Signal transduction and activation of the NADPH oxidase in eosinophils

Lindsay, Mark A.; Giembycz, Mark A.

doi:10.1590/s0074-02761997000800016

Cited by 9 publications

(3 citation statements)

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“…35,36,44 Therefore, we evaluated the ability of LTs to modulate NADPHox activation during bacterial infection of the AM. In these experiments, we used the potent and specific NADPHox inhibitor DPI.…”

Section: Lts Increase Am Microbicidal Activity Through the Activationmentioning

confidence: 99%

“…In eosinophils, LTB 4 was shown to enhance NADPHox activity, but the exact mechanisms responsible for this activation were not investigated. 35,36 In neutrophils, LTB 4 induced NADPHox activation through a Rac-dependent pathway; this effect was dependent on ERK and cytosolic phospholipase A 2 activities but not on p38 kinase 37 Despite the critical role of AMs in innate immunity, little is known about the activation of NADPHox in these cells. Moreover, although AMs are known to have a far greater capacity for LT synthesis than macrophages from other sites, 38 virtually nothing is known about the influence of these lipid mediators on this process.…”

Section: Introductionmentioning

confidence: 99%

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Leukotrienes enhance the bactericidal activity of alveolar macrophages against Klebsiella pneumoniae through the activation of NADPH oxidase

Serezani

Aronoff

Jancar

et al. 2005

Blood

143

174

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Leukotrienes (LTs) are lipid mediators that participate in inflammatory diseases and innate immune function. We sought to investigate the importance of LTs in regulating the microbicidal activity of alveolar macrophages (AMs) and the molecular mechanisms by which this occurs. The role of LTs in enhancing AM microbicidal activity was evaluated pharmacologically and genetically using in vitro challenge with Klebsiella pneumoniae. Exogenous LTs increased AM microbicidal activity in a dose-and receptor-dependent manner, and endogenous production of LTs was necessary for optimal killing. Leukotriene B 4 (LTB 4 ) was more potent than cysteinyl LTs. An important role for nicotinamide adenine dinucleotide (NADPH) oxidase in LT-induced microbicidal activity was indicated by the fact that bacterial killing was abrogated by the NADPH oxidase inhibitor diphenyleneiodonium (DPI; 10 M) and in AMs derived from gp91phox-deficient mice. By contrast, LT-induced microbicidal activity was independent of the generation of nitric oxide. LTs increased H 2 O 2 production, and LTB 4 was again the more potent agonist. Both classes of LTs elicited translocation of p47phox to the cell membrane, and LTB 4 induced phosphorylation of p47phox in a manner dependent on protein kinase C-␦ (PKC-␦) activity. In addition, the enhancement of microbicidal activity by LTs was also dependent on PKC-␦ activity. Our results demonstrate that LTs, especially LTB 4 , enhance AM microbicidal activity through the PKC-␦-dependent activation of NADPH oxidase. IntroductionPneumonia is the leading cause of death from infection in the United States, 1 and its global mortality is 4.3 million people per year. 2 This problem is compounded by growing numbers of immunosuppressed patients and multidrug-resistant microorganisms. Developing more effective agents for the prevention and treatment of pneumonia requires a better understanding of how innate pulmonary defense mechanisms are regulated.The alveolar macrophage (AM) patrols the epithelial surface of the distal lung and maintains sterility by phagocytosing and killing microorganisms. 3,4 AMs are the first line of defense against invading microorganisms and, as such, are capable of secreting cytokines, lipid mediators, and microbicidal molecules. Among the lipid mediators generated by AMs, the leukotrienes (LTs) play an important role in lung innate immunity, inducing neutrophil recruitment and enhancing macrophage antimicrobial functions. 5 LTs are derived from the metabolism of the cell-membrane fatty acid arachidonic acid (AA) through the enzyme 5-lipoxygenase (5-LO), in concert with its helper protein, 5-LO-activating protein (FLAP). 6 5-LO oxygenates AA to the intermediate 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which is either enzymatically reduced by 5-LO to the unstable epoxide leukotriene A 4 (LTA 4 ) or alternatively is reduced to 5-hydroxyeicosatetraenoic acid (5-HETE). LTA 4 can be hydrolyzed to form LTB 4 or can be conjugated with glutathione to form the cysteinyl LTs (cysLTs), LTC 4 , LTD 4 , and ...

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Section: Lts Increase Am Microbicidal Activity Through the Activationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Leukotrienes enhance the bactericidal activity of alveolar macrophages against Klebsiella pneumoniae through the activation of NADPH oxidase

Serezani

Aronoff

Jancar

et al. 2005

Blood

143

174

View full text Add to dashboard Cite

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“…Mainly using as cell model guinea-pig eosinophils, it has been shown that LTB 4 was capable of stimulating eosinophil recruitment, release of AA, homotypic eosinophil aggregation, as well as, rapid and transient activation of the NADPH oxidase (Faccioli et al, 1991; Lindsay and Giembycz, 1997; Teixeira et al, 1999). Of note, the intracellular mechanisms that mediate LTB 4 -induced NADPH oxidase activation involve mediation by lyn kinase, PKC, and PLA 2 , but occurs essentially independently of changes in the intracellular calcium, phospholipase D, PI3K, and ERK1/2 (Perkins et al, 1995; Lindsay et al, 1998a,b; Lynch et al, 1999) Specifically regarding induction of LTC 4 synthesizing function, stimulation of human eosinophils with LTB 4 failed to mount a LTC 4 synthesizing response ( Figure 1 , right panel).…”

Section: Do Lipid Mediators Activate Eosinophil Effector Functions?mentioning

confidence: 99%

Eosinophil recruitment and activation: the role of lipid mediators

Luna-Gomes¹,

Bozza²,

Bandeira‐Melo³

2013

Front. Pharmacol.

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Eosinophils are effector cells that migrate toward several mediators released at inflammatory sites to perform their multiple functions. The mechanisms driving eosinophil selective accumulation in sites of allergic inflammation are well-established and involve several steps controlled by adhesion molecules, priming agents, chemotactic, and surviving factors. Even though the majority of studies focused on role of protein mediators like IL-5 and eotaxins, lipid mediators also participate in eosinophil recruitment and activation. Among the lipid mediators with distinguish eosinophil recruitment and activation capabilities are platelet activating factor and the eicosanoids, including leukotriene B4, cysteinyl leukotrienes, and prostaglandin D2. In this review, we focused on the role of these four lipid mediators in eosinophil recruitment and activation, since they are recognized as key mediators of eosinophilic inflammatory responses.

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