Monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor (TGF)-β₁ 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-β₁. However, a potential role for TGF-β₁ 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-β₁ 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-β₁ induced MCP-1 in a time- and dose-dependent manner without increasing transcription of the MCP-1 gene. TGF-β₁-mediated induction of MCP-1 occurred without activation of the NF-κB pathway. Rp blocked TGF-β₁-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-β₁. TGF-β₁-mediated induction of MCP-1 required activation of ERK and p38, both of which were suppressed by a PDE4 inhibitor. TGF-β₁-stimulated reactive oxygen species (ROS) generation by MCs, and Rp inhibited ROS generation in TGF-β₁-stimulated MCs; in addition, both Rp and ROS scavengers blocked TGF-β₁-stimulated MCP-1 expression. We conclude that TGF-β₁ stimulates MCP-1 expression through pathways involving activation of ERK, p38, and ROS generation. Positive cross-talk between TGF-β₁ and MCP-1 signaling in MCs may underlie the development of progressive renal disease. Rp, by preventing TGF-β₁-stimulated MCP-1 production, may offer a therapeutic approach in retarding the progression of renal disease.