The involvement of extracellular calcium in the formation of 5‐lipoxygenase metabolites by human polymorphonuclear leukocytes

Schatz-Munding, M.; Hatzelmann, Armin; Ullrich, Volker

doi:10.1111/j.1432-1033.1991.tb15936.x

Cited by 42 publications

(31 citation statements)

References 38 publications

(9 reference statements)

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“…Extracellular Ca ϩϩ was removed by 1 mM EDTA and for depletion of intracellular Ca ϩϩ cell-permeable BAPTA/AM (30 M) was added to the incubations. As found by others, 35 chelation of Ca ϩϩ by EDTA or BAPTA/AM dramatically reduced 5-LO product formation in PMNLs stimulated with ionophore or thapsigargin ( Figure 7B), and depletion of intracellular Ca ϩϩ by BAPTA/AM clearly suppressed 5-LO product formation in PMNLs challenged with fMLP ( Figure 7B) or with PAF (P Ͻ .01; not shown). In contrast, 5-LO product formation induced by NaCl was unaffected by addition of EDTA or BAPTA/AM, and there was no significant change in the 5-LO product pattern.…”

Section: Metabolites To 5-h(p)etesupporting

confidence: 55%

“…Interestingly, a lower concentration of Ca ϩϩ (200 nM) seemed sufficient for activation of 5-LO in intact PMNLs. 35 However, a clearly lower Ca ϩϩ concentration (Ͻ10 nM) was monitored for PMNLs treated with EDTA and BAPTA/AM, indicating that stress-induced 5-LO product formation under such conditions is independent of Ca ϩϩ . Another finding supporting that stress-induced 5-LO activation does not involve Ca ϩϩ is the different effects of exogenous AA.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it was reported that extracellular Ca ϩϩ was only partially required for 5-LO product formation in PMNLs when exogenous AA was present. 35 Also, it was suggested that when LT biosynthesis in mast cells was stimulated via IgE receptors, another unidentified pathway could act in conjunction with Ca ϩϩ to activate 5-LO. 45 In a model for AA-induced LT biosynthesis in PMNLs, it was implied that an initial burst of 5-LO activity was Ca ϩϩ independent.…”

mentioning

confidence: 99%

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Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes

Werz

Bürkert

Samuelsson

et al. 2002

Blood

168

166

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5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of proinflammatory leukotrienes. This study showed that various forms of cell stress, such as chemical stress (sodium arsenite), osmotic stress, or heat shock lead to substantial formation of 5-LO products in freshly isolated human polymorphonuclear leukocytes (PMNLs), when exogenous arachidonic acid (10 M) was present. In parallel, cell stress led to activation of p38 MAPK (mitogen-activated protein kinase) and mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) kinases, which can phosphorylate 5-LO in vitro. Interestingly, arsenite also caused redistribution of 5-LO from the cytosol to the nuclear membrane. Only minor activation of extracellular signal-regulated kinases and cjun NH 2 -terminal kinases was observed, implying that these MAPKs are less important for 5-LO product formation in stressstimulated PMNLs. Stimulation of 5-LO product formation by Ca ؉؉ -ionophore A23187 or thapsigargin depended on Ca ؉؉ ; almost no 5-LO product formation was observed in freshly isolated PMNLs when Ca ؉؉ was depleted by chelating agents. Also the response to N-formylmethionyl-leucyl-phenylalanine (fMLP) was clearly diminished, but some 5-LO product formation remained. In contrast, stress-induced product formation and translocation of 5-LO, as well as activation of p38 MAPK, occurred also after Ca ؉؉ depletion. Moreover, the p38 MAPK inhibitor SB203580 blocked stress-induced 5-LO product formation efficiently, whereas ionophore-or thapsigargin-induced formation of 5-LO products was less sensitive. These data show that cell stress can activate 5-LO in isolated PMNLs by a mechanism that does not involve Ca IntroductionMetabolism of arachidonic acid (AA) by 5-lipoxygenase (5-LO) initializes the biosynthesis of biologically active leukotrienes (LTs), which are potent mediators in inflammatory and allergic reactions. 1 Whereas LTB 4 is considered as a potent chemotactic and chemokinetic agent for phagocytes, the cysteinyl-LTs C 4 , D 4 , and E 4 cause smooth muscle contraction and increase vascular permeability. Formation of LTs in leukocytes depends on the availability of free AA from either endogenous pools liberated by activated cytosolic phospholipase A 2 (cPLA 2 ) or from transcellular migration of AA, released from surrounding cells like platelets or endothelial cells. cPLA 2 is regulated by phosphorylation on serine residues and by Ca ϩϩ , which binds to the C2 domain of the enzyme and induces its translocation and binding to the nuclear membrane (for a review, see Gijon and Leslie 2 ).In resting cells, depending on the cell type, 5-LO can occur in different soluble loci. On cell stimulation, 5-LO translocates to the nuclear membrane where it colocalizes with 5-lipoxygenaseactivating protein (FLAP) and cPLA 2 , and an orchestrated interplay between these enzymes is of importance for efficient LT formation (for reviews, see Peters-Golden and Brock 3 and Rådmark 4 ). The activation of cellular 5-LO can be induced by ligation of specific receptor...

