Neutrophil chemotaxis induced by the diacylglycerol kinase inhibitor R59022

Boonen, G. J. J. C.; Koster, Ben M. de; VanSteveninck, John; Elferink, J. G. R.

doi:10.1016/0167-4889(93)90114-5

Cited by 20 publications

(18 citation statements)

References 26 publications

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“…Chemotaxis induced by Lx or its diol was inhibited by pertussis toxin, suggesting that pertussis toxin sensitive Gproteins, which have been reported to be important for neutrophil migration induced by fMLP, are also involved in the chemotaxis of neutrophils induced by both Lx and its diol [10,15]. The current results showing that fMLPinduced chemotaxis is inhibited by PTK inhibitors, but not by PKC inhibitors or PI3-K inhibitors, confirmed previous studies [10,18,19].…”

Section: ±10supporting

confidence: 80%

“…2). The inhibition was more potent in the former two than in the latter one and more susceptible to a low dose of pertussis toxin in Lx than its diol, suggesting that both Lx and its diol induce chemotaxis via a pertussis toxin-sensitive G-protein [15]. Both Lx and its diol-induced chemotaxis were inhibited by the phosphatidylinositol-3-kinase (PI3-K) inhibitors, Wortmannin and LY294002 [12] (fig.…”

Section: ±10mentioning

confidence: 99%

“…However, the mechanisms of Lx-induced lung injury are still unclear. It has been reported previously [2±4] that Lx causes oedematous lung injury, which is inhibited by either nitric oxide synthase (NOS) inhibitors or superoxide dismutase in isolated perfused rat lungs, and that Lx augments superoxide anion (O 2 .-] production by human pulmonary artery endothelial cells [15]. Polymorphonuclear neutrophils (PMNs) infiltrating the perivascular lesions and alveoli were observed after an intravenous injection of Lx in rats [6].…”

mentioning

confidence: 93%

“…Signal transduction pathways different from those activated by fMLP have been reported in neutrophil migration [10,12,15,18,19]. Therefore, the authors analysed the signal transduction pathways involved in the chemotaxis of neutrophils treated with Lx or its diol by using the inhibitors of G-protein, PKC, PTK, and PI3-K.…”

Section: ±10mentioning

confidence: 99%

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Leukotoxin and its diol induce neutrophil chemotaxis through signal transduction different from that of fMLP

Totani¹,

Saito²,

Ishizaki³

et al. 2000

Eur Respir J

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When injected into animals, leukotoxin (Lx) causes acute lung injury which is associated with neutrophils infiltrating the lung tissues. However, the effect of Lx on neutrophils is still unknown, and recently it has been reported that Lx diol, a hydrolyzed metabolite, should be more potent than Lx in vitro. In this study, the authors examined the effect of Lx and its diol on human neutrophils by assessing their chemotactic response, expression of adhesion molecules, and production of peroxides.Both Lx and its diol induced chemotaxis in human neutrophils via an involvement of pertussis toxin-sensitive G-proteins, but they did not influence the expression of adhesion molecules or the production of peroxides. Furthermore, Lx synergistically affected chemotaxis with N-formyl-methionyl-leucyl-phenylalanine (fMLP), but not with endothelin-1.Neutrophil chemotaxis induced by both Lx and its diol was inhibited by phosphatidylinositol-3-kinase (PI3-K) inhibitors, but not by protein tyrosine kinase (PTK) inhibitors or by protein kinase C (PKC) inhibitors, whereas fMLP-induced chemotaxis was inhibited by PTK inhibitors, but not by PI3-K inhibitors or by PKC inhibitors. These results suggest that neutrophil chemotaxis induced by both Lx and its diol involves pathways different from those induced by fMLP.In conclusion, both leukotoxin and its diol metabolite induce chemotaxis in human neutrophils in a unique way and may act as important bioactive lipids when considering the pathological mechanism of acute lung injury. Eur Respir J 2000; 15: 75±79.

