Formation of Eicosanoids during Differentiation of Thp-1 Cells

Schwende, H.; Fitzke, Edith; Ambs, Petra; Dieter, Peter

doi:10.1007/978-1-4899-1813-0_73

Cited by 4 publications

(5 citation statements)

References 3 publications

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“…We then wondered if the CF 3 group in the 4-position could be replaced to gain additional potency. Substituting the 4-CF 3 group with a chlorine (30) modestly decreased (~3-fold) ABHD12 inhibitory activity, while conversion to a methoxy group (31) had an even more deleterious effect. Interestingly, elaborating the 4-position with alkoxyl, benzyloxy, and phenoxy groups furnished a set of compounds (32)(33)(34)(35) with superior activity to the 5methoxy analog (31) and revealed a scaffold trajectory that tolerated large substitutuents to potentially enhance potency.…”

Section: Exploration Of Pyridine Substituent Effectsmentioning

confidence: 99%

“…Substituting the 4-CF 3 group with a chlorine (30) modestly decreased (~3-fold) ABHD12 inhibitory activity, while conversion to a methoxy group (31) had an even more deleterious effect. Interestingly, elaborating the 4-position with alkoxyl, benzyloxy, and phenoxy groups furnished a set of compounds (32)(33)(34)(35) with superior activity to the 5methoxy analog (31) and revealed a scaffold trajectory that tolerated large substitutuents to potentially enhance potency. Given the superior ABHD12 inhibition of phenoxy analogue 35, we introduced substitutents to the 4-position of the distal phenyl group and observed that while a methoxy group slightly impaired activity, fluoro (37) and especially OCF 3 (38) groups increased potency.…”

Section: Exploration Of Pyridine Substituent Effectsmentioning

confidence: 99%

“…Considering that ABHD12 is highly expressed in macrophages and microglia [17][18] , and that genetic or pharmacological perturbation of ABHD12 produces heightened (neuro)immunological phenotypes in mice 16,19,28 , we next tested whether DO264 affected cytokine production using the human monocyte THP-1 cell line as a model system. THP1 monocytes were first treated with phorbol 12-myristate 13-acetate (PMA) to produce resting macrophages characterized by changes in morphology and increased cell surface expression of CD11 and CD14 [30][31][32] . Cells were allowed to rest for 24 h followed by polarization to the M1 stage with lipopolysaccharide (LPS) and IFN-γ.…”

Section: Abhd12 Inhibition Modulates Cytokine Production In Human Thpmentioning

confidence: 99%

“…Chloropyridines 54 and 60a-60j were coupled with the appropriate Boc-protected diamines to give intermediates 61a-61s and subsequently deprotected. As described for previous analogs, the final thioureas (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) were obtained through treatment of the free amines with pyridine-3-isothiocyanate. For access to 4-alkoxy or 4-phenoxy substituted pyridines 67-81, 2,4-dichloro or 2-chloro-4fluoro pyridines were subjected to SnAr conditions in the presence of various alcohols and phenols which primarily displaced the halogen at the 4-position (Scheme 5).…”

Section: Chemistrymentioning

confidence: 99%

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Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase α/β-Hydrolase Domain-Containing 12 (ABHD12)

et al. 2019

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ABHD12 is a membrane-bound hydrolytic enzyme that acts on the lyso-phosphatidylserine (lyso-PS) and lyso-phosphatidylinositol (lyso-PI) classes of immunomodulatory lipids. Human and mouse genetic studies point to a key role for the ABHD12-(lyso)-PS/PI pathway in regulating (neuro)immunological functions in both the central nervous system and periphery. Selective inhibitors of ABHD12 would offer valuable pharmacological probes to complement genetic models of ABHD12-regulated (lyso)-PS/PI metabolism and signaling. Here, we provide a detailed description of the discovery and activity-based protein profiling (ABPP)-guided optimization of reversible thiourea inhibitors of ABHD12 that culminated in the identification of DO264 as a potent, selective, and in vivo-active ABHD12 inhibitor. We also show that DO264, but not a structurally related inactive control probe (S)-DO271, augments inflammatory cytokine production from human THP-1 macrophage cells. The in vitro and in vivo properties of DO264 designate this compound as a suitable chemical probe for studying the biological functions of ABHD12-(lyso)-PS/PI pathways.

