A20 regulates IL-1-induced tolerant production of CXC chemokines in human mesangial cells via inhibition of MAPK signaling.
A20 regulates IL-1-induced tolerant production of CXC chemokines in human mesangial cells via inhibition of MAPK signaling.
复制标题
A20 通过抑制 MAPK 信号传导来调节人系膜细胞中 IL-1 诱导的 CXC 趋化因子的耐受性产生。
DOI：
10.1038/srep18007
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发表时间：
2015-12-09
影响因子：
4.6
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Luo H;Liu Y;Li Q;Liao L;Sun R;Liu X;Jiang M;Hu J
趋化因子和趋化因子受体参与肾脏疾病的消退或进展。局部分泌的趋化因子在肾脏炎症的起始和扩增阶段介导白细胞募集。然而，趋化因子诱导的调控尚不完全清楚。在本研究中，我们发现IL-1诱导人系膜细胞中CXC趋化因子CXCL1、2和8的mRNA和蛋白水平显著上调。趋化因子的诱导是耐受的，因为IL-1预处理HMC可下调IL-1再刺激诱导的趋化因子的诱导。IL-1上调泛素编辑酶A20。A20过表达下调IL-1诱导的趋化因子上调，A20下调逆转IL-1预处理诱导的趋化因子抑制，提示A20在趋化因子耐受产生中发挥重要作用。出乎意料的是，A20过表达抑制了ERK、JNK和P38的激活，但没有抑制NF-κ b的激活。此外，IL-1处理和A20过表达均诱导IRAK1的降解，IRAK1是IL-1R1信号转导的重要接头，通过RNA干扰抑制A20可部分逆转IRAK1的降解。综上所述，il -1诱导的A20负向调节趋化因子的产生，提示A20可能是预防和控制肾脏炎症的重要靶点。
Chemokines and chemokine receptors are involved in the resolution or progression of renal diseases. Locally secreted chemokines mediated leukocyte recruitment during the initiation and amplification phase of renal inflammation. However, the regulation of chemokine induction is not fully understood. In this study, we found that IL-1 induced a significant up-regulation of CXC chemokines CXCL1, 2, and 8 at both mRNA and protein levels in human mesangial cells. The induction of chemokines was tolerant, as the pre-treatment of HMC with IL-1 down-regulated the induction of chemokines induced by IL-1 re-stimulation. IL-1 up-regulated the ubiquintin-editing enzyme A20. A20 over-expression down-regulated IL-1-induced up-regulation of chemokines, and A20 down-regulation reversed chemokine inhibition induced by IL-1 pre-treatment, suggested that A20 played important roles in the tolerant production of chemokines. Unexpectedly, A20 over- expression inhibited the activation of ERK, JNK, and P38, but did not inhibit the activation of NF-κB. In addition, both IL-1 treatment and A20 over-expression induced the degradation of IRAK1, an important adaptor for IL-1R1 signaling, and A20 inhibition by RNA interference partly reversed the degradation of IRAK1. Taken together, IL-1-induced A20 negatively regulated chemokine production, suggesting that A20 may be an important target for the prevention and control of kidney inflammation.