Induction of a calcium/calmodulin-dependent phosphodiesterase during phytohemagglutinin-stimulated lymphocyte mitogenesis.

Hurwitz, Richard L.; Hirsch, Kenneth M.; Clark, Dorothy J.; Holcombe, Vien N.; Hurwitz, Mary Y.

doi:10.1016/s0021-9258(19)38973-2

Cited by 36 publications

References 35 publications

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Early increase in lymphocyte cyclic nucleotide phosphodiesterase activity upon mitogenic activation of human peripheral blood mononuclear cells

Meskini

Hosni

Némoz

et al. 1992

Journal Cellular Physiology

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Cyclic nucleotide phosphodiesterase activity of human peripheral blood mononuclear cells was significantly increased following a short (30 min) incubation with the mitogenic lectin Concanavalin A. Con A stimulated phosphodiesterase activity to the same extent whatever the subcellular compartment (homogenate, cytosol or pellet). Further separation of the Con A-activated mononuclear cells into lymphocyte-enriched and monocyte-enriched populations showed that the Con A-induced increase of phosphodiesterase activity exclusively affected the lymphocyte-enriched population. In lymphocytes, cyclic GMP phosphodiesterase activity was more importantly enhanced by Con A (+275%) than cyclic AMP phosphodiesterase activity (+75%). The increase of both activities occurred as early as from 10 min of Con A incubation and proved to be maximal with Con A doses of 2.5 and 5 micrograms per 10(6) cells, lower and higher doses being less effective. Inhibition experiments with reference inhibitors suggested that, among the high affinity phosphodiesterase isoforms, the cyclic GMP-inhibited enzyme might be more selectively enhanced by Con A than the cyclic AMP-specific, Rolipram-sensitive one. The non-mitogenic lectin Helix pomatia hemagglutinin, was not able to enhance cyclic nucleotide phosphodiesterase activity of human mononuclear cells whereas anti-CD3 monoclonal antibody, although being less effective than Con A, exhibited a significant stimulatory effect. Putting together these results suggest that the early increase in phosphodiesterase activity might be a normal step involved in the mitogenic activation of human lymphocyte.

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Early increase in lymphocyte cyclic nucleotide phosphodiesterase activity upon mitogenic activation of human peripheral blood mononuclear cells

Meskini

Hosni

Némoz

et al. 1992

Journal Cellular Physiology

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Identification, Quantitation, and Cellular Localization of PDE1 Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterases

Sonnenburg

Rybalkin

Bornfeldt

et al. 1998

Methods

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Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies

Giembycz

Newton

2011

Phosphodiesterases as Drug Targets

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Phosphodiesterase (PDE) 4 inhibitors have been in development as a novel anti-inflammatory therapy for more than 20 years, with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, only one selective PDE4 inhibitor, roflumilast (Daxas (®)), has been approved for use in humans and available in Canada and the European Union in 2011 for the treatment of a specific population of patients with severe COPD. In many other cases, the development of PDE4 inhibitors of various structural classes has been discontinued due to lack of efficacy and/or dose-limiting adverse events. Indeed, for many of these compounds, it is likely that the maximum tolerated dose is either subtherapeutic or at the very bottom of the efficacy dose-response curve. Thus, a significant ongoing challenge that faces the pharmaceutical industry is to synthesize compounds with therapeutic ratios that are superior to roflumilast. Several strategies are being considered, but clinically effective compounds with an optimal pharmacophore have not, thus far, been reported. In this chapter, alternative means of harnessing the clinical efficacy of PDE4 inhibitors are described. These concepts are based on the assumption that additive or synergistic anti-inflammatory effects can be produced with inhibitors that target either two or more PDE families or with a PDE4 inhibitor in combination with other anti-inflammatory drugs such as a glucocorticoid.

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Induction of a calcium/calmodulin-dependent phosphodiesterase during phytohemagglutinin-stimulated lymphocyte mitogenesis.

Cited by 36 publications

References 35 publications

Early increase in lymphocyte cyclic nucleotide phosphodiesterase activity upon mitogenic activation of human peripheral blood mononuclear cells

Early increase in lymphocyte cyclic nucleotide phosphodiesterase activity upon mitogenic activation of human peripheral blood mononuclear cells

Identification, Quantitation, and Cellular Localization of PDE1 Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterases

Harnessing the Clinical Efficacy of Phosphodiesterase 4 Inhibitors in Inflammatory Lung Diseases: Dual-Selective Phosphodiesterase Inhibitors and Novel Combination Therapies

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