 also reduce LPS-induced cytokines (70–80%) in mouse bone marrow-derived DC, but significantly less reduction in DC derived from SIGIRR deficient mice. Intraperitoneal injection of recombinant IL-37 also reduces circulating and cytokine production in LPS injected mice. This study reveals that in addition to a nuclear function, picomolar concentrations of recombinant IL-37 are active as an extracellular cytokine by first binding to the IL-18 receptor. Furthermore, the anti-inflammatory effects of recombinant IL-37 reduce MAPK activity and require the presence of SIGIRR.