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Section: ±10supporting

confidence: 80%

Section: ±10mentioning

confidence: 99%

mentioning

confidence: 93%

Section: ±10mentioning

confidence: 99%

See 2 more Smart Citations

Leukotoxin and its diol induce neutrophil chemotaxis through signal transduction different from that of fMLP

Totani¹,

Saito²,

Ishizaki³

et al. 2000

Eur Respir J

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“…27. Moreover, DAGK inhibition or treatment with synthetic DAG species leads to alterations in normal PMN motility (35)(36)(37). Therefore, defective DAGK expression provides a potential molecular basis that may explain disparate functional responses in PMN from patients with LAP, namely, agonist-specific reduced motility and enhanced production of superoxide anions and related reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

A Molecular Defect in Intracellular Lipid Signaling in Human Neutrophils in Localized Aggressive Periodontal Tissue Damage

Gronert

Kantarcı

Levy

et al. 2004

The Journal of Immunology

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Host defense mechanisms are impaired in patients with congenital neutrophil (polymorphonuclear neutrophils (PMN)) defects. Impaired PMN chemotaxis is observed in localized aggressive periodontitis (LAP), a familial disorder characterized by destruction of the supporting structures of dentition. In the present studies, we sought evidence for molecular events underlying this aberrant human PMN phenotype. To this end, PMN transendothelial migration and superoxide anion generation were assessed with LAP patients and asymptomatic family members, as well as patients with other chronic mucosal inflammation. PMN from LAP patients showed decreased transmigration across vascular endothelial monolayers (18 ± 12% of control, n = 4) and increased superoxide anion generation (358 ± 37%, p = 0.003). Gene expression was analyzed using oligonucleotide microarrays and fluorescence-based kinetic PCR. cDNA microarray and kinetic-PCR analysis revealed diminished RNA expression of leukocyte-type diacylglycerol (DAG) kinase α in PMN from LAP patients (4.6 ± 1.7 relative units, n = 6, p = 0.007) compared with asymptomatic individuals (51 ± 27 relative units, n = 7). DAG kinase activity was monitored by DAG phosphorylation and individual DAG molecular species were quantified using liquid chromatography and tandem mass spectrometry-based lipidomics. DAG kinase activity was also significantly decreased (73 ± 2%, p = 0.007) and correlated with increased accumulation of 1,2-diacyl-sn-3-glycerol substrates (p = 0.01). These results implicate defects in both PMN transendothelial migration and PMN DAG kinase α signaling as disordered functions in LAP. Moreover, they identify a potential molecular lesion in PMN signal transduction that may account for their aberrant responses and tissue destruction in this disease.

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Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: Findings in a prospective, randomized, double-blind clinical trial in fifteen patients

Kraan

Koster

Elferink

et al. 2000

Arthritis & Rheumatism

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107

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Objective. Leflunomide is a novel immunomodu-lating drug that has recently been approved as a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). The aim of this study was to determine the relationship between the clinical effects of leflunomide and neutrophil migration. Methods. The effects of leflunomide and metho-trexate on neutrophil chemotaxis were studied in 15 RA patients who participated in a prospective, randomized, double-blind clinical trial. When possible, neutrophil numbers were counted in synovial fluid (SF) samples at baseline and after 14 days, 4 months, and 1 year of treatment. The chemotactic properties of peripheral blood neutrophils from RA patients treated with either leflunomide or methotrexate were studied by the Boyden chamber technique, using the activators formyl-methionyl-leucyl-phenylalanine (fMLP) and interleukin-8 (IL-8). The in vitro effects of A77 1726, the active metabolite of leflunomide, and methotrexate on peripheral blood neu-trophils from 7 healthy control subjects were also investigated. Results. Both therapy groups exhibited clinical improvement, including rapid reductions in SF neutro-phil counts and reduced joint swelling and tenderness. On day 14, 3 of 7 patients who received leflunomide showed no detectable effusions. There was a significant effect on neutrophil chemotaxis (P < 0.001), which was similar for leflunomide and methotrexate. The direct effects on the neutrophils diminished over time. Incubation of peripheral blood neutrophils from healthy controls with A77 1726 confirmed the inhibitory effect on chemotaxis. Conclusion. Leflunomide treatment is beneficial in RA patients. Different mechanisms are operative in various phases of treatment, leading to decreased recruitment of inflammatory cells in the joints.

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Neutrophil chemotaxis induced by the diacylglycerol kinase inhibitor R59022

Cited by 20 publications

References 26 publications

Leukotoxin and its diol induce neutrophil chemotaxis through signal transduction different from that of fMLP

Leukotoxin and its diol induce neutrophil chemotaxis through signal transduction different from that of fMLP

A Molecular Defect in Intracellular Lipid Signaling in Human Neutrophils in Localized Aggressive Periodontal Tissue Damage

Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: Findings in a prospective, randomized, double-blind clinical trial in fifteen patients

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