Potentiation and inhibition of fMLP-activated exocytosis in neutrophils by exogenous nitric oxide

Vanuffelen, B. E.; VanSteveninck, John; Elferink, J. G. R.

doi:10.1016/s0162-3109(97)00072-6

Cited by 11 publications

(7 citation statements)

References 38 publications

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“…inhibition of leukocyte functions including chemotaxis and superoxide generation, especially when these NO donors were used at higher concentrations (25)(26)(27). With respect to degranulation, published reports indicate a biphasic dose response in which NO and cGMP enhance exocytosis at low concentrations and inhibits exocytosis at higher concentrations (48,(57)(58)(59). The inhibitory effect in leukocyte functions may be attributed to the ability of several NO donors and cGMP analogs to stimulate cAMP accumulation when used at high concentrations (60).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Leukocyte Degranulation by cGMP-Dependent Protein Kinase and Phosphoinositide 3-Kinase: Potential Roles in Phosphorylation of Target Membrane SNARE Complex Proteins in Rat Mast Cells

Nanamori

Chen

et al. 2007

The Journal of Immunology

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We examined the roles of cGMP-dependent protein kinase (PKG) and PI3K in degranulation induced by fMLF and by FcεRI cross-linking. In rat basophilic leukemia-2H3 cells expressing formyl peptide receptor, the PKG inhibitors KT5823 and Rp-8-Br-PET-cGMP, as well as the PI3K inhibitor LY294002, reduced agonist-stimulated β-hexosaminidase release in a dose-dependent manner. These inhibitors also abolished vesicular fusion with the plasma membrane, as evidenced by diminished annexin V staining. Agonist-induced degranulation was completely blocked when LY294002 was applied together with one of the PKG inhibitors, suggesting an additive and possibly synergistic effect. In contrast, the PKG inhibitors did not affect fMLF-induced intracellular calcium mobilization and Akt phosphorylation. Likewise, LY294002 did not alter fMLF-induced elevation of intracellular cGMP concentration, and the inhibitory effect of LY294002 was not reversed by a cell-permeable analog of cGMP. Treatment with fMLF induced phosphorylation of soluble N-ethylmaleimide-sensitive factor-attachment protein (SNAP)-23, syntaxins 2, 4, and 6, and Monc18-3. The induced phosphorylation of SNAP-23 and syntaxins 2 and 4 was blocked by Rp-8-Br-PET-cGMP and LY294002. However, LY294002 was less effective in inhibiting Munc18-3 phosphorylation. The induced phosphorylation of syntaxin 6 was not effectively blocked by either Rp-8-Br-PET-cGMP or LY294002. Treatment of human neutrophils with the PKG inhibitors and LY294002 reduced enzyme release from primary, secondary, and tertiary granules. These results suggest that PKG and PI3K are involved in degranulation, possibly through phosphorylation of target membrane SNAP receptor proteins and their binding proteins.

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Section: Discussionmentioning

confidence: 99%

Regulation of Leukocyte Degranulation by cGMP-Dependent Protein Kinase and Phosphoinositide 3-Kinase: Potential Roles in Phosphorylation of Target Membrane SNARE Complex Proteins in Rat Mast Cells

Nanamori

Chen

et al. 2007

The Journal of Immunology

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“…The precise function of cGMP-elevating agents and NO donors in regulating neutrophil chemotaxis, granule secretion, and the respiratory burst is controversial (8, 10, 18 -21). NO has diverse effects on neutrophil functions, because a concentration-dependent biphasic effect has been reported for chemotaxis and granule secretion (22)(23)(24). Interestingly, high concentrations of NO-releasing compounds and cGMP analogues inhibit chemotaxis, whereas lower concentrations facilitate this response (20,(22)(23)(24).…”

mentioning

confidence: 99%

“…NO has diverse effects on neutrophil functions, because a concentration-dependent biphasic effect has been reported for chemotaxis and granule secretion (22)(23)(24). Interestingly, high concentrations of NO-releasing compounds and cGMP analogues inhibit chemotaxis, whereas lower concentrations facilitate this response (20,(22)(23)(24). Evidence suggests that exogenous NO or L-Arg regulates chemotaxis and granule secretion via a cGKI-dependent mechanism (9,(22)(23)(24)(25).…”

mentioning

confidence: 99%

“…Interestingly, high concentrations of NO-releasing compounds and cGMP analogues inhibit chemotaxis, whereas lower concentrations facilitate this response (20,(22)(23)(24). Evidence suggests that exogenous NO or L-Arg regulates chemotaxis and granule secretion via a cGKI-dependent mechanism (9,(22)(23)(24)(25). cGKI is an established downstream target of the NO/cGMP signaling cascade.…”

mentioning

confidence: 99%

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Neutrophil Dysfunction in Guanosine 3′,5′-Cyclic Monophosphate-Dependent Protein Kinase I-Deficient Mice

