Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein
Prolonged Toll-like receptor stimulation leads to down-regulation of IRAK-4 protein
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DOI：
10.1189/jlb.0504277
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发表时间：
2004-10-01
影响因子：
5.5
通讯作者：
Tanamoto, K
中科院分区：
文献类型：
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作者：
Hatao, F;Muroi, M;Tanamoto, K
Interleukin-1 受体相关激酶 (IRAK)-4 是 Toll 样受体 (TLR) 信号传导的关键介质。我们发现，刺激 TLR2、TLR4 或 TLR9（而非 TLR3）会导致小鼠巨噬细胞系 RAW 264 中 IRAK-4 蛋白的减少，而不影响其 mRNA 水平。IRAK-4 的减少伴随着较小分子量蛋白质 (32 kD) 的出现，该蛋白质可被针对 G 末端区域的抗 IRAK-4 抗体识别。 IRAK-4 的减少和 32-kD 蛋白质的出现以比 IRAK-1 的激活更慢的动力学发生，并被蛋白酶体抑制剂、kappaBα 磷酸化或蛋白质合成的诱导抑制剂抑制，但不被 caspase 抑制剂抑制。这些结果表明，长时间刺激 TLR2、TLR4 或 TLR9 会导致 IRAK-4 蛋白下调，这可能是通过核因子 kappaB 激活诱导的蛋白酶裂解 IRAK-4 来介导的。
Interleukin-1 receptor-associated kinase (IRAK)-4 is a key mediator in the Toll-like receptor (TLR) signaling. We found that stimulation of TLR2, TLR4, or TLR9, but not TLR3, caused a decrease in IRAK-4 protein without affecting its mRNA level in a mouse macrophage cell line, RAW 264. The decrease in IRAK-4 was accompanied by the appearance of a smaller molecular weight protein (32 kD), which was recognized by an anti-IRAK-4 antibody raised against the G terminal region. The decrease in IRAK-4 and the appearance of the 32-kD protein occurred with slower kinetics than the activation of IRAK-1 and were suppressed by inhibitors of the proteasome, inducible inhibitor of kappaBalpha phosphorylation or protein synthesis, but not by caspase inhibitors. These results indicate that prolonged stimulation of TLR2, TLR4, or TLR9 causes a down-regulation of IRAK-4 protein, which may be mediated through cleavage of IRAK-4 by a protease induced by the activation of nuclear factor-kappaB.