Regulation of monocyte chemoattractant protein-1 and macrophage colony- stimulating factor-1 by IFN-γ, tumor necrosis factor-α, IgG aggregates, and cAMP in mouse mesangial cells

The interaction of mesangial cells and monocyte-macrophages plays an important role in renal glomerular immune injury. We have, therefore, examined the regulation of two monocyte-specific cytokines, i.e., macrophage CSF-1 and monocyte chemoattractant protein (MCP-1), the product of the mouse JE gene, in mouse mesangial cells. TNF-α, IFN-γ, and aggregates of IgG increased the synthesis of CSF-1 (determined by RIA) and of MCP-1 (determined by biolabeling and immunoprecipitation). Stimulation of cAMP generation by forskolin or PGE₂ decreased basal CSF-1 synthesis and attenuated the responses to TNF-α, IFN-γ, and IgG. Forskolin and PGE₂ also decreased biolabeled MCP-1 generation after stimulation with IFN-γ, TNF-α, or IgG. By Northern blot analysis steady state levels of mRNA for CSF-1 and JE/MCP-1 were increased after incubation with IFN-γ, TNF-α, or IgG, and these effects were attenuated by forskolin. By using nuclear run-on assays the decrease in CSF-1 and JE/MCP-1 mRNA levels induced by stimulation of cAMP generation with forskolin was attributed to decreased transcription of these genes. Thus, agents stimulating cAMP generation, including PGE₂, counterbalance the generation of CSF-1 and JE/MCP-1 in response to IFN-γ, TNF-α, and IgG complexes. The locally produced CSF-1 and MCP-1 may in turn influence the interaction between mesangial cells and monocyte-macrophages in glomerular injury.