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Abstract. Cytokine secretion by mesangial cells (MC) plays a major role in the pathogenesis of glomerulonephritis. To define signaling events that occur during the activation of MC, the cell-specific transcriptional regulation of the interleukin-6 (IL-6) gene was studied. Stimulation with lipopolysaccharide and IL-1β resulted in the full induction of IL-6 expression only if the cells were coincubated with cAMP agonists; this effect was attenuated by protein kinase A inhibitors. In reporter gene experiments, the IL-6 promoter showed a stimulation pattern comparable to that of the endogenous gene. Elimination of individual transcription factor binding sites provided evidence for functional roles for four cis-acting elements, i.e., activator protein-1, cAMP response element-binding protein (CREB), nuclear factor for IL-6 expression (NF-IL6), and nuclear factor-κB (NF-κB). Electrophoretic mobility shift assays using nuclear extracts from MC revealed that the DNA-binding activities of activator protein-1 and NF-κB were inducible, whereas no change could be observed for CREB and NF-IL6. The presence of several transcription factor proteins, including JunB, JunD, c-Fos, Fra-1, CREB-1, activating transcription factor-2, NF-κB p50, p52, and p65, and CAAT/enhancer-binding protein-δ, was demonstrated by supershift analysis. Of particular interest was the novel finding of the participation of NF-κB p65 in the NF-IL6 complex. In summary, a signal transduction pathway in MC that requires protein kinase A activation in addition to a second signal provided by lipopolysaccharide or IL-1β was identified.