Epidermal Growth Factor and Interleukin-1β Utilize Divergent Signaling Pathways to Synergistically Upregulate Cyclooxygenase-2 Gene Expression in Human Amnion-Derived WISH Cells1
Epidermal Growth Factor and Interleukin-1β Utilize Divergent Signaling Pathways to Synergistically Upregulate Cyclooxygenase-2 Gene Expression in Human Amnion-Derived WISH Cells1
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表皮生长因子和 IL-1β 利用不同的信号通路协同上调人羊膜来源的 WISH 细胞中的 Cyclooxygenase-2 基因表达1
作者：
W. Ackerman;B. Rovin;D. Kniss
人类分娩过程中，子宫紧张性前列腺素（PGs）主要通过子宫内组织中环氧合酶-2（考克斯-2 [也称为前列腺素合成酶2]）表达增加而产生。白细胞介素-1（IL-1）和表皮生长因子（EGF）都是考克斯-2转录的诱导剂，是随着妊娠进展在羊水中积累的众多因子之一。先前证明EGF可以增强羊膜和羊膜衍生（WISH）细胞中IL-1β驱动的PGE 2产生。为了解释这一观察结果的机制，我们假设EGF和IL-1β可能在调节考克斯-2基因表达方面表现出协同作用。在WISH细胞中，EGF和IL-1β联合处理导致考克斯-2 mRNA相对于单独使用任何一种试剂的攻击的增加大于相加。在携带单独携带核因子-κ B（NFκB）调控元件的报告质粒的细胞中，未观察到EGF对IL-1β诱导的反式激活的增强，但当存在考克斯-2基因5′-启动子的片段（−891/ +9）时，这种增强是明显的。这两种药物瞬时激活可能参与考克斯-2基因表达调控的多种信号通路的中间体。26 S蛋白酶体抑制剂MG-132可选择性抑制IL-1β诱导的NFκB活化和考克斯-2 mRNA表达。只有p38丝裂原活化蛋白激酶的药理学阻断消除考克斯-2表达后，表皮生长因子的刺激。我们的结论是，EGF和IL-1β似乎通过不同的信号传导级联信号，导致考克斯-2基因的表达。IL-1β主要利用NFκB途径，而EGF信号转导谱更广，包括p38激酶。在IL-1β和EGF之间观察到的协同作用并不依赖于增强的NFκB功能，而是通过考克斯-2启动子内独立反应元件的差异使用而发生。
Abstract In human parturition, uterotonic prostaglandins (PGs) arise predominantly via increased expression of cyclooxygenase-2 (COX-2 [also known as prostaglandin synthase 2]) within intrauterine tissues. Interleukin-1 (IL-1) and epidermal growth factor (EGF), both inducers of COX-2 transcription, are among numerous factors that accumulate within amniotic fluid with advancing gestation. It was previously demonstrated that EGF could potentiate IL-1β-driven PGE2 production in amnion and amnion-derived (WISH) cells. To define the mechanism for this observation, we hypothesized that EGF and IL-1β might exhibit synergism in regulating COX-2 gene expression. In WISH cells, combined treatment with EGF and IL-1β resulted in a greater-than-additive increase in COX-2 mRNA relative to challenge with either agent independently. Augmentation of IL-1β-induced transactivation by EGF was not observed in cells harboring reporter plasmids bearing nuclear factor-kappa B (NFκB) regulatory elements alone, but was evident when a fragment (−891/ +9) of the COX-2 gene 5′-promoter was present. Both agents transiently activated intermediates of multiple signaling pathways potentially involved in the regulation of COX-2 gene expression. The 26 S proteasome inhibitor, MG-132, selectively abrogated IL-1β-driven NFκB activation and COX-2 mRNA expression. Only pharmacologic blockade of the p38 mitogen-activated protein kinase eliminated COX-2 expression following EGF stimulation. We conclude that EGF and IL-1β appear to signal through different signaling cascades leading to COX-2 gene expression. IL-1β employs the NFκB pathway predominantly, while the spectrum of EGF signaling is broader and includes p38 kinase. The synergism observed between IL-1β and EGF does not rely on augmented NFκB function, but rather, occurs through differential use of independent response elements within the COX-2 promoter.
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Interleukin-1 beta 调节羊膜来源的 WISH 细胞中的诱导型环氧合酶。
DOI：
10.1016/0090-6980(94)90006-x
发表时间：
1994
期刊：
Prostaglandins
影响因子：
--
作者：
Albert,TJ;Su,HC;Zimmerman,PD;Iams,JD;Kniss,DA
通讯作者：
Kniss,DA
DOI：
10.1006/bbrc.1994.2167
发表时间：
1994-08-30
影响因子：
3.1
作者：
TAZAWA, R;XU, XM;WANG, LH
通讯作者：
WANG, LH
DOI：
10.1016/s1071-5576(99)00034-9
发表时间：
1999-11
期刊：
Journal of The Society for Gynecologic Investigation
影响因子：
--
作者：
D. Kniss
通讯作者：
D. Kniss
DOI：
10.1016/s0090-6980(97)00144-5
发表时间：
1997-10
期刊：
Prostaglandins
影响因子：
--
作者：
D. Perkins;D. Kniss
通讯作者：
D. Perkins;D. Kniss
在人羊膜来源的 WISH 细胞中，表皮生长因子快速瞬时诱导环加氧酶 2。
DOI：
10.1042/bj3210677
发表时间：
1997
期刊：
The Biochemical journal
影响因子：
--
作者：
Perkins,DJ;Kniss,DA
通讯作者：
Kniss,DA