Phosphodiesterase 4B Gene Transcription Is Activated by Lipopolysaccharide and Inhibited by Interleukin-10 in Human Monocytes

Ma, Dongmin; Wu, Ping; Egan, Robert W.; Billah, M. Motasim; Wang, Peng

doi:10.1124/mol.55.1.50

Cited by 63 publications

(38 citation statements)

References 33 publications

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“…PDE4 was previously reported to be predominant in monocytes and macrophages, wherein LPS strongly stimulates the mRNA expression of the PDE4B subtype, and in neutrophils, wherein PDE4B is constitutively expressed at high levels. The specific isoform implicated in the PDE4 activity increase under LPS in monocytes was identified as PDE4B2 (19,32,33). It is well documented that PDE4-selective inhibitors produce profound inhibitory effect on LPS-stimulated TNF-␣ production in circulating monocytes (34).…”

Section: Discussionmentioning

confidence: 99%

The PDE4 Inhibitor Rolipram Prevents NF-κB Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells

Hervé

Schmitz

Évain-Brion

et al. 2008

The Journal of Immunology

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Spontaneous preterm delivery is linked to intrauterine inflammation. Fetal membranes are involved in the inflammatory process as an important source of mediators, and the chorion leave produces high levels of the proinflammatory cytokine TNF-α when stimulated by LPS. The transcription factor NF-κB is the main regulator of this inflammatory process and controls the production of cytokines by the chorion leave. Phosphodiesterase 4 inhibitors are recognized for their anti-inflammatory and myorelaxant effects. The purpose of this study was to investigate whether PDE4 inhibition affects the LPS signaling in human cultured chorionic cells. We showed that these cells express TLR4, the main LPS receptor, and exhibit a predominant PDE4 activity. Upon LPS challenge, PDE4 activity increases concomitantly to the induction of the specific isoform PDE4B2 and chorionic cells secrete TNF-α. LPS induces the nuclear translocation of the NF-κB p65 subunit and the activation of three different NF-κB complexes in chorionic cells. The presence of the PDE4 inhibitor rolipram reduces the TNF-α production and the activation of the three NF-κB complexes. These data indicate that the PDE4 family interacts with the LPS signaling pathway during the inflammatory response of chorionic cells. PDE4 selective inhibitors may thus represent a new therapeutic approach in the management of inflammation-induced preterm delivery.

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Section: Discussionmentioning

confidence: 99%

The PDE4 Inhibitor Rolipram Prevents NF-κB Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells

Hervé

Schmitz

Évain-Brion

et al. 2008

The Journal of Immunology

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“…In human monocytes the expression of PDE-4B is increased by LPS stimulation (24). Therefore, the role of zinc inhibition in PDE activity and expression was investigated as a possible mechanism to inhibit LPS-induced signals.…”

Section: Zinc Suppresses Lps-induced Up-regulation Of Pde-4b Expressionmentioning

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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“…PDE-4 activity was increased after BAL, albeit insignificantly, and PDE-4 can be activated by PKA phosphorylation or ERK-mediated phosphorylation (8,18). Chronic regulation of PDE-3 and PDE-4 expression by a cAMP-dependent feedback stimulus also has been demonstrated (7,30,31,33,52), and the mechanism underlying upregulation of PDEs by BAL remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of phosphodiesterase PDE-3/PDE-4-specific inhibitors on vasoconstriction and cAMP-dependent vasorelaxation following balloon angioplasty

Zhao

Montrose²,

Rajagopalan³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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It is known that cAMP and cGMP are important for vasorelaxation, and cyclic nucleotide phosphodiesterases (PDEs) regulate their levels. Balloon angioplasty (BAL) is associated with reduced cAMP and cGMP levels, and inhibition of PDE-3 reduces restenosis. In this study, we found that BAL increased PDE-3 activity, which affected vasoreactivity of rat aortic rings 24-h post-BAL; these were compared with intact (INT) and ex vivo endothelium-denuded rings (RUB) from sham rats. In BAL and RUB rings, vasorelaxant responses to ACh were abolished. The EC50 for phenylephrine (PE) was 1.8-fold less in RUB than in INT or BAL, whereas the maximal contractile effect of PE was greater in BAL than in INT or RUB. PDE-3 inhibitors reduced the maximal response to PE by Ͼ65% in BAL compared with 10 -30% in INT and RUB; the reduction of the maximal response to U-46619 was 37% in BAL compared with 8% in INT with no reduction in RUB. PDE-4 inhibitors reduced PE-induced tone by Ͻ30% in an endotheliumdependent manner. Vasorelaxant responses to agonists that utilize cAMP were greatly impaired in BAL and RUB rings, and inhibition of PDE-3 enhanced the vasorelaxant responses in BAL or RUB. Inhibition of PDE-4 increased vasorelaxant responses to isoproterenol (ISO) to a much lesser degree. Thus PDE-3 and PDE-4 inhibitors exhibited differential effects on PE-induced tone and vasorelaxant responses to ISO. Inhibition of PDE-3 also produced a greater increase in cAMP in BAL than INT or RUB rings. These results suggest that increased PDE-3 activity after BAL may promote a vasospastic state and that the reduction in cAMP may, possibly, influence vessel remodeling. rat aorta; cyclic adenosine 3Ј, 5Ј-cyclic monophosphate BALLOON ANGIOPLASTY (BAL) is widely used to treat obstructive coronary artery disease, yet restenosis following BAL limits the efficacy of this procedure, which can be improved with a drug-eluting stent (3). In preclinical studies, it has been shown that enhanced smooth muscle cell (SMC) proliferation and migration account for the neointimal thickening that follows BAL (6, 21). Cyclic AMP inhibits proliferation of SMC (20) and other cells in vitro (4,11,44), and reduced cAMP levels were found in rat aorta following BAL (40). Thus increasing cAMP levels after BAL should help reduce neointimal thickening. Moreover, cAMP is an important second messenger for vasorelaxation (41), and reduced cAMP levels in BAL should affect vasoreactivity. Recent studies on ␣ 1 -adrenoceptor-mediated vasoconstriction after BAL have yielded conflicting results, where both hyperreactivity and hyporeactivity were reported (1, 17, 29). The effects of BAL on responses to several vasorelaxant agents have also been studied, but only one addressed the cAMP pathway using a ␤-adrenergic agonist (16). In that study, the authors showed an initially decreased ␤-agonist-induced relaxation followed by an increase during neointimal formation.Phosphodiesteases (PDEs) play an integral role in regulation of cyclic nucleotide levels. There are 11 PDE families in mammals, ...

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Phosphodiesterase 4B Gene Transcription Is Activated by Lipopolysaccharide and Inhibited by Interleukin-10 in Human Monocytes

Cited by 63 publications

References 33 publications

The PDE4 Inhibitor Rolipram Prevents NF-κB Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells

The PDE4 Inhibitor Rolipram Prevents NF-κB Binding Activity and Proinflammatory Cytokine Release in Human Chorionic Cells

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

Differential effects of phosphodiesterase PDE-3/PDE-4-specific inhibitors on vasoconstriction and cAMP-dependent vasorelaxation following balloon angioplasty

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