Temporal control of NF-κB activation by ERK differentially regulates interleukin-1β-induced gene expression
Temporal control of NF-κB activation by ERK differentially regulates interleukin-1β-induced gene expression
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DOI：
10.1074/jbc.m307521200
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发表时间：
2004-01-09
影响因子：
4.8
通讯作者：
Cohen, RA
中科院分区：
文献类型：
--
作者：
Jiang, BB;Xu, SQ;Cohen, RA
在培养的大鼠血管平滑肌细胞中，ERK的持续激活是白细胞介素-1 β持续激活NF-κ B所必需的。在没有ERK激活的情况下，白细胞介素-1 β仅诱导急性和短暂的NF-κ B激活。本研究检测ERK对NF-κ B激活的时间控制是否可以差异调节NF-κ B依赖性基因的表达，包括诱导型一氧化氮合酶（iNOS）、环氧合酶-2（考克斯-2）、血管细胞粘附分子-1（VCAM-1）和含锰超氧化物歧化酶（Mn-SOD）。IL-1 β处理血管平滑肌细胞后诱导iNOS、考克斯-2、VCAM-1和Mn-SOD表达呈时间依赖性，但表达模式不同。选择性MEK抑制剂PD 98059或U 0126或显性失活MEK-1的过表达均抑制IL-1 β诱导的ERK激活以及iNOS和考克斯-2的表达，但对VCAM-1和Mn-SOD的表达基本无影响。当NF-κ B激活被MG 132（一种蛋白酶体抑制剂）下调，或通过过表达阻止NF-κ B瞬时和持续激活的I-κ B α突变体时，这些基因的表达被抑制。抑制ERK不影响白细胞介素1 β诱导的I-κ B α磷酸化和降解，但减弱I-κ B β降解。因此，虽然NF-κ B激活是必不可少的白细胞介素-1 β诱导的每一个蛋白质的研究，基因表达的差异调节ERK和NF-κ B激活的持续时间。这些结果揭示了ERK作为NF-κ B激活和NF-κ B依赖性基因表达的重要时间调节剂的新功能作用。
In cultured rat vascular smooth muscle cells, sustained activation of ERK is required for interleukin-1beta to persistently activate NF-kappaB. Without ERK activation, interleukin-1beta induces only acute and transient NF-kappaB activation. The present study examined whether the temporal control of NF-kappaB activation by ERK could differentially regulate the expression of NF-kappaB-dependent genes, including inducible nitric oxide synthase ( iNOS), cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1), and manganese-containing superoxide dismutase (Mn-SOD). Treatment of vascular smooth muscle cells with interleukin-1beta induced the expression of iNOS, COX-2, VCAM-1, and Mn-SOD in a time-dependent manner, but with different patterns. Either PD98059 or U0126, selective inhibitors of MEK, or overexpression of a dominant negative MEK-1 inhibited interleukin-1beta-induced ERK activation and the expression of iNOS and COX-2 but had essentially no effect on the expression of VCAM-1 and Mn-SOD. The expression of these genes was inhibited when NF-kappaB activation was down-regulated by MG132, a proteasome inhibitor, or by overexpression of an I-kappaBalpha mutant that prevented both the transient and the persistent activation of NF-kappaB. Inhibition of ERK did not affect interleukin-1beta-induced I-kappaBalpha phosphorylation and degradation but attenuated I-kappaBbeta degradation. Thus, although NF-kappaB activation was essential for interleukin-1beta induction of each of the proteins studied, gene expression was differentially regulated by ERK and by the duration of NF-kappaB activation. These results reveal a novel functional role for ERK as an important temporal regulator of NF-kappaB activation and NF-kappaB-dependent gene expression.