Phosphodiesterase 4B gene transcription is activated by lipopolysaccharideand 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 in duce PDE4 gene expression. In the present study, we demonstrate, for the fi rst time, that lipopolysaccharide (LPS) significantly and selectively stimu lated PDE4B mRNA production in human monocytes. The LPS stimulation occurre d very vapidly (in 30-45 min) and in a dose-dependent manner (0.01-100 ng/m l). We also demonstrate that LPS induction of PDE4B mRNA expression was inh ibited 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 l esser extent than IL-10. PDE4B mRNA expression was also stimulated by dibut yryl-cAMP. Interestingly, unlike LPS induction, the dibutyryl-cAMP inductio n of PDE I B mRNA expression was not inhibited by IL-10. By performing nucl ear run-on and mRNA stability assays, we demonstrate further that IL-10 inh ibited LPS-stimulated PDE4B mRNA synthesis by abolishing the gene transcrip tion rather than by enhancing mRNA degradation. The present study suggests that PDE4B, as the only LPS-inducible PDE4 subtype; may be an appropriate t arget for discovering anti-inflammatory drugs.