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 ,vith 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 mu M 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 formulation and attenuating TNF synthesis.