Prostaglandins, Leukotrienes and Essential Fatty Acids
Eosinophils and cysteinyl leukotrienes☆
Section snippets
Background
Leukotrienes are lipid mediators that play major roles in the pathogenesis of asthma and other forms of allergic inflammation [1]. Eosinophils, one of the principal cell types recruited to and activated at sites of allergic inflammation, are capable of elaborating lipid mediators, including leukotrienes derived from the oxidative metabolism of arachidonic acid (AA) [2]. Of the leukotrienes, eosinophils synthesize leukotriene (LT) C4, but not LTB4. The enzymatic pathways by which eosinophils
How AA is metabolized in eosinophils?
In human eosinophils, the oxidative metabolism of AA may occur via pathways mediated by two LO enzymes, as well as, two cyclooxygenase (COX, prostaglandin (PG) H synthase) enzymes. Briefly, COX catalyzes two reactions, a cyclooxygenase reaction that inserts two molecules of oxygen into substrate AA to form PGG2 and a subsequent endoperoxidase reaction that reduces PGG2 to its 15-hydroxy analogue, PGH2. COX pathway eicosanoids produced by human eosinophils include thromboxane B2 and PGE2 with
How do eosinophils synthesize and release cysteinyl leukotrienes?
Acting extracellularly, the cysteinyl leukotrienes (CysLTs)—LTC4 and its extracellular derivatives, LTD4 and LTE4—are key paracrine mediators pertinent to asthma and allergic diseases. Based on their receptor-mediated capabilities, they can elicit bronchoconstriction, mucous hypersecretion, bronchial hyperresponsiveness, increased microvascular permeability, and additional eosinophil infiltration [24], [25], [26]. Eosinophils are a major source of CysLTs [10], [27] and have been identified as
Nuclear envelope
When the integral membrane proteins, FLAP, and 5-LO were localized by immunogold electron microscopy to perinuclear membranes in activated human neutrophils and monocytes, attention was directed to the nuclear envelope as a site of LT biosynthesis [35]; although initially plasma membranes were assumed to be the sites of paracrine mediator eicosanoid synthesis in leukocytes. Of note, LTC4 synthase, an integral membrane protein homologous to FLAP, was also localized to the nuclear envelope [36].
Possible functional correlates of compartmentalized eicosanoid formation in eosinophils
The capacity of eosinophils to synthesize eicosanoids (e.g. LTC4) at two discrete sites, perinuclear membranes and lipid bodies, raises questions of the roles of these eicosanoids in the functioning of eosinophils in inflammation:
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As noted above, CysLTs are well-recognized paracrine mediators pertinent to asthma and allergic inflammation, but how do these eicosanoids transit from their intracellular sites of synthesis for their extracellular release, which is requisite for their paracrine
CysLTs function as eosinophil autocrine and/or intracrine mediators
In addition to their potential roles as paracrine mediators, eicosanoids and related lipids are increasingly being recognized to have autocrine effects. For instance, eosinophil CysLTs exert autocrine effects to enhance eosinophil survival [55]; and the enhanced plasma membrane expression of activation-related CD69 on human eosinophils induced by PAF and IL-5 is dependent on endogenous eosinophil-derived 5-LO metabolites [56]. Moreover, endogenous 5-LO activation to form 5-HETE is obligately
How many CysLTs receptors do eosinophils express?
The CysLTs exert their actions by engaging specific receptors (for review see [64]). To date, two CysLT receptors (CysLTRs) have been cloned and characterized, the CysLT1 and CysLT2 receptors [65], [66], [67], [68]. As detailed in Table 1, CysLT1 and CysLT2 are 7 transmembrane spanning receptors that may signal at least some responses via G proteins and can be distinguished with pharmacologic inhibitors and by their differing ligand binding affinities, as studied in transfected cells. CysLT1,
Final remarks
The generation of eicosanoids within eosinophils and other cells is important not only for the roles of eicosanoids as extracellular paracrine mediators of inflammation, but also for their roles as intracrine signal transducing molecules that may regulate fundamental cellular responses within the nucleus or cytoplasm, such as the release of cytokines from eosinophils. Distinct intracellular domains within eosinophils, perinuclear membranes and lipid bodies, are now recognized as sites of
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Supported by NIH grants AI20241, AI22571, AI51645, HL70270