IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3.
IL-33 regulates cytokine production and neutrophil recruitment via the p38 MAPK-activated kinases MK2/3.
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DOI：
10.1111/imcb.12200
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发表时间：
2019-01
影响因子：
4
通讯作者：
Arthur JSC
中科院分区：
文献类型：
--
作者：
McCarthy PC;Phair IR;Greger C;Pardali K;McGuire VA;Clark AR;Gaestel M;Arthur JSC
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，可以起到警示作用。一旦释放，它可以靶向各种免疫细胞，包括肥大细胞、固有淋巴样细胞和T细胞，以诱导Th2样免疫反应。我们在这里展示了骨髓来源的肥大细胞在IL-33刺激下产生IL-13、IL-6、肿瘤坏死因子、GM-CSF、CCL3和CCL4。抑制p38MAPK，或抑制或敲除其下游的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，但MK2和MK3能够调节肿瘤坏死因子和GM-CSF mRNA的稳定性。先前在巨噬细胞中的研究表明，MK2通过RNA结合蛋白TTP(Zfp36)的磷酸化来调节mRNA的稳定性。然而，肥大细胞中细胞因子产生的调节是独立于TTP的。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和L1)，提示MK2/3可能控制这些细胞中的mRNA稳定性。与其在体外调节IL-33刺激的细胞因子产生的能力一致，MK2和MK3在小鼠体内的双重敲除阻止了在腹腔注射IL-33后中性粒细胞的招募。
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.
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DOI：
10.1073/pnas.0812690106
发表时间：
2009-06-02
影响因子：
11.1
作者：
Cayrol, Corinne;Girard, Jean-Philippe
通讯作者：
Girard, Jean-Philippe
影响因子：
5.4
作者：
Andrade, Marcus V.;Iwaki, Shoko;Ropert, Catherine;Gazzinelli, Ricardo T.;Cunha-Melo, Jose R.;Beaven, Michael A.
通讯作者：
Beaven, Michael A.
影响因子：
4.1
作者：
Darragh, J;Soloaga, A;Arthur, JSC
通讯作者：
Arthur, JSC
影响因子：
5
作者：
Iikura, Motoyasu;Suto, Hajime;Nakae, Susumu
通讯作者：
Nakae, Susumu
影响因子：
3.7
作者：
Elcombe SE;Naqvi S;Van Den Bosch MW;MacKenzie KF;Cianfanelli F;Brown GD;Arthur JS
通讯作者：
Arthur JS