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.
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.
Kambayashi
T
T
Department of Immunology, Otsuka-America Pharmaceutical Inc., Rockville, MD 20850, USA.
Jacob
C O
CO
Zhou
D
D
Mazurek
N
N
Fong
M
M
Strassmann
G
G
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D016753:Interleukin-10 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases; D011760:Pyrrolidinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020889:Rolipram; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000093242:Interleukin-6 Inhibitors
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D016753:Interleukin-10; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D011760:Pyrrolidinones; D012333:RNA, Messenger; D020889:Rolipram; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C571338:Cnp protein, mouse