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TAK1 protein kinase activity is required for TLR signalling and cytokine production in myeloid cells
Biochemical Journal ( IF 4.1 ) Pub Date : 2022-09-16 , DOI: 10.1042/bcj20220314
Melissa Rodrigues 1 , Tsvetana Petrova 1 , Brendan Tibbs 1 , J Simon C Arthur 2 , Philip Cohen 1
Affiliation  

A conditional knock-in mouse was generated in which the TAK1 catalytic subunit was largely replaced by the kinase-inactive TAK1[D175A] mutant in immune cells. The activation of p38α MAP kinase, c-Jun N-terminal kinases 1 and 2 (JNK1/2) and the canonical IKK complex induced by stimulation with several TLR-activating ligands was reduced in bone marrow-derived macrophages (BMDM) from TAK1[D175A] mice. TLR signalling in TAK1[D175A] BMDM was catalysed by the residual wild-type TAK1 in these cells because it was abolished by either of two structurally unrelated TAK1 inhibitors (NG25 and 5Z-7-oxozeaenol) whose off-target effects do not overlap. The secretion of inflammatory mediators and production of the mRNAs encoding these cytokines induced by TLR ligation was greatly reduced in peritoneal neutrophils or BMDM from TAK1[D175A] mice. The Pam3CSK4- or LPS-stimulated activation of MAP kinases and the canonical IKK complex, as well as cytokine secretion, was also abolished in TAK1 knock-out human THP1 monocytes or macrophages. The results establish that TAK1 protein kinase activity is required for TLR-dependent signalling and cytokine secretion in myeloid cells from mice. We discuss possible reasons why other investigators, studying myeloid mice with a conditional knock-out of TAK1 or a different conditional kinase-inactive knock-in of TAK1, reported TAK1 to be a negative regulator of LPS-signalling and cytokine production in mouse macrophages and neutrophils.

中文翻译:

骨髓细胞中 TLR 信号传导和细胞因子产生需要 TAK1 蛋白激酶活性

产生了条件性敲入小鼠,其中 TAK1 催化亚基在很大程度上被免疫细胞中激酶失活的 TAK1[D175A] 突变体取代。在来自 TAK1 的骨髓衍生巨噬细胞 (BMDM) 中,p38α MAP 激酶、c-Jun N 末端激酶 1 和 2 (JNK1/2) 以及由几种 TLR 激活配体刺激诱导的经典 IKK 复合物的激活降低[ D175A] 小鼠。TAK1[D175A] BMDM 中的 TLR 信号传导由这些细胞中残留的野生型 TAK1 催化,因为它被两种结构不相关的 TAK1 抑制剂(NG25 和 5Z-7-oxozaeenol)中的任何一种所消除,其脱靶效应不重叠。在来自 TAK1[D175A] 小鼠的腹膜中性粒细胞或 BMDM 中,炎症介质的分泌和 TLR 连接诱导的编码这些细胞因子的 mRNA 的产生大大减少。Pam3CSK4 或 LPS 刺激的 MAP 激酶和经典 IKK 复合物的激活,以及细胞因子的分泌,在 TAK1 敲除的人 THP1 单核细胞或巨噬细胞中也被消除了。结果表明,小鼠骨髓细胞中 TLR 依赖性信号传导和细胞因子分泌需要 TAK1 蛋白激酶活性。我们讨论了其他研究人员在研究条件性敲除 TAK1 或不同条件性激酶失活 TAK1 敲入的骨髓小鼠时,报告 TAK1 是小鼠巨噬细胞中 LPS 信号传导和细胞因子产生的负调节因子的可能原因,并且中性粒细胞。结果表明,小鼠骨髓细胞中 TLR 依赖性信号传导和细胞因子分泌需要 TAK1 蛋白激酶活性。我们讨论了其他研究人员在研究条件性敲除 TAK1 或不同条件性激酶失活 TAK1 敲入的骨髓小鼠时,报告 TAK1 是小鼠巨噬细胞中 LPS 信号传导和细胞因子产生的负调节因子的可能原因,并且中性粒细胞。结果表明,小鼠骨髓细胞中 TLR 依赖性信号传导和细胞因子分泌需要 TAK1 蛋白激酶活性。我们讨论了其他研究人员在研究条件性敲除 TAK1 或不同条件性激酶失活 TAK1 敲入的骨髓小鼠时,报告 TAK1 是小鼠巨噬细胞中 LPS 信号传导和细胞因子产生的负调节因子的可能原因,并且中性粒细胞。
更新日期:2022-09-16
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