Phosphodiesterase 4B gene transcription is activated by lipopolysaccharide and inhibited by interleukin-10 in human monocytes.
There are four different genes encoding the cAMP-specific phosphodiesterase (PDE4) isozymes (A, B, C, and D). cAMP has been the only agent known to induce PDE4 gene expression. In the present study, we demonstrate, for the first time, that lipopolysaccharide (LPS) significantly and selectively stimulated PDE4B mRNA production in human monocytes. The LPS stimulation occurred very rapidly (in 30-45 min) and in a dose-dependent manner (0.01-100 ng/ml). We also demonstrate that LPS induction of PDE4B mRNA expression was inhibited strongly by interleukin (IL)-10. The inhibition with IL-10 was dose-dependent (0.1-10 ng/ml). IL-4 also inhibited the LPS induction, but to a lesser extent than IL-10. PDE4B mRNA expression was also stimulated by dibutyryl-cAMP. Interestingly, unlike LPS induction, the dibutyryl-cAMP induction of PDE4B mRNA expression was not inhibited by IL-10. By performing nuclear run-on and mRNA stability assays, we demonstrate further that IL-10 inhibited LPS-stimulated PDE4B mRNA synthesis by abolishing the gene transcription rather than by enhancing mRNA degradation. The present study suggests that PDE4B, as the only LPS-inducible PDE4 subtype, may be an appropriate target for discovering anti-inflammatory drugs.
Ma
D
D
Allergy Department, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Wu
P
P
Egan
R W
RW
Billah
M M
MM
Wang
P
P
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000235:genetics*; D003994:Bucladesine / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D016753:Interleukin-10; D003994:Bucladesine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517360:PDE4B protein, human