We have previously proposed that activated mesangial cells (MC) have a direct role in the initiation and propagation of inflammatory events within the glomerulus via the generation of the mesangioproliferative cytokine IL-6 and the chemokines IL-8 and MCP-1. The objective of this study was to investigate the role of cAMP in the regulation of IL-6 and IL-8 gene expression and peptide production in IL-1 stimulated human MC. Agents known to elevate cAMP, including dibutyryl cAMP (db-cAMP), forskolin or isobutyl-methylxanthine (IBMX) were alone unable to induce IL-6 or IL-8 expression or production above media control levels, indicating activation of the cAMP pathway could not mimic IL-1 signaling events. In the presence of IL-1, all three agents produced a marked potentiation of IL-6 mRNA expression and dose-dependent increase in IL-6 peptide production (twofold), but had little or no effect on IL-8 mRNA expression or peptide generation. In marked contrast cholera toxin (CT) caused a dose-dependent potentiation of both IL-1-induced IL-6 (approximately fourfold) and IL-8 peptide (approximately twofold) generation. The control agent, the purified binding subunit of cholera toxin (CT-B) which is devoid of ADP-ribosylating activity also enhanced IL-6 and IL-8 (approximately twofold) peptide generation indicating cAMP-independent mechanisms may be involved in the CT up-regulation of these cytokines. Treatment of MC with the cycloxygenase inhibitor indomethacin resulted in partial inhibition (37%) of IL-6 production but had no effect on IL-8 generation. Thus our data show that cAMP can potentiate IL-1 induced IL-6 production, while having no effect on IL-8 induction, and PGE2 may operate via a positive feedback loop to up-regulate IL-1 induced IL-6. Taken together, our results demonstrate that cAMP differentially regulates IL-6 and IL-8 production in IL-1-stimulated human MC.