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  • Title: Cyclic nucleotide phosphodiesterase type IV participates in the regulation of IL-10 and in the subsequent inhibition of TNF-alpha and IL-6 release by endotoxin-stimulated macrophages.
    Author: Kambayashi T, Jacob CO, Zhou D, Mazurek N, Fong M, Strassmann G.
    Journal: J Immunol; 1995 Nov 15; 155(10):4909-16. PubMed ID: 7594495.
    Abstract:
    We have recently shown that PGE2 inhibits the release of TNF-alpha from LPS-stimulated murine peritoneal macrophages via a feedback mechanism involving IL-10. Here we demonstrate that a rolipram-sensitive phosphodiesterase (PDE) type IV participates in the regulation of IL-10 synthesis. Selective PDE IV inhibitors (rolipram and RO-20-1724), but not selective inhibitors of other types of PDE, significantly augment marcrophage IL-10 production and contribute to the inhibition of TNF-alpha and IL-6 release. The addition of rolipram to LPS-stimulated macrophages results in the accumulation of cAMP and in the significant augmentation of IL-10 release. Competitive PCR analysis reveals that the drug dramatically increases IL-10 mRNA, but does not affect TNF-alpha mRNA. The inhibitory effect of rolipram on TNF-alpha can be significantly but incompletely reversed by anti-IL-10 Ab, whereas the effect of the drug on IL-6 can be completely reversed by anti-IL-10. In endotoxemic mice, the administration of rolipram increases serum IL-10 and reduces TNF-alpha and IL-6 levels. Northern blot analysis of spleens from these mice shows that rolipram increases IL-10 mRNA, whereas TNF-alpha mRNA remains largely unchanged. These results suggest that a rolipram-sensitive PDE type IV is involved in the production of IL-10 and in turn contributes to the inhibition of TNF-alpha and IL-6 release.
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