Effects of cAMP-Phosphodiesterase Isozyme Inhibitor on Cytokine Production by Lipopolysaccharide-Stimulated Human Peripheral Blood Mononuclear Cells

Yoshimura, Tomoaki; Kurita, Chikako; Nagao, Tomomi; Usami, Eiseki; Nakao, Tomohiro; Watanabe, Shino; Kobayashi, J; Yamazaki, Futoshi; Tanaka, Hiroyuki; Nagai, Hiroichi

doi:10.1016/s0306-3623(96)00580-0

Cited by 67 publications

(32 citation statements)

References 22 publications

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“…The intracellular level of cyclic nucleotides is regulated by their synthesis by adenylate (AC) 3 and guanylate cyclases and their hydrolysis into the corresponding inactive 5Ј-nucleotide monophosphates by phophodiesterases (PDE). Numerous studies show that selective PDE-4 inhibitors, such as rolipram and Ro-20-1724, attenuate TNF-␣ production in human monocytes and PBMC by elevation of the intracellular cAMP concentration (7)(8)(9)(10)(11). The cGMP analogues, dibutyryl cGMP (DB-cGMP) and 8-bromo-cGMP (8-Br-cGMP) were found to attenuate LPS-induced TNF-␣ secretion in primary monocytes and murine bone marrow-derived macrophages (8,12).…”

mentioning

confidence: 99%

Zinc-Mediated Inhibition of Cyclic Nucleotide Phosphodiesterase Activity and Expression Suppresses TNF-α and IL-1β Production in Monocytes by Elevation of Guanosine 3′,5′-Cyclic Monophosphate

Bülow

Rink

Haase

2005

The Journal of Immunology

141

110

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The trace element zinc affects several aspects of immune function, such as the release of proinflammatory cytokines from monocytes. We investigated the role of cyclic nucleotide signaling in zinc inhibition of LPS-induced TNF-α and IL-1β release from primary human monocytes and the monocytic cell line Mono Mac1. Zinc reversibly inhibited enzyme activity of phosphodiesterase-1 (PDE-1), PDE-3, and PDE-4 in cellular lysate. It additionally reduced mRNA expression of PDE-1C, PDE-4A, and PDE-4B in intact cells. Although these PDE can also hydrolyze cAMP, only the cellular level of cGMP was increased after incubation with zinc, whereas cAMP was found to be even slightly reduced due to inhibition of its synthesis. To investigate whether an increase in cGMP alone is sufficient to inhibit cytokine release, the cGMP analogues 8-bromo-cGMP and dibutyryl cGMP as well as the NO donor S-nitrosocysteine were used. All three treatments inhibited TNF-α and IL-1β release after stimulation with LPS. Inhibition of soluble guanylate cyclase-mediated cGMP synthesis with LY83583 reversed the inhibitory effect of zinc on LPS-induced cytokine release. In conclusion, inhibition of PDE by zinc abrogates the LPS-induced release of TNF-α and IL-1β by increasing intracellular cGMP levels.

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mentioning

confidence: 99%

Zinc-Mediated Inhibition of Cyclic Nucleotide Phosphodiesterase Activity and Expression Suppresses TNF-α and IL-1β Production in Monocytes by Elevation of Guanosine 3′,5′-Cyclic Monophosphate

Bülow

Rink

Haase

2005

The Journal of Immunology

141

110

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“…It was previously reported that subtype non-selective PDE4 inhibitors strongly suppressed LPS-stimulated TNF-a release but IL-1b or IL-6 release were partial or absent from human monocytes (9,10). Rofl umilast and cilomolast inhibited the TNF-a production in a concentration-dependent manner (Fig.…”

