Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-α involves activation of the MKK6/p38MAPK/MK2 cascade
Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-α involves activation of the MKK6/p38MAPK/MK2 cascade
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DOI：
10.4049/jimmunol.178.5.2813
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Bode, Johannes G.
中科院分区：
文献类型：
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作者：
Ehlting, Christian;Lai, Wi S.;Bode, Johannes G.
一些促炎介质通过增强细胞因子信号传导抑制因子（SOCS） 3的表达来抑制gp130依赖性STAT3的激活，这是一种重要的分子机制，可以调节gp130介导的信号对细胞的反应。因此，有必要了解促炎介质调节SOCS3表达的机制。在这项研究中，我们研究了促炎细胞因子tnf - α引发的SOCS3表达。与IL-6相反，tnf - α通过稳定SOCS3 mRNA来增加SOCS3的表达。激活MAPK激酶6 (MKK6)/p38（MAPK）级联是tnf α介导的SOCS3 mRNA稳定所必需的，并导致SOCS3蛋白表达增强。在MAPK激活的蛋白激酶2 (MK2) （MKK6/p38（MAPK）级联的下游MAPK靶点）缺乏的成纤维细胞或巨噬细胞中，基础SOCS3表达强烈降低，tnf α诱导的SOCS3 mrna稳定性受损，表明MK2对于通过p38（MAPK）依赖信号控制SOCS3表达至关重要。作为SOCS3 mRNA稳定性调节信号的靶标，一个包含三个拷贝的五元AUUUA基序的区域靠近位于SOCS3 3'非翻译区2422和2541之间的富u区。锌指蛋白三戊三醇（TTP）是一个可能靶向该区域的因子，它被证明能够通过该区域破坏SOCS3 mRNA的稳定。然而，来自TTP缺陷细胞的数据表明，TTP在tnf - α对SOCS3 mRNA稳定性的调节中并不起不可替代的作用。综上所述，这些数据表明，tnf - α通过激活MKK6/p38（MAPK）级联在mRNA稳定水平上调控SOCS3的表达，而MK2 （p38（MAPK）的下游靶点）的激活对SOCS3的表达调控很重要。
The potential of some proinflammatory mediators to inhibit gp130-dependent STAT3 activation by enhancing suppressor of cytokine signaling (SOCS) 3 expression represents an important molecular mechanism admitting the modulation of the cellular response toward gp130-mediated signals. Thus, it is necessary to understand the mechanisms involved in the regulation of SOCS3 expression by proinflammatory mediators. In this study, we investigate SOCS3 expression initiated by the proinflammatory cytokine TNF-alpha. In contrast to IL-6, TNF-alpha increases SOCS3 expression by stabilizing SOCS3 mRNA. Activation of the MAPK kinase 6 (MKK6)/p38(MAPK)-cascade is required for TNF-alpha-mediated stabilization of SOCS3 mRNA and results in enhanced SOCS3 protein expression. In fibroblasts or macrophages deficient for MAPK-activated protein kinase 2 (MK2), a downstream MAPK target of the MKK6/p38(MAPK) cascade, basal SOCS3-expression is strongly reduced and TNF-alpha-induced SOCS3-mRNA stabilization is impaired, indicating that MK2 is crucial for the control of SOCS3 expression by p38(MAPK)-dependent signals. As a target for SOCS3 mRNA stability-regulating signals, a region containing three copies of a pentameric AUUUA motif in close proximity to a U-rich region located between positions 2422 and 2541 of the 3' untranslated region of SOCS3 is identified. One factor that could target this region is the zinc finger protein tristetraprolin (TTP), which is shown to be capable of destabilizing SOCS3 mRNA via this region. However, data from TTP-deficient cells suggest that TTP does not play an irreplaceable role in the regulation of SOCS3 mRNA stability by TNF-alpha. In summary, these data indicate that TNF-alpha regulates SOCS3 expression on the level of mRNA stability via activation of the MKK6/p38(MAPK) cascade and that the activation of MK2, a downstream target of p38(MAPK), is important for the regulation of SOCS3 expression.