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RECEPTORS AND SIGNAL TRANSDUCTION

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

¹Department of Laboratory Medicine and Pathology, and ²Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota

Submitted 1 April 2005 ; accepted in final form 26 May 2005

Monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor (TGF)-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-₁. However, a potential role for TGF-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-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 anti-inflammatory properties, alters MCP-1 expression. TGF-₁ induced MCP-1 in a time- and dose-dependent manner without increasing transcription of the MCP-1 gene. TGF-₁-mediated induction of MCP-1 occurred without activation of the NF-B pathway. Rp blocked TGF-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-₁. TGF-₁-mediated induction of MCP-1 required activation of ERK and p38, both of which were suppressed by a PDE4 inhibitor. TGF-₁-stimulated reactive oxygen species (ROS) generation by MCs, and Rp inhibited ROS generation in TGF-₁-stimulated MCs; in addition, both Rp and ROS scavengers blocked TGF-₁-stimulated MCP-1 expression. We conclude that TGF-₁ stimulates MCP-1 expression through pathways involving activation of ERK, p38, and ROS generation. Positive cross-talk between TGF-₁ and MCP-1 signaling in MCs may underlie the development of progressive renal disease. Rp, by preventing TGF-₁-stimulated MCP-1 production, may offer a therapeutic approach in retarding the progression of renal disease.

cAMP; inflammation; mitogen-activated protein kinase; reactive oxygen species

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