Vol. 300, Issue 2, 567-576, February 2002

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

John J. Haddad, Stephen C. Land, William O. Tarnow-Mordi, Marek Zembala, Danuta Kowalczyk and Ryszard Lauterbach

Neuroscience Research Laboratory, Department of Anesthesia and Perioperative Care, University of California Medical Center, San Francisco, California (J.J.H.); Oxygen Signaling Group, Center for Research into Human Development, Tayside Institute of Child Health, Faculty of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom (S.C.L.); Department of Neonatal Medicine, Westmead Hospital and New Children's Hospital Neonatal Service, University of Sydney, New South Wales, Sydney, Australia (W.O.T.-M.); and Departments of Clinical Immunology and Microbiology and Neonatology, Jagiellonian University Medical College, Cracow, Poland (M.Z., D.K., R.L.)

In this report we investigated the immunopharmacological role of selective and nonselective phosphodiesterase (PDE) inhibition in regulating the inhibitory-B (IB-)/nuclear factor-B (NF-B) 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 IB-, the major cytosolic inhibitor of NF-B. 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-B₁ (p50), RelA (p65), RelB (p68), and c-Rel (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-B translocation. Pentoxifylline, a nonspecific PDE inhibitor, reversed the excitatory effect of LPS on NF-B subunit nuclear localization, in a dose-dependent manner. Furthermore, analysis of NF-B activation under the same conditions revealed a biphasic effect mediated by LPS. PDEs 1, 3, and 4 inhibition was associated with up-regulating NF-B transcriptional activity. In contrast, blockading the activity of PDEs 5, 6, and 9 negatively attenuated LPS-mediated NF-B 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 nonselective 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 IB-/NF-B pathway.