Differential inhibitory mechanism of cyclic AMP on TNF‐α and IL‐12 synthesis by macrophages exposed to microbial stimuli

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Abstract
Microbial stimuli such as bacterial lipopolysaccharide (LPS) or glycosylphosphatidylinositol‐mucins derived from Trypanosoma cruzi trypomastigotes (tGPI‐mucins) are effective stimulators of the synthesis of cytokines by macrophages. Here, we evaluated the ability of cyclic AMP mimetic or elevating agents to modulate TNF‐α and IL‐12 synthesis by murine inflammatory macrophages. Cholera Toxin (ChTx) inhibited tGPI‐mucins (2.5 nM) or LPS (100 ng ml−1) induced TNF‐α and IL‐12(p40) synthesis in a concentration‐dependent manner. Similarly, the cyclic AMP mimetics, 8‐bromo cyclic AMP or dibutyryl cyclic AMP, or prostaglandin (PG) E2 inhibited the synthesis of both cytokines by macrophages exposed to microbial stimuli. The protein kinase A inhibitor H‐89 partially reversed the inhibitory effects of dibutyryl cyclic AMP and PGE2 on both IL‐12(p40) and TNF‐α synthesis. Pretreatment of macrophages with dibutyryl cyclic AMP or ChTx augmented the synthesis of IL‐10 triggered by microbial products. Elevation of cyclic AMP inhibited the synthesis of TNF‐α, but not IL‐12(p40), by inflammatory macrophages from IL‐10 knockout mice. Kinetic studies showed that synthesis of both TNF‐α and IL‐10 peaked at 8 h and IL‐12 at 24 h after stimulation with microbial stimuli. Together, our findings favour the hypothesis that the cyclic AMP inhibitory activity on IL‐12(p40) but not on TNF‐α synthesis is dependent on de novo protein synthesis, most likely involving IL‐10, by macrophages stimulated with microbial products. Accordingly, dibutyryl cyclic AMP inhibited IL‐12(p40) synthesis only when added before or at the same time of the stimuli. In contrast, the effect of this cyclic AMP analogue on TNF‐α synthesis was protracted and observed even 2 h after the addition of the stimuli. British Journal of Pharmacology (1999) 127, 1195–1205; doi:10.1038/sj.bjp.0702624

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