IL-33 is an IL-1-related cytokine that can act as an alarmin when released from necrotic cells. Once released, it can target various immune cells including mast cells, innate lymphoid cells and T cells to elicit a Th2-like immune response. We show here that bone marrow-derived mast cells produce IL-13, IL-6, TNF, GM-CSF, CCL3 and CCL4 in response to IL-33 stimulation. Inhibition of the p38 MAPK, or inhibition or knockout of its downstream kinases MK2 and MK3, blocked the production of these cytokines in response to IL-33. The mechanism downstream of MK2/3 was cytokine specific; however, MK2 and MK3 were able to regulate TNF and GM-CSF mRNA stability. Previous studies in macrophages have shown that MK2 regulates mRNA stability via phosphorylation of the RNA-binding protein TTP (Zfp36). The regulation of cytokine production in mast cells was, however, independent of TTP. MK2/3 were able to phosphorylate the TTP-related protein Brf1 (Zfp36 l1) in IL-33-stimulated mast cells, suggesting a mechanism by which MK2/3 might control mRNA stability in these cells. In line with its ability to regulate in vitro IL-33-stimulated cytokine production, double knockout of MK2 and 3 in mice prevented neutrophil recruitment following intraperitoneal injection of IL-33.

中文翻译：

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IL-33 通过 p38 MAPK 激活激酶 MK2/3 调节细胞因子的产生和中性粒细胞的募集。

IL-33 是一种与 IL-1 相关的细胞因子，当从坏死细胞中释放出来时，它可以起到警报的作用。一旦释放，它可以靶向各种免疫细胞，包括肥大细胞、先天淋巴细胞和 T 细胞，以引发类似 Th2 的免疫反应。我们在这里展示了骨髓来源的肥大细胞响应 IL-33 刺激产生 IL-13、IL-6、TNF、GM-CSF、CCL3 和 CCL4。抑制 p38 MAPK，或抑制或敲除其下游激酶 MK2 和 MK3，可阻止这些细胞因子的产生以响应 IL-33。MK2/3 下游的机制是细胞因子特异性的；然而，MK2 和 MK3 能够调节 TNF 和 GM-CSF mRNA 的稳定性。先前对巨噬细胞的研究表明，MK2 通过磷酸化 RNA 结合蛋白 TTP (Zfp36) 来调节 mRNA 的稳定性。肥大细胞中细胞因子产生的调节是，然而，独立于TTP。MK2/3 能够磷酸化 IL-33 刺激的肥大细胞中的 TTP 相关蛋白 Brf1 (Zfp36 l1)，表明 MK2/3 可能控制这些细胞中 mRNA 稳定性的机制。与其调节体外 IL-33 刺激的细胞因子产生的能力一致，小鼠中 MK2 和 3 的双重敲除阻止了腹膜内注射 IL-33 后的中性粒细胞募集。