Section: Inhibitory Eff Ect Of Compound a On Lps-induced Tnf-α Releasmentioning

confidence: 70%

The role of phosphodiesterase 4B in IL-8/LTB₄-induced human neutrophil chemotaxis evaluated with a phosphodiesterase 4B inhibitor

et al. 2015

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PDE4B was previously shown to be a dominant PDE4 subtype of neutrophils. However, its physiological role in the neutrophil function has not been evaluated. In this study, the inhibitory eff ects of a phosphodiesterase 4B (PDE4B)-selective inhibitor (compound A) and subtype non-selective PDE4 inhibitors (rofl umilast and cilomilast) were evaluated in human peripheral blood cells. Compound A, rofl umilast and cilomilast in a similar manner inhibited TNF-a production by LPS-stimulated human mononuclear cells. However, the inhibitory eff ect of compound A on IL-8 or LTB 4 -induced chemotactic response of neutrophils was modest even at the highest concentration (10 µmol L -1 ), whereas rofl umilast and cilomilast inhibited IL-8 or LTB 4 -induced neutrophil chemotaxis. Our results suggest that PDE4B does not play an important role during the chemotactic response of human neutrophils.Keywords: phosphodiesterase 4B, phosphodiesterase 4D, mo nonuclear cells, neutrophils Eleven structurally related but functionally distinct gene families (PDE1 to PDE11) have been identifi ed in mammalians and comprise the PDE superfamily (1, 2). PDE4 is a cAMP-specifi c phosphodiesterase and has been shown to play key roles in the regulation of a number of infl ammatory processes such as cell tracking, release of infl ammatory mediators and immune cell proliferation. The PDE4 family is composed of 4 diff erent genes, PDE4A, B, C, and D, which are distinguished from other PDEs by a unique N terminus, which is involved in intracellular targeting and regulating catalytic activity.The physiological role of PDE4 subtypes in human blood leukocytes has been investigated mainly in monocytes and T cells but not in neutrophils. It has been suggested that PDE4A and/or PDE4B play key roles in the LPS-induced TNF-α release from monocyte and T cell proliferation using several PDE4 inhibitors with diff erent subtype specifi city (3).

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“…Several investigators reported that milrinone and other PDE inhibitors have the potential to inhibit inflammatory cell activation, 11 e.g. milrinone suppressed the endotoxin-stimulated production of TNF-alpha and IL-1 beta in human monocytes 12,13 and inhibited the respiratory burst of polymorphonuclear neutrophils to a certain degree. 1 4 Recently, Möllhoff et al 3 6 investigated the effects of milrinone on splanchnic oxygenation, systemic inflammation, and the subsequent acute-phase response in patients undergoing coronary artery bypass grafting.…”

Section: Discussionmentioning

confidence: 99%

“…However, milrinone has been shown to possess additional anti-inflammatory properties besides its cardiovascular effects. [11][12][13][14] Immune cells contain type IV and type III PDE, thus PDE inhibitors are potent regulators of various immune processes. Sepsis and endotoxemia lead to the activation and accumulation of leukocytes and circulatory disorders in several tissues.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

