Anti-inflammatory activities of cAMP-elevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production

Interleukin‐10 (IL‐10) and tumor necrosis factor (TNF) exert key roles in some acute and chronic inflammatory diseases. In this study we investigated (1) the potency of different cAMP‐elevating agents in enhancing IL‐10 synthesis, (2) the involvement of protein kinase A in this enhancement, and (3) the mutual dependence of cAMP‐enhanced IL‐10 formation and cAMP‐suppressed TNF synthesis. Rolipram, a specific phosphodiesterase inhibitor and cicaprost, a prostacyclin analogue, were applied as cAMP‐elevating agents. The stable cAMP antagonist (Rp)‐cAMPS was used to abrogate activation of protein kinase A. Human peripheral blood mononuclear cells were stimulated with lipopolysaccharide (LPS). TNF was quantified by radioimmunoassay, IL‐10 by enzyme‐linked immunosorbent assay, and mRNA by reverse transcriptase‐polymerase chain reaction. After LPS stimulation alone 253 ± 45 pg/mL IL‐10 was synthesized, which increased to 644 ± 117 pg/mL in the presence of 1 μM rolipram. (Rp)‐cAMPS reversed this increase of IL‐10 formation. In the same samples, the LPS‐stimulated production of TNF was markedly attenuated by rolipram or cicaprost. A kinetic analysis revealed a significant increase in TNF production before IL‐10 formation was detectable. These results demonstrate that (1) cAMP‐elevating agents enhance IL‐10 synthesis and suppress TNF production; (2) these regulative functions of cAMP‐elevating agents are mediated by activation of protein kinases A; (3) suppression of TNF synthesis by cAMP in the early phase is not mediated by endogenous IL‐10. Taken together, rolipram and cicaprost exert a dual regulatory function by enhancing IL‐10 formation and attenuating TNF synthesis. J. Leukoc. Biol. 63: 101–107; 1998.