Immunopharmacological Potential of Selective Phosphodiesterase Inhibition. II. Evidence for the Involvement of an Inhibitory-κB/Nuclear Factor-κB-Sensitive Pathway in Alveolar Epithelial Cells

In this report we investigated the immunopharmacological role of selective and nonselective phosphodiesterase (PDE) inhibition in regulating the inhibitory-κB (IκB-α)/nuclear factor-κB (NF-κB) signaling transduction pathway. In fetal alveolar type II epithelial cells, PDE blockade at the level of the diverging cAMP/cGMP pathways differentially regulated the phosphorylation and degradation of IκB-α, the major cytosolic inhibitor of NF-κB. Whereas selective inhibition of PDEs 1, 3, and 4, by the action of 8-methoxymethyl-3-isobutyl-1- methylxanthine, amrinone, and rolipram, respectively, exhibited a tendency to augment the translocation of NF-κB₁ (p50), ReIA (p65), ReIB (p68), and c-ReI (p75), selective blockade of PDE 5, 6, and 9, by the action of 4-([3′,4′-(methylenedioxy)benzyl]amino)-6-methoxyquinazoline and zaprinast, attenuated lipopolysaccharide-endotoxin (LPS)-mediated NF-κB translocation. Pentoxifylline, a nonspecific PDE inhibitor, reversed the excitatory effect of LPS on NF-κB subunit nuclear localization, in a dose-dependent manner. Furthermore, analysis of NF-κB activation under the same conditions revealed a biphasic effect mediated by LPS. PDEs 1, 3, and 4 inhibition was associated with up-regulating NF-κB transcriptional activity. In contrast, blockading the activity of PDEs 5, 6, and 9 negatively attenuated LPS-mediated NF-κB activation, similar to the effect of 3,7-dihydro-3,7-dimethyl-1-(5-oxohexyl)-1H-purine-2,6-dione (pentoxifylline). These results indicate that selective and non-selective interference with the control of the dynamic equilibrium of cyclic nucleotides via PDE isoenzyme regulation represents an immunoregulatory mechanism that requires the differential, biphasic targeting of the IκB-α/NF-κB pathway.