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

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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)567-576
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume300
Issue number2
DOIs
Publication statusPublished - 1 Feb 2002

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Alveolar Epithelial Cells
Phosphoric Diester Hydrolases
Endotoxins
Pentoxifylline
Lipopolysaccharides
Type 6 Cyclic Nucleotide Phosphodiesterases
Amrinone
Rolipram
Type 5 Cyclic Nucleotide Phosphodiesterases
Phosphodiesterase Inhibitors
Cyclic Nucleotides
Isoenzymes
Phosphorylation
3'-(1-butylphosphoryl)adenosine

Cite this

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title = "Immunopharmacological Potential of Selective Phosphodiesterase Inhibition. II. Evidence for the Involvement of an Inhibitory-κB/Nuclear Factor-κB-Sensitive Pathway in Alveolar Epithelial Cells",
abstract = "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.",
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Immunopharmacological Potential of Selective Phosphodiesterase Inhibition. II. Evidence for the Involvement of an Inhibitory-κB/Nuclear Factor-κB-Sensitive Pathway in Alveolar Epithelial Cells. / Haddad, John J.; Land, Stephen C.; Tarnow-Mordi, William O.; Zembala, Marek; Kowalczyk, Danuta; Lauterbach, Ryszard.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 300, No. 2, 01.02.2002, p. 567-576.

Research output: Contribution to journalArticle

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T1 - Immunopharmacological Potential of Selective Phosphodiesterase Inhibition. II. Evidence for the Involvement of an Inhibitory-κB/Nuclear Factor-κB-Sensitive Pathway in Alveolar Epithelial Cells

AU - Haddad, John J.

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AB - 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.

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