Eosinophils and cysteinyl leukotrienes

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Abstract

Eosinophils are the main source of the cysteinyl leukotrienes, LTC4/D4/E4, which are lipid mediators that play major roles in the pathogenesis of asthma and other forms of allergic inflammation. Here, we review the mechanisms governing eosinophil LTC4 synthesis, focusing on the distinct intracellular domains that regulate eicosanoid formation and function within eosinophils. Cysteinyl leukotrienes exert their actions by engaging specific receptors. As recently shown, eosinophils express CysLT1 and CysLT2, the only cloned receptors for cysteinyl leukotrienes. Therefore, here we also present some of the new findings regarding the paracrine/autocrine activation of these CysLT receptors on eosinophils, and discuss some data on novel intracrine effects of LTC4 triggered by a putative third CysLT receptor expressed intracellularly within eosinophils.

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:

  • (i)

    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

References (75)

  • P.F. Weller et al.

    Arachidonic acid incorporation by cytoplasmic lipid bodies of human eosinophils

    Blood

    (1985)
  • P.F. Weller et al.

    Cytoplasmic lipid bodies in eosinophilscentral roles in eicosanoid generation

    Allergol. Int.

    (1997)
  • G. Bannenberg et al.

    Leukotriene C4 is a tight-binding inhibitor of microsomal glutathione transferase-1. Effects of leukotriene pathway modifiers

    J. Biol. Chem.

    (1999)
  • I. Leier et al.

    The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates

    J. Biol. Chem.

    (1994)
  • M. Bhattacharya et al.

    Localization of functional prostaglandin E2 receptors EP3 and EP4 in the nuclear envelope

    J. Biol. Chem.

    (1999)
  • T.G. Brock et al.

    Peters-Golden M. Co-localization of leukotriene A4 hydrolase with 5-lipoxygenase in nuclei of alveolar macrophages and rat basophilic leukemia cells but not neutrophils

    J. Biol. Chem.

    (2001)
  • J.F. Evans

    Cysteinyl leukotriene receptors

    Prostaglandins Other Lipid Mediat.

    (2002)
  • C.E. Heise et al.

    Characterization of the human cysteinyl leukotriene 2 (CysLT2) receptor

    J. Biol. Chem.

    (2000)
  • C. Bandeira-Melo et al.

    Cysteinyl leukotrienes induce IL-4 release from cord blood-derived human eosinophils

    J. Allergy Clin. Immunol.

    (2002)
  • P.E. Christie et al.

    Lipid inflammatory mediatorsleukotrienes, prostaglandins, platelet-activating factor

    Clin. Allergy Immunol.

    (2002)
  • P.F. Weller

    Lipid peptide and cytokine mediators elaborated by eosinophils

  • M.K. Hodges et al.

    Heterogeneity of leukotriene C4 production by eosinophils from asthmatic and normal subjects

    Am. Rev. Respir. Dis.

    (1988)
  • C. Bandeira-Melo et al.

    Contributing to the diversity of eosinophil recruitment and activation

    Am. J. Respir. Cell Mol. Biol.

    (2001)
  • A.G. Stewart et al.

    Platelet-activating factor may act as a second messenger in the release of icosanoids and superoxide anions from leukocytes and endothelial cells

    Proc. Natl. Acad. Sci. USA

    (1990)
  • S. Takafugi et al.

    IL-3 and IL-5 prime normal human eosinophils to produce leukotriene C4 in response to soluble agonists

    J. Immunol.

    (1991)
  • T.G. Brock et al.

    Decreased leukotriene C4 synthesis accompanies adherence-dependent nuclear import of 5-lipoxygenase in human blood eosinophils

    J. Immunol.

    (1999)
  • C. Bandeira-Melo et al.

    Cyclooxygenase-2-derived prostaglandin E2 and lipoxin A4 accelerate resolution of allergic edema in Angiostrongylus costaricensis-infected ratsrelationship with concurrent eosinophilia

    J. Immunol.

    (2000)
  • C. Bandeira-Melo et al.

    Involvement of prostaglandins in the down-regulation of allergic plasma leakage observed in rats undergoing pleural eosinophilia

    Br. J. Pharmacol.

    (1996)
  • P.F. Weller et al.

    Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophilspredominant production of leukotriene C4

    Proc. Natl. Acad. Sci. USA

    (1983)
  • W.G. Parsons et al.

    Transformation of prostaglandin D2 to isomeric prostaglandin F2 compounds by human eosinophils A potential mast cell-eosinophil interaction

    J. Immunol.

    (1988)
  • M.L. Foegh et al.

    Human peritoneal eosinophils and formation of arachidonate cylooxygenase products

    Scand. J. Immunol.

    (1986)
  • P.L.B. Bruijnzeel et al.

    Lipid metabolism by eosinophils

  • R. Taha et al.

    Prostaglandin H synthase 2 expression in airway cells from patients with asthma and chronic obstructive pulmonary disease

    Am. J. Respir. Crit. Care Med.

    (2000)
  • A. Sousa et al.

    Enhanced expression of cyclo-oxygenase isoenzyme 2 (COX-2) in asthmatic airways and its cellular distribution in aspirin-sensitive asthma

    Thorax

    (1997)
  • J.F. Penrose et al.

    LTC4 synthasea key enzyme in cysteinyl leukotriene formation

  • A.W. Ford-Hutchinson

    Arachidonate 15-lipoxygenase; characteristics and potential biological significance

    Eicosanoids

    (1991)
  • R.A. Lewis et al.

    Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases

    N. Engl. J. Med.

    (1990)
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    Supported by NIH grants AI20241, AI22571, AI51645, HL70270

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