MK2/3 Are Pivotal for IL-33-Induced and Mast Cell-Dependent Leukocyte Recruitment and the Resulting Skin Inflammation
MK2/3 Are Pivotal for IL-33-Induced and Mast Cell-Dependent Leukocyte Recruitment and the Resulting Skin Inflammation
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DOI：
10.4049/jimmunol.1600658
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发表时间：
2016-11-01
影响因子：
4.4
通讯作者：
Kamradt, Thomas
中科院分区：
文献类型：
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作者：
Drube, Sebastian;Kraft, Florian;Kamradt, Thomas
IL-1R 家族成员 IL-33R 介导肥大细胞的 Fc ε 受体-I (Fc ε RI) 独立激活，导致 NF-κ B 激活，从而产生细胞因子。 IL-33 还诱导 MAPK 的激活，例如 p38。我们的目的是确定 p38 靶标、MAPK 激活的蛋白激酶 2 和 3（MK2 和 MK3）在 IL-33 诱导的信号传导中的相关性以及由此产生的体外和体内肥大细胞效应器功能。我们证明 IL-33 诱导的 IL-6 和 IL-13 产生强烈依赖于 MK2/3 介导的 ERK1/2 和 PI3K 信号传导激活。此外，在干细胞因子存在的情况下，IL-33确实诱导MK2/3、ERK1/2和PI3K依赖性TNF-α的产生。在体内，肥大细胞中 MK2/3 的缺失减少了 IL-33 诱导的白细胞募集以及由此产生的皮肤炎症。因此，肥大细胞中 MK2/3 依赖性信号传导对于介导 IL-33 诱导的炎症反应至关重要。因此，MK2/3 是抑制 IL-33 诱导的炎症性皮肤病（例如牛皮癣）的潜在治疗靶点。
The IL-1R family member IL-33R mediates Fc epsilon-receptor-I (Fc epsilon RI)-independent activation of mast cells leading to NF-kappa B activation and consequently the production of cytokines. IL-33 also induces the activation of MAPKs, such as p38. We aimed to define the relevance of the p38-targets, the MAPK-activated protein kinases 2 and 3 (MK2 and MK3) in IL-33-induced signaling and the resulting mast cell effector functions in vitro and in vivo. We demonstrate that the IL-33-induced IL-6 and IL-13 production strongly depends on the MK2/3-mediated activation of ERK1/2 and PI3K signaling. Furthermore, in the presence of the stem cell factors, IL-33 did induce an MK2/3-, ERK1/2- and PI3K-dependent production of TNF-alpha. In vivo, the loss of MK2/3 in mast cells decreased the IL-33-induced leukocyte recruitment and the resulting skin inflammation. Therefore, the MK2/3-dependent signaling in mast cells is essential to mediate IL-33-induced inflammatory responses. Thus, MK2/3 are potential therapeutic targets for suppression of IL-33-induced inflammation skin diseases such as psoriasis.