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Section: Metabolites To 5-h(p)etesupporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes

Werz

Bürkert

Samuelsson

et al. 2002

Blood

168

166

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“…17,18 These pro-inflammatory interactions of the toxin with neutrophils were associated with influx of Ca 2+ , 11 an event which precedes and is a pre-requisite for mobilization of secondary/tertiary granules 19 and eicosanoid production. 20 Although Δ6 PLY at 1000 ng/ml caused modest Ca 2+ influx following a protracted lag phase, the resultant increment in cytosolic Ca 2+ did not achieve the necessary threshold for either degranulation or production of LTB 4 .…”

Section: Discussionmentioning

confidence: 96%

Characterization of the interactions of the pneumolysoid, Δ6 PLY, with human neutrophils in vitro

Cockeran

Steel

Theron

et al. 2011

Vaccine

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The pneumolysin toxoid, Δ6 PLY, is a prototype pneumococcal protein vaccine candidate. However, its potentially detrimental residual proinflammatory interactions with human neutrophils are unknown. In the current study the effects of the toxoid (8-1000 ng/ml) have been compared with those of wild-type pneumolysin (WT/PLY, 8 ng/ml) on neutrophil cytosolic Ca 2+ fluxes, generation of leukotriene B 4 (LTB 4 ), and release of matrix metalloproteinase-9 (MMP-9), using spectrofluorimetric, and ELISA procedures (LTB 4 and MMP-9) respectively. Exposure of neutrophils to WT/PLY resulted in influx of Ca 2+ and significant (P<0.05) release of MMP-9 and generation of LTB 4 . However, treatment of the cells with Δ6 PLY at concentrations of up to 1000 ng/ml had only trivial effects on Ca 2+ influx and no effects on either release of MMP-9 or LTB 4 production. The observed absence of pro-inflammatory interactions of Δ6 PLY with neutrophils is clearly an important property of this pneumococcal protein vaccine candidate.

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“…Early studies on the source of calcium for 5-LO activation stressed the importance of extracellular calcium, rather than calcium released from internal stores [Schatz-Munding et al, 1991;Wong et al, 1991]. In these and similar studies, extracellular calcium was thought to move into the cytoplasm, where it activated 5-LO and cPLA 2 , consequently leading to LT synthesis.…”

Section: Calcium and Atp Effectsmentioning

confidence: 99%

Regulating leukotriene synthesis: The role of nuclear 5‐lipoxygenase

Brock

2005

J of Cellular Biochemistry

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Leukotrienes are lipid messengers involved in autocrine and paracrine cellular signaling. They are synthesized from arachidonic acid by the 5-lipoxygenase pathway. Current models of this enzymatic pathway recognize that a key step in initiating leukotriene synthesis is the calcium-mediated movement of enzymes, including 5-lipoxygenase, to intracellular membranes. However, 5-lipoxygenase can be imported into or exported from the nucleus before calcium activation. As a result, its subcellular localization will affect its ability to be activated by calcium, as well as the membrane to which it binds and its interaction with other enzymes. This commentary focuses on the role of 5-lipoxygenase compartmentation in determining its regulation and, ultimately, leukotriene synthesis.

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The involvement of extracellular calcium in the formation of 5‐lipoxygenase metabolites by human polymorphonuclear leukocytes

Cited by 42 publications

References 38 publications

Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes

Activation of 5-lipoxygenase by cell stress is calcium independent in human polymorphonuclear leukocytes

Characterization of the interactions of the pneumolysoid, Δ6 PLY, with human neutrophils in vitro

Regulating leukotriene synthesis: The role of nuclear 5‐lipoxygenase

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