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Section: Exploration Of Pyridine Substituent Effectsmentioning

confidence: 99%

Section: Exploration Of Pyridine Substituent Effectsmentioning

confidence: 99%

Section: Abhd12 Inhibition Modulates Cytokine Production In Human Thpmentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

See 2 more Smart Citations

Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase α/β-Hydrolase Domain-Containing 12 (ABHD12)

et al. 2019

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“…macrophages [12]. THP-1 cell line has been extensively characterized [13], [14], [15] and widely used as a model for studying macrophage cell type [16], [17], [18]. In addition, due to the good labeling efficiency and reproducibility, THP-1 cells have very often been a cell type of choice for characterizing the SPIO labeling agents [19], [20].…”

Section: Introductionmentioning

confidence: 99%

Effects of Ferumoxides – Protamine Sulfate Labeling on Immunomodulatory Characteristics of Macrophage-like THP-1 Cells

et al. 2008

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Superparamagnetic Iron Oxide (SPIO) complexed with cationic transfection agent is used to label various mammalian cells. Labeled cells can then be utilized as an in vivo magnetic resonance imaging (MRI) probes. However, certain number of in vivo administered labeled cells may be cleared from tissues by the host's macrophages. For successful translation to routine clinical application of SPIO labeling method it is important that this mode of in vivo clearance of iron does not elicit any diverse immunological effects. The purpose of this study was to demonstrate that SPIO agent ferumoxides-protamine sulfate (FePro) incorporation into macrophages does not alter immunological properties of these cells with regard to differentiation, chemotaxis, and ability to respond to the activation stimuli and to modulate T cell response. We used THP-1 cell line as a model for studying macrophage cell type. THP-1 cells were magnetically labeled with FePro, differentiated with 100 nM of phorbol ester, 12-Myristate-13-acetate (TPA) and stimulated with 100 ng/ml of LPS. The results showed 1) FePro labeling had no effect on the changes in morphology and expression of cell surface proteins associated with TPA induced differentiation; 2) FePro labeled cells responded to LPS with slightly higher levels of NFκB pathway activation, as shown by immunobloting; TNF-α secretion and cell surface expression levels of CD54 and CD83 activation markers, under these conditions, were still comparable to the levels observed in non-labeled cells; 3) FePro labeling exhibited differential, chemokine dependent, effect on THP-1 chemotaxis with a decrease in cell directional migration to MCP-1; 4) FePro labeling did not affect the ability of THP-1 cells to down-regulate T cell expression of CD4 and CD8 and to induce T cell proliferation. Our study demonstrated that intracellular incorporation of FePro complexes does not alter overall immunological properties of THP-1 cells. The described experiments provide the model for studying the effects of in vivo clearance of iron particles via incorporation into the host's macrophages that may follow after in vivo application of any type of magnetically labeled mammalian cells. To better mimic the complex in vivo scenario, this model may be further exploited by introducing additional cellular and biological, immunologically relevant, components.

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Nicotinic acid induces secretion of prostaglandin D2 in human macrophages: An in vitro model of the niacin flush

Meyers¹,

Liu²,

Kamanna³

et al. 2007

Atherosclerosis

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Formation of Eicosanoids during Differentiation of Thp-1 Cells

Cited by 4 publications

References 3 publications

Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase α/β-Hydrolase Domain-Containing 12 (ABHD12)

Discovery and Optimization of Selective and in Vivo Active Inhibitors of the Lysophosphatidylserine Lipase α/β-Hydrolase Domain-Containing 12 (ABHD12)

Effects of Ferumoxides – Protamine Sulfate Labeling on Immunomodulatory Characteristics of Macrophage-like THP-1 Cells

Nicotinic acid induces secretion of prostaglandin D2 in human macrophages: An in vitro model of the niacin flush

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