TRANSCRIPTIONAL MODULATION OF PLATELET-ACTIVATING-FACTOR RECEPTOR GENE-EXPRESSION BY CYCLIC-AMP

We examined the effects of increasing intracellular cyclic AMP levels on the expression of human PAF receptor (hPAF-R). Peripheral blood mon ocytes constitutively expressed hPAF-R mRNA transcripts. A transiently elevated intracellular concentration of AMP induced with prostaglandi n E2, cholera toxin, or forskolin was a sufficient signal to inhibit P AF-R expression. To determine the mechanisms of this inhibition, human monocytes were treated with dibutyryl cAMP, a cell-permeable cAMP ana logue. cAMP reduced the expression of hPAF-R in a concentration- and a time-dependent manner. The effect was seen as early as 1 h and was es sentially total by 4 h. Stability of hPAF-R mRNA was not markedly decr eased by cAMP, as assessed by measuring the half-lives of the transcri pts. Moreover, the nuclear transcription rate of the hPAF-R gene was r educed as early as 30 min after stimulation with cAMP. The inhibition of hPAF-R mRNA accumulation was associated with diminished responsiven ess to PAF, as assayed by intracellular Ca2+ fluxes, decreased number of binding sites, and decreased hPAF-R protein expression on the cell surface, as assessed by flow cytometry using a polyclonal anti-hPAFR a ntibody. These data indicate that PAF-R expression can be regulated at the transcriptional and possibly post-transcriptional levels by eleva tion of intracellular cAMP.