Immunopharmacological potential of selective phosphodiesterase inhibition. II. Evidence for the involvement of an inhibitory-kappaB/nuclear factor-kappaB-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-kappaB (IkappaB-alpha)/nuclear factor-kappaB (NF-kappaB) 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 IkappaB-alpha, the major cytosolic inhibitor of NF-kappaB. 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-kappaB(1) (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-kappaB translocation. Pentoxifylline, a nonspecific PDE inhibitor, reversed the excitatory effect of LPS on NF-kappaB subunit nuclear localization, in a dose-dependent manner. Furthermore, analysis of NF-kappaB activation under the same conditions revealed a biphasic effect mediated by LPS. PDEs 1, 3, and 4 inhibition was associated with up-regulating NF-kappaB transcriptional activity. In contrast, blockading the activity of PDEs 5, 6, and 9 negatively attenuated LPS-mediated NF-kappaB 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 IkappaB-alpha/NF-kappaB pathway.
Haddad
John J
JJ
Neuroscience Research Laboratory, Department of Anesthesia and Perioperative Care, University of California Medical Center, San Francisco, California 94143, USA. jhaddad@itsa.ucsf.edu
Land
Stephen C
SC
Tarnow-Mordi
William O
WO
Zembala
Marek
M
Kowalczyk
Danuta
D
Lauterbach
Ryszard
R
D000199:Actins / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002467:Cell Nucleus / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D014178:Translocation, Genetic / Q000187:drug effects
D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D004247:DNA; D010727:Phosphoric Diester Hydrolases