Induction of Interleukin-8 Synthesis Integrates Effects on Transcription and mRNA Degradation from at Least Three Different Cytokine- or Stress-Activated Signal Transduction Pathways
Induction of Interleukin-8 Synthesis Integrates Effects on Transcription and mRNA Degradation from at Least Three Different Cytokine- or Stress-Activated Signal Transduction Pathways
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DOI：
10.1128/mcb.19.10.6742
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发表时间：
1999-10
影响因子：
5.3
通讯作者：
H. Holtmann;R. Winzen;P. Holland;S. Eickemeier;E. Hoffmann;D. Wallach;N. Malinin;Jonathan A. Cooper;K. Resch;M. Kracht
中科院分区：
文献类型：
--
作者：
H. Holtmann;R. Winzen;P. Holland;S. Eickemeier;E. Hoffmann;D. Wallach;N. Malinin;Jonathan A. Cooper;K. Resch;M. Kracht
炎症的一个特征是由细胞应激和促炎细胞因子如白介素1(IL-1)和肿瘤坏死因子等同时激活不同的丝裂原激活蛋白(MAP)激酶和核因子-κB的刺激引起的某些蛋白质的爆发式形成。通过表达活性和非活性形式的蛋白激酶，研究了这些信号通路在诱导IL-8形成的过程中的协同作用。MKK7是应激激活蛋白激酶/c-jun氨基末端激酶(SAPK/JNK)途径的激活剂，可诱导IL-8的合成和转录。此外，MKK7与核因子-κB诱导激酶(NIK)具有协同作用。IL-8启动子的激活需要有功能的NF-κB和AP-1结合。而NIK和MKK7不影响IL-8mRNA的降解，而MKK6的一种活性形式选择性地激活p38 MAP激酶，导致转录显著稳定，并进一步增加NIK和MKK7诱导的IL-8蛋白的形成。一直以来，能够激活核因子-κB、SAPK/JNK和p38的MAP激酶MEKK1最能有效地诱导IL-8的形成。这些结果表明，IL-8基因的最大表达需要至少三条不同的信号转导途径的协同作用，这三条信号转导途径共同作用于诱导基因合成和抑制基因降解。
ABSTRACT A hallmark of inflammation is the burst-like formation of certain proteins, initiated by cellular stress and proinflammatory cytokines like interleukin 1 (IL-1) and tumor necrosis factor, stimuli which simultaneously activate different mitogen-activated protein (MAP) kinases and NF-κB. Cooperation of these signaling pathways to induce formation of IL-8, a prototype chemokine which causes leukocyte migration and activation, was investigated by expressing active and inactive forms of protein kinases. Constitutively active MAP kinase kinase 7 (MKK7), an activator of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) pathway, induced IL-8 synthesis and transcription from a minimal IL-8 promoter. Furthermore, MKK7 synergized in both effects with NF-κB-inducing kinase (NIK). Activation of the IL-8 promoter by either of the kinases required functional NF-κB and AP-1 sites. While NIK and MKK7 did not affect degradation of IL-8 mRNA, an active form of MKK6, which selectively activates p38 MAP kinase, induced marked stabilization of the transcript and further increased IL-8 protein formation induced by NIK plus MKK7. Consistently, the MAP kinase kinase kinase MEKK1, which can activate NF-κB, SAPK/JNK, and p38 MAP kinases, most potently induced IL-8 formation. These results provide evidence that maximal IL-8 gene expression requires the coordinate action of at least three different signal transduction pathways which cooperate to induce mRNA synthesis and suppress mRNA degradation.