Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade
Human RPE-monocyte co-culture induces chemokine gene expression through activation of MAPK and NIK cascade
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DOI：
10.1016/s0014-4835(03)00029-0
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发表时间：
2003-05-01
影响因子：
3.4
通讯作者：
Elner, VM
中科院分区：
文献类型：
--
作者：
Bian, ZM;Elner, SG;Elner, VM
人视网膜色素上皮（hRPE）细胞和单核细胞之间的细胞-细胞接触发生在许多涉及血-视网膜屏障破坏的视网膜疾病中。本研究探讨了hRPE细胞和单核细胞共培养诱导的趋化因子分泌，并阐明了p38激酶、ERK、JNK/SAPK和NF-κ B诱导激酶信号通路在hRPE与单核细胞共培养诱导的hRPE IL-8和MCP-1分泌中的作用。hRPE细胞与单核细胞的共培养增加了稳态IL-8和MCP-1 mRNA和蛋白的分泌。单核细胞刺激hRPE细胞导致p38、ERK 1/2和JNK/SAPK磷酸化、IkappaB α降解和NF-κ B核转位显著增加。诱导的IL-8和MCP-1蛋白几乎完全被特异性丝裂原活化蛋白激酶激酶（MEK）抑制剂U 0126或选择性p38抑制剂SB 203580抑制。同时给予U 0126和SB 203580可完全阻断趋化因子分泌。IL-8和MCP-1的诱导被PKC抑制剂Ro 318220以及PTK抑制剂genistein或herbimycin A废除。此外，抗炎药地塞米松（DEX）和环孢菌素A（CSA）均能阻断JNKS/SAPK的激活以及细胞接触诱导的hRPE IL-8和MCP-1的产生，而p38和ERK的激活仅被DEX抑制，CSA则无此作用。这些结果表明，DEX敏感的、CSA抗性的MEK/ERK和p38通路的激活以及NF-κ B、PKC和PTK的激活对于hRPE细胞表达IL-8和MCP-1是必需的。(C)2003爱思唯尔科技有限公司版权所有。
Cell-cell contact between human retinal pigment epithelium (hRPE) cells and monocytes occurs in many retinal diseases involving blood-retinal barrier breakdown. This study investigates chemokine secretion induced by co-culture of hRPE cells and monocytes and illustrates the roles of p38 kinase, ERK, JNK/SAPK and NF-kappaB-inducing kinase signaling pathways for hRPE IL-8 and MCP-1 secretion induced in hRPE by co-culture with monocytes. Co-culture of hRPE cells with monocytes increased steady-state IL-8 and MCP-1 mRNA and protein secretion. Stimulation of hRPE cells by monocytes resulted in prominent increases in p38, ERK1/2 and JNK/SAPK phosphorlation, IkappaBalpha degradation, and NF-kappaB nuclear translocation. The induced IL-8 and MCP-1 proteins were almost completely supporessed by U0126, a specific mitogen-activated protein kinase kinase (MEK) inhibitor, or by SB203580, a selective p38 inhibitor. Chemokine secretion was completely blocked by simultaneous administration of U0126 and SB203580. Induction of IL-8 and MCP-1 was abrogated by Ro318220, an inhibitor of PKC, as well as by genistein or herbimycin A, inhibitors of PTK. In addition, anti-inflammatory drugs dexamethasone (DEX) and cyclosporin A (CSA) both blocked activation of JNKS/SAPK and the cell-cell contact induced production of hRPE IL-8 and MCP-1, while activation of p38 and ERK was only inhibited by DEX, but not by CSA. These results suggest that activation of DEX-sensitive, CSA-resistant MEK/ERK and p38 pathways, and activation of NF-kappaB, PKC, and PTK are essential for IL-8 and MCP-1 expression by hRPE cells. (C) 2003 Elsevier Science Ltd. All rights reserved.