Selenium‐Dependent Peroxidases Suppress 5‐Lipoxygenase Activity in B‐Lymphocytes and Immature Myeloid Cells

Werz, Oliver; Steinhilber, Dieter

doi:10.1111/j.1432-1033.1996.0090r.x

Cited by 96 publications

(75 citation statements)

References 42 publications

(18 reference statements)

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“…After the addition of 1 ml methanol, fatty acids were extracted by solid-phase extraction and analyzed by highperformance liquid chromatography (HPLC) as described (40). LTB 4 , its all-trans isomers, and 5-HETE were combined to give a global indication of 5-LO product formation.…”

Section: High-performance Liquid Chromatography-based Fatty Acid Quanmentioning

confidence: 99%

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

Awwad

Steinbrink²,

Frömel³

et al. 2014

Antioxidants & Redox Signaling

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Aims: The reaction of nitric oxide and nitrite-derived species with polyunsaturated fatty acids yields electrophilic fatty acid nitroalkene derivatives (NO 2 -FA), which display anti-inflammatory properties. Given that the 5-lipoxygenase (5-LO, ALOX5) possesses critical nucleophilic amino acids, which are potentially sensitive to electrophilic modifications, we determined the consequences of NO 2 -FA on 5-LO activity in vitro and on 5-LOmediated inflammation in vivo. Results: Stimulation of human polymorphonuclear leukocytes (PMNL) with nitro-oleic (NO 2 -OA) or nitro-linoleic acid (NO 2 -LA) (but not the parent lipids) resulted in the concentrationdependent and irreversible inhibition of 5-LO activity. Similar effects were observed in cell lysates and using the recombinant human protein, indicating a direct reaction with 5-LO. NO 2 -FAs did not affect the activity of the platelet-type 12-LO (ALOX12) or 15-LO-1 (ALOX15) in intact cells or the recombinant protein. The NO 2 -FAinduced inhibition of 5-LO was attributed to the alkylation of Cys418, and the exchange of Cys418 to serine rendered 5-LO insensitive to NO 2 -FA. In vivo, the systemic administration of NO 2 -OA to mice decreased neutrophil and monocyte mobilization in response to lipopolysaccharide (LPS), attenuated the formation of the 5-LO product 5-hydroxyeicosatetraenoic acid (5-HETE), and inhibited lung injury. The administration of NO 2 -OA to 5-LO knockout mice had no effect on LPS-induced neutrophil or monocyte mobilization as well as on lung injury. Innovation: Prophylactic administration of NO 2 -OA to septic mice inhibits inflammation and promotes its resolution by interfering in 5-LO-mediated inflammatory processes. Conclusion: NO 2 -FAs directly and irreversibly inhibit 5-LO and attenuate downstream acute inflammatory responses. Antioxid. Redox Signal. 20, 2667Signal. 20, -2680

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Section: High-performance Liquid Chromatography-based Fatty Acid Quanmentioning

confidence: 99%

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

Awwad

Steinbrink²,

Frömel³

et al. 2014

Antioxidants & Redox Signaling

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“…This migration of 5-LO is most probably of importance for regulation of cellular 5-LO activity. Also, the cellular redox state determines leukotriene synthesis (3,4). Furthermore, other proteins interacting with 5-LO could influence its subcellular distribution and catalytic activity.…”

mentioning

confidence: 99%

5-Lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases

Werz

Klemm

Samuelsson

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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162

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5-lipoxygenase (5-LO) catalyzes the initial steps in the formation of leukotrienes, a group of inflammatory mediators derived from arachidonic acid (AA). Here we describe that activation of p38 mitogenactivated protein kinase in human polymorphonuclear leukocytes and in Mono Mac 6 cells leads to activation of downstream kinases, which can subsequently phosphorylate 5-LO in vitro. Different agents activated the 5-LO kinase activities, including stimuli for cellular leukotriene biosynthesis (A23187, thapsigargin, N-formyl-leucyl-phenylalanine), compounds that up-regulate the capacity for leukotriene biosynthesis (phorbol 12-myristate 13-acetate, tumor necrosis factor ␣, granulocyte͞macrophage colony-stimulating factor), and well known p38 stimuli as sodium arsenite and sorbitol. For all stimuli, 5-LO kinase activation was counteracted by SB203580 (3 M or less), an inhibitor of p38 kinase. At least two p38-dependent 5-LO kinase activities were found. Based on migration properties in in-gel kinase assays and immunoreactivity, one of these was identified as mitogenactivated protein kinase-activated protein kinase 2 (MAPKAP kinase 2). The other appeared to be MAPKAP kinase 3; however, it could not be excluded that also other p38-dependent kinases contributed. When polymorphonuclear leukocytes were incubated with sodium arsenite (strong activator of 5-LO kinases), platelet-activating factor and exogenous AA, there was a 4-fold increase in 5-LO activity as compared with incubations with only platelet-activating factor and AA. This indicates that 5-LO phosphorylation can be one factor determining cellular 5-LO activity.

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“…The phosphorylation of 5-LO on Ser523 by protein kinase A (PKA) inhibits LT synthesis [Luo et al, 2004a]. In addition, 5-LO activity can be suppressed by nitric oxide [Brunn et al, 1997;Brock et al, 2003] and glutathione peroxidases (GPx) [Werz and Steinhilber, 1996;Straif et al, 2000]. [Mandal et al, 2004].…”

Section: Lt Synthesis: a Conceptual Modelmentioning

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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Selenium‐Dependent Peroxidases Suppress 5‐Lipoxygenase Activity in B‐Lymphocytes and Immature Myeloid Cells

Cited by 96 publications

References 42 publications

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

Electrophilic Fatty Acid Species Inhibit 5-Lipoxygenase and Attenuate Sepsis-Induced Pulmonary Inflammation

5-Lipoxygenase is phosphorylated by p38 kinase-dependent MAPKAP kinases

Regulating leukotriene synthesis: The role of nuclear 5‐lipoxygenase

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