Werner

Godfrey²,

Arnold³

et al. 2005

The Journal of Immunology

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The regulation of neutrophil functions by Type I cGMP-dependent protein kinase (cGKI) was investigated in wild-type (WT) and cGKI-deficient (cGKI−/−) mice. We demonstrate that murine neutrophils expressed cGKIα. Similar to the regulation of Ca2+ by cGKI in other cells, there was a cGMP-dependent decrease in Ca2+ transients in response to C5a in WT, but not cGKI−/− bone marrow neutrophils. In vitro chemotaxis of bone marrow neutrophils to C5a or IL-8 was significantly greater in cGKI−/− than in WT. Enhanced chemotaxis was also observed with cGKI−/− peritoneal exudate neutrophils (PE-N). In vivo chemotaxis with an arachidonic acid-induced inflammatory ear model revealed an increase in both ear weight and myeloperoxidase (MPO) activity in ear punches of cGKI−/− vs WT mice. These changes were attributable to enhanced vascular permeability and increased neutrophil infiltration. The total extractable content of MPO, but not lysozyme, was significantly greater in cGKI−/− than in WT PE-N. Furthermore, the percentage of MPO released in response to fMLP from cGKI−/− (69%) was greater than that from WT PE-N (36%). PMA failed to induce MPO release from PE-N of either genotype. In contrast, fMLP and PMA released equivalent amounts of lysozyme from PE-N. However, the percentage released was less in cGKI−/− (∼60%) than in WT (∼90%) PE-N. Superoxide release (maximum velocity) revealed no genotype differences in responses to PMA or fMLP stimulation. In summary, these results show that cGKIα down-regulates Ca2+ transients and chemotaxis in murine neutrophils. The regulatory influences of cGKIα on the secretagogue responses are complex, depending on the granule subtype.

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“…Given the potentially damaging influence of high cytoplasmic iron on mRNA stability [37], this may prove the safest route for recycling of iron from effete red cells. NO is known to enhance secretory and\or excretory mechanisms in other cells [38], which could account for its ability to enhance iron release here. Direct extracellular secretion of iron from phagosomal contents would also imply that most if not all iron entering a cell by phagocytosis never enters the cytoplasm.…”

Section: Discussionmentioning

confidence: 92%

Regulation of phagosomal iron release from murine macrophages by nitric oxide

Mulero

Wei

Liew

et al. 2002

Biochemical Journal

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The role of NO in macrophage iron turnover was studied in macrophages from inducible nitric oxide synthase (iNOS)-deficient mice. Interferon gamma/lipopolysaccharide (IFNgamma/LPS)-activated bone marrow-derived macrophages from iNOS-deficient mice, following phagocytosis of 59Fe-labelled transferrin-anti-transferrin immune complexes, showed reduced iron release compared with cells from wild-type iNOS littermates. Uptake of the complexes by macrophages was similar in iNOS-deficient and wild-type mice. Ferritin was up-regulated by IFNgamma/LPS treatment, but NO exercised a modest opposing down-regulatory effect. No effect of iNOS deficiency was seen when iron was taken up from iron citrate, which enters via a non-phagocytic route. These results suggest that NO plays a key role in regulating iron turnover in macrophages acquiring iron by phagocytosis of erythrocytes or cell debris, and thus the supply to peripheral tissues, such as to the bone marrow for erythropoiesis.

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Potentiation and inhibition of fMLP-activated exocytosis in neutrophils by exogenous nitric oxide

Cited by 11 publications

References 38 publications

Regulation of Leukocyte Degranulation by cGMP-Dependent Protein Kinase and Phosphoinositide 3-Kinase: Potential Roles in Phosphorylation of Target Membrane SNARE Complex Proteins in Rat Mast Cells

Regulation of Leukocyte Degranulation by cGMP-Dependent Protein Kinase and Phosphoinositide 3-Kinase: Potential Roles in Phosphorylation of Target Membrane SNARE Complex Proteins in Rat Mast Cells

Neutrophil Dysfunction in Guanosine 3′,5′-Cyclic Monophosphate-Dependent Protein Kinase I-Deficient Mice

Regulation of phagosomal iron release from murine macrophages by nitric oxide

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