TGF-β1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process
TGF-β1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process
复制标题
DOI：
10.1152/ajpcell.00153.2005
复制
发表时间：
2005-10-01
影响因子：
5.5
通讯作者：
Grande, JP
中科院分区：
文献类型：
--
作者：
Cheng, JF;Encarnacion, MMD;Grande, JP
单核细胞趋化蛋白-1(MCP-1)和转化生长因子-β(1)是肾脏损伤的关键介质，促进过度炎症和细胞外基质沉积，从而促进肾脏疾病的进展。在肾脏疾病模型中，MCP-1刺激转化生长因子-β的产生(1)。然而，转化生长因子-β(1)在调节系膜细胞(MC)产生单核细胞趋化蛋白-1(MCP-1)中的潜在作用之前还没有得到评估。本研究的目的是明确转化生长因子-β(1)在调节MCs MCP-1表达中的作用，并明确具有抗炎作用的磷酸二酯酶4(PDE4)抑制剂罗利普兰(RP)改变MCP-1表达的机制。转化生长因子-β(1)以时间和剂量依赖的方式诱导MCP-1，但不增加MCP-1基因的转录。转化生长因子-β(1)介导的单核细胞趋化蛋白-1的诱导并不激活核因子-kappaB途径。RP通过蛋白激酶A依赖的过程抑制转化生长因子-β(1)刺激的单核细胞趋化蛋白-1的表达，至少部分通过降低单核细胞趋化蛋白-1的信息稳定性。RP对转化生长因子-β(1)激活Smad通路无影响。转化生长因子-β1介导的单核细胞趋化蛋白-1的诱导需要ERK和p38的激活，这两个信号通路都被PDE4抑制剂抑制。转化生长因子-β(1)刺激系膜细胞产生ROS，RP抑制转化生长因子-β(1)刺激的系膜细胞产生ROS；此外，RP和ROS清除剂均抑制转化生长因子-β(1)刺激的MCP-1的表达。我们得出结论，转化生长因子-β(1)通过激活ERK、p38和ROS产生途径来刺激MCP-1的表达。MCs中转化生长因子-β(1)和单核细胞趋化蛋白-1(MCP-1)信号的正相互作用可能是进行性肾脏疾病发生的基础。RP通过阻止转化生长因子-β(1)刺激的单核细胞趋化蛋白-1的产生，可能为延缓肾脏疾病的进展提供一种治疗方法。
Monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor (TGF)-beta(1) are critical mediators of renal injury by promoting excessive inflammation and extracellular matrix deposition, thereby contributing to progressive renal disease. In renal disease models, MCP-1 stimulates the production of TGF-beta(1). However, a potential role for TGF-beta(1) in the regulation of MCP-1 production by mesangial cells (MCs) has not previously been evaluated. The objectives of this study were to define the role of TGF-beta(1) in regulation of MCP-1 expression in cultured MCs and to define mechanisms through which rolipram (Rp), a phosphodiesterase isoenzyme 4 (PDE4) inhibitor with antiinflammatory properties, alters MCP-1 expression. TGF-beta(1) induced MCP-1 in a time- and dose-dependent manner without increasing transcription of the MCP-1 gene. TGF-beta(1)-mediated induction of MCP-1 occurred without activation of the NF-kappa B pathway. Rp blocked TGF-beta(1)-stimulated MCP-1 expression via a protein kinase A-dependent process, at least in part, by decreasing MCP-1 message stability. Rp exerted no effect on activation of the Smad pathway by TGF-beta(1). TGF-beta 1-mediated induction of MCP-1 required activation of ERK and p38, both of which were suppressed by a PDE4 inhibitor. TGF-beta(1)-stimulated reactive oxygen species (ROS) generation by MCs, and Rp inhibited ROS generation in TGF-beta(1)-stimulated MCs; in addition, both Rp and ROS scavengers blocked TGF-beta(1)-stimulated MCP-1 expression. We conclude that TGF-beta(1) stimulates MCP-1 expression through pathways involving activation of ERK, p38, and ROS generation. Positive cross-talk between TGF-beta(1) and MCP-1 signaling in MCs may underlie the development of progressive renal disease. Rp, by preventing TGF-beta(1)-stimulated MCP-1 production, may offer a therapeutic approach in retarding the progression of renal disease.