Milrinone improves intestinal villus blood flow during endotoxemia

Schmidt

Tinelli

Secchi

et al. 2000

Can J Anesth/J Can Anesth

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Purpose: To determine whether the compromised intestinal villus blood flow in a rat model of endotoxemia could be improved by continuous infusion of the phosphodiesterase (PDE) inhibitor milrinone.Methods: Twenty-four anesthetized and ventilated rats were laparotomized and an ileal portion was exteriorized and opened by an antimesenteric incision. The ileal segment was fixed with the mucosal surface upward. Microcirculatory parameters were assessed by intravital videomicroscopy. The animals were randomly assigned to receive one of three treatments: infusion of Escherichia coli lipopolysaccharides without phosphodiesterase inhibitor pretreatment (=LPS group); or infusion of LPS with milrinone pretreatment (= milrinone group), or without infusion of LPS or milrinone (=control group). Macrohemodynamic parameters (MAP, HR) and microhemodynamic parameters of ileal mucosa (mean diameter of central arterioles = D A and mean erythrocyte velocity within the arterioles= V E ) were measured 30 min before and at 0, 60, and 120 min after induction of endotoxemia. Mucosal villus blood flow was calculated from D A and V E .Results: In the milrinone group MAP decreased 60 min after induction of endotoxemia whereas it remained stable in the control and the LPS group. In both groups given endotoxin V E decreased after start of LPS infusion. In contrast, D A decreased in the LPS group, but increased in the milrinone group after 120 min of endotoxemia. Thus, the endotoxin-induced decrease of intestinal villus blood flow was diminished but not fully restored by milrinone infusion. Conclusion:Our results indicate that milrinone has some beneficial microcirculatory effects during endotoxemia. Although it contributed to systemic hypotension, it attenuated intestinal mucosal hypoperfusion.Objectif : Déterminer si le flot sanguin intestinal dont les grandes fonctions sont altérées dans un modèle d'endotoxémie chez le rat peut être amélioré par une perfusion continue d'un inhibiteur de la phosphodiestérase (PDE), la milrinone.Méthode : Vingt-quatre rats sous anesthésie et ventilation ont été laparotomisés et une portion iléale a été extériorisée et ouverte par une incision antimésentérique. Le segment iléal a été fixé par la surface muqueuse extériorisée. Les paramètres microcirculatoires ont été évalués par vidéomicroscopie vitale. Les animaux ont été assignés à l'un des trois groupes de traitements : une perfusion de lipopolysaccharides d'Escherichia coli sans pré-traitement avec l'inhibiteur de la phosphodiestérase (groupe LPS), ou une perfusion de LPS avec un prétraitement à la milrinone (groupe milrinone), ou sans perfusion de LPS ou de milrinone (groupe témoin). Les paramètres macrohémodynamiques (TAM, FC) et microhémodynamiques de la muqueuse iléale (diamètre moyen des artéri-oles centrales D A et vélocité moyenne des érythrocytes dans les artérioles V E ) ont été mesurés 30 min avant l'induction de l'endotoxémie et à 0, 60 et 120 min après. Le flot sanguin des villosités muqueuses a été calculé à partir de D A et de V E .Résultats...

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Effects of cAMP-Phosphodiesterase Isozyme Inhibitor on Cytokine Production by Lipopolysaccharide-Stimulated Human Peripheral Blood Mononuclear Cells

Cited by 67 publications

References 22 publications

Zinc-Mediated Inhibition of Cyclic Nucleotide Phosphodiesterase Activity and Expression Suppresses TNF-α and IL-1β Production in Monocytes by Elevation of Guanosine 3′,5′-Cyclic Monophosphate

Zinc-Mediated Inhibition of Cyclic Nucleotide Phosphodiesterase Activity and Expression Suppresses TNF-α and IL-1β Production in Monocytes by Elevation of Guanosine 3′,5′-Cyclic Monophosphate

The role of phosphodiesterase 4B in IL-8/LTB₄-induced human neutrophil chemotaxis evaluated with a phosphodiesterase 4B inhibitor

Milrinone improves intestinal villus blood flow during endotoxemia

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Effects of cAMP-Phosphodiesterase Isozyme Inhibitor on Cytokine Production by Lipopolysaccharide-Stimulated Human Peripheral Blood Mononuclear Cells

Cited by 67 publications

References 22 publications

Zinc-Mediated Inhibition of Cyclic Nucleotide Phosphodiesterase Activity and Expression Suppresses TNF-α and IL-1β Production in Monocytes by Elevation of Guanosine 3′,5′-Cyclic Monophosphate

Zinc-Mediated Inhibition of Cyclic Nucleotide Phosphodiesterase Activity and Expression Suppresses TNF-α and IL-1β Production in Monocytes by Elevation of Guanosine 3′,5′-Cyclic Monophosphate

The role of phosphodiesterase 4B in IL-8/LTB4-induced human neutrophil chemotaxis evaluated with a phosphodiesterase 4B inhibitor

Milrinone improves intestinal villus blood flow during endotoxemia

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The role of phosphodiesterase 4B in IL-8/LTB₄-induced human neutrophil chemotaxis evaluated with a phosphodiesterase 4B inhibitor