Phosphodiesterase 4-dependent regulation of cyclic AMP levels and leukotriene B4 biosynthesis in human polymorphonuclear leukocytes

Several selective phosphodiesterase 4 inhibitors were found to be potent inhibitors of the N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene B-4 biosynthesis by human polymorphonuclear leukocytes with IC(50)s in the nanomolar range (0.09-26 nM). The rank order of potency was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (RS-14203) > 3-benzyl-5-phenyl-3 H-imidazo[4,5-c][1,8]naphthyridin-4(5H)-one (KF18280)> 8-aza-1-(3-nitrophenyl)-3-(4-pyridylmethyl)-2,4-quinazoline dione (RS-25344)> 3-cyclo-pentyloxy-N-[3,5-dichloro-4-pyridyl]-4-methoxybenzamide (RP-73401) > R-rolipram > R-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl] pyridine (CDP840)> S-rolipram. Isoproterenol (IC50 = 350 nM) and prostaglandin E-2 (IC50 = 59 nM) also suppressed leukotriene B-4 biosynthesis. Inhibitors of the phosphodiesterase 1 (8-methoxymethyl-1-methyl-3-(2-methylpropyl)xanthine (8-MeOMe-IBMX)), phosphodiesterase 2 (erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA)), phosphodiesterase 3 (quazinone and milrinone) and phosphodiesterase 5 (zaprinast and dipyridamole) had no inhibitory effects on the fMLP-induced leukotriene B-4, biosynthesis (IC(50)s> 20 mu M). All phosphodiesterase 4 inhibitors caused an accumulation of cellular cyclic AMP to 140-185% over the basal level of fMLP-treated control cells, comparable to that observed with high concentrations of isoproterenol and prostaglandin E-2,. In contrast, the complete inhibition of leukotriene B-4, production by 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) inhibitors had no effect on cyclic AMP levels. Phosphodiesterase 1, 2, 3 and 5 inhibitors had little effect on the level of cellular cyclic AMP (89-126% of the basal cyclic AMP level). Dose-dependencies for R-rolipram, RS-14203 and CDP840 indicated that the maximal accumulation of cyclic AMP occurred at concentrations of phosphodiesterase 4 inhibitors higher than those required for the inhibition of leukotriene B-4, production. The presence of a mixture of 8-MeOMe-IBMX, EHNA, milrinone and zaprinast to inhibit phosphodiesterase 1, 2, 3 and 5 had little effect on the dose-dependence of R-rolipram for the inhibition of leukotriene B-4, biosynthesis or cyclic AMP accumulation. These data demonstrate that selective phosphodiesterase 4 inhibitors can inhibit the fMLP-induced leukotriene B-4, biosynthesis in human polymorphonuclear leukocytes with a potency similar or greater than that of potent 5-lipoxygenase or FLAP inhibitors. This inhibition is accompanied by small variations in the levels of cellular cyclic AMP and appears to proceed independently of the other phosphodiesterases. (C) 1999 Elsevier Science B.V. All rights reserved.