TGF-β1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process

被引:57
作者
Cheng, JF
Encarnacion, MMD
Warner, GM
Gray, CE
Nath, KA
Grande, JP
机构
[1] Mayo Clin Coll Med, Dept Lab Med & Pathol, Rochester, MN 55905 USA
[2] Mayo Clin Coll Med, Div Nephrol & Hypertens, Rochester, MN 55905 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY | 2005年 / 289卷 / 04期
关键词
cAMP; inflammation; mitogen; activated protein kinase; reactive oxygen species;
D O I
10.1152/ajpcell.00153.2005
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:C959 / C970
页数:12
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