Role of mitogen-activated protein kinase cascades in mediating lipopolysaccharide-stimulated induction of cyclooxygenase-2 and IL-1β in RAW264 macrophages
Role of mitogen-activated protein kinase cascades in mediating lipopolysaccharide-stimulated induction of cyclooxygenase-2 and IL-1β in RAW264 macrophages
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DOI：
10.4049/jimmunol.164.6.3018
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发表时间：
2000-03-15
影响因子：
4.4
通讯作者：
Cohen, P
中科院分区：
文献类型：
--
作者：
Caivano, M;Cohen, P
脂多糖刺激RAW264巨噬细胞可激活丝裂原和应激激活蛋白激酶-1和-2(MSK1、MSK2)及其底物转录因子cAMP反应元件结合蛋白(CREB)和。在激活转录因子-1(Atf1)的过程中，MSK1/MSK2的激活可以通过两种药物的联合预先孵育来阻止，这两种药物分别抑制经典的丝裂原激活蛋白激酶级联和应激激活蛋白激酶/p38的激活，但在任何一种抑制剂的存在下，抑制作用都只是部分的。内毒素刺激的CREB和ATF1的激活，环氧合酶-2(COX-2)和IL-1β基因的转录(其启动子包含一个环磷酸腺苷反应元件)，以及COX-2蛋白的诱导，都被相同的药物组合以及MSK1/MSK2的有效抑制剂Ro 318220或H89所阻止。另外两种转录因子C/ERPβ和NF-kappa B也参与了COX-2基因的转录。然而，PD 98059和/或SE 203580不能阻止内毒素诱导的转录因子C/EBPβ水平的升高，本研究中使用的四种抑制剂都不能阻止核因子-kappaB的激活。我们的结果表明，两种不同的丝裂原激活的蛋白激酶级联反应对内毒素诱导的CREB/ATF1的激活以及COX-2和IL-1β基因的转录具有限速作用。他们还提示，MSK1和MSK2可能在这些过程中发挥作用，因此是开发新型抗炎药物的潜在靶点。
LPS stimulation of RAW264 macrophages triggered the activation of mitogen- and stress-activated protein kinases-1 and -2 (MSK1, MSK2) and their putative substrates, the transcription factors cyclic AMP response element-binding protein (CREB) and. activating transcription factor-1 (ATF1), The activation of MSK1/MSK2 was prevented by preincubating the cells with a combination of two drugs that suppress activation of the classical mitogen-activated protein kinase cascade and stress-activated protein kinase/p38, respectively, but inhibition was only partial in the presence of either inhibitor. The LPS-stimulated activation of CREB and ATF1, the transcription of the cyclooxygenase-2 (COX-2) and IL-1 beta genes (the promoters of which contain a cyclic AMP response element), and the induction of the COX-2 protein were prevented by the same drug combination, as well as by Ro 318220 or H89, potent inhibitors of MSK1/MSK2 Two other transcription factors, C/ERP beta and NF-kappa B have been implicated in the transcription of the COX-2 gene. However, PD 98059 and/or SE 203580 did not prevent the LPS-induced increase in the level of the transcription factor C/EBP beta, and none of the four inhibitors used in this study prevented the activation of NF-kappa B, Our results demonstrate that two different mitogen-activated protein kinase cascades are rate limiting for the LPS-induced activation of CREB/ATF1 and the transcription of the COX-2 and IL-1 beta genes. They also suggest that MSK1 and MSK2 may play a role in these processes and hence are potential targets for the development of novel antiinflammatory drugs.