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The Journal of Immunology, 2004, 173: 1503-1510.
Copyright © 2004 by The American Association of Immunologists

BRIEF REVIEWS

Cysteinyl Leukotrienes and Their Receptors: Cellular Distribution and Function in Immune and Inflammatory Responses1

Yoshihide Kanaoka*,{ddagger} and Joshua A. Boyce2,*,{dagger},{ddagger},§

Departments of * Medicine and {dagger} Pediatrics, Harvard University Medical School, and {ddagger} Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, and § Partners Asthma Center, Boston, MA 02115


   Abstract
Top
 Abstract
Introduction
 cys-LT biosynthesis
 Molecular biology of the...
 Involvement of cys-LTs and...
 Functions of the cys-LTs...
 Roles of cys-LTs and...
 Summary
 References
 
The cysteinyl leukotrienes (cys-LTs) are a family of potent bioactive lipids that act through two structurally divergent G protein-coupled receptors, termed the CysLT1 and CysLT2 receptors. The cloning and characterization of these two receptors has not only reconciled findings of previous pharmacologic profiling studies of contractile tissues, but also has uncovered their expression on a wide array of circulating and tissue-dwelling leukocytes. With the development of receptor-selective reagents, as well as mice lacking critical biosynthetic enzymes, transporter proteins, and the CysLT1 receptor, diverse functions of cys-LTs and their receptors in immune and inflammatory responses have been identified. We review cys-LT biosynthesis; the molecular biology and distribution of the CysLT1 and CysLT2 receptors; the functions of cys-LTs and their receptors in the recruitment and activation of effector leukocytes and induction of adaptive immunity; and the development of fibrosis and airway remodeling in animal models of lung injury and allergic inflammation.


   Introduction
Top
 Abstract
 Introduction
cys-LT biosynthesis
 Molecular biology of the...
 Involvement of cys-LTs and...
 Functions of the cys-LTs...
 Roles of cys-LTs and...
 Summary
 References
 
Leukotriene (LT)3 C4, LTD4, and LTE4, collectively termed the cysteinyl LTs (cys-LTs), are peptide-conjugated lipids that are prominent products of activated eosinophils, basophils, mast cells (MCs), and macrophages. Originally identified on the basis of their contractile properties for intestinal and bronchial smooth muscle (1, 2, 3, 4, 5), they are now recognized as potent inflammatory mediators that initiate and propagate a diverse array of biologic responses. In the last decade, two receptors for the cys-LTs, termed the type 1 and type 2 cys-LT receptors (CysLT1 and CysLT2 receptors, respectively) have been identified, cloned, and characterized; null mouse strains respectively lacking the CysLT1 receptor and the biosynthetic enzymes involved in cys-LT synthesis have been derived; and clinically efficacious receptor antagonists and inhibitors of cys-LT synthesis have been introduced to treat humans with asthma. These advances confirm the earlier observations regarding the actions of cys-LTs at the level of smooth muscle function in vivo. They have also revealed unanticipated functions for the cys-LTs, acting nonredundantly through the CysLT1 and CysLT2 receptors, in both innate and adaptive immune responses, as well as in the effector phase of inflammation, tissue repair, and fibrosis. We will review these findings and discuss their implications for the role of cys-LTs and their receptors in host defense and disease.


   cys-LT biosynthesis
Top
 Abstract
 Introduction
 cys-LT biosynthesis
Molecular biology of the...
 Involvement of cys-LTs and...
 Functions of the cys-LTs...
 Roles of cys-LTs and...
 Summary
 References
 
The cys-LTs are rapidly generated de novo from cell membrane phospholipid-associated arachidonic acid, which is liberated by cytosolic phospholipase A2 (cPLA2) in response to cell activation (6). Arachidonic acid is converted to 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) and subsequently to an unstable intermediate, LTA4, by the enzyme 5-lipoxygenase (5-LO) (7). 5-LO translocates from its cytosolic or nucleoplasmic location to the perinuclear envelope, where it acts in concert with 5-LO-activating protein (FLAP), which is required for 5-LO to function enzymatically in intact cells (8, 9). In neutrophils, LTA4 is preferentially hydrolyzed to the dihydroxy leukotriene, LTB4, by LTA4 hydrolase (10), whereas eosinophils, basophils, MCs, and macrophages preferentially form LTC4 through conjugation of LTA4 to reduced glutathione by LTC4 synthase (LTC4S), the terminal enzyme involved in cys-LT synthesis (11, 12, 13) (Fig. 1). LTC4 is exported to the cell surface via a specific, energy-dependent step (14) that requires multidrug resistance-associated protein 1 (MRP1) (15). It is converted extracellularly to LTD4 by a {gamma}-glutamyl transpeptidase ({gamma}-GT) (16) or by a more functionally specific enzyme, {gamma}-glutamyl leukotrienase ({gamma}-GL) (17), and then to LTE4 by a dipeptidase (18). LTE4 is excreted in the urine without further chemical modification.



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  		FIGURE 1. Biosynthesis and molecular structures of cys-LTs. cPLA2 catalyzes the liberation of arachidonic acid from cell membranes. 5-LO translocates to the nuclear envelope, requiring the integral membrane protein FLAP to convert arachidonic acid to the precursor LTA4. LTA4 can spontaneously convert to the inactive metabolite 6-trans LTB4, specifically hydrolyzed by LTA4 hydrolase (LTA4H) to LTB4, or conjugated to reduced glutathione by LTC4S, forming LTC4, the first committed molecule of the cys-LTs (red). Following specific export, LTC4 is converted by the extracellular enzymes {gamma}-GT and {gamma}-GL to LTD4, and to LTE4 by dipeptidase. Enzymes essential for cys-LT synthesis are in bold.

 
LTC4S is structurally homologous to FLAP (12, 13). These proteins both belong to the microsomal-associated proteins involved in eicosanoid and glutathione metabolism family, which also includes microsomal GST-2 and PGE2 synthase. Microsomal GST-2 conjugates LTA4 to reduced glutathione and forms LTC4 in vitro, but this activity is weak compared with that of authentic LTC4S. Moreover, homogenates of most tissues from mice with a targeted deletion of LTC4S are unable to perform this conjugation, and MCs derived from LTC4S knockout mice generate no cys-LTs when activated ex vivo (19). Both FLAP and LTC4S constitutively localize to the perinuclear envelope, the subcellular location where cys-LT synthesis is thought to occur. Interestingly, FLAP and LTC4S also colocalize with 5-LO to inducible electron-dense cytoplasmic lipid bodies in activated eosinophils (20). Whether lipid bodies are accessory sites of LT synthesis or are transport organelles for eicosanoid-synthesizing enzymes is not known.

Although the enzymes of the 5-LO/LTC4S pathway are expressed constitutively, their activity and expression in human and mouse MCs is subject to modulation by exogenous cytokines. Mouse MCs derived in vitro from bone marrow cells cultured in the presence of recombinant mouse stem cell factor and IL-10 respond to exogenous IL-3 with marked proliferation and progressive increments in their expression of 5-LO, FLAP, and LTC4S (21). These IL-3-treated MCs respond to cross-linkage of their high-affinity FcR for IgE, Fc{epsilon}RI, by generating LTC4 in markedly increased quantities as compared with replicates not treated with IL-3. Cord blood-derived human MCs respond to short-term (1–5 days) priming with recombinant human IL-4 with a striking up-regulation in LTC4S protein and mRNA expression, accompanied by a parallel increase in enzymatic function (22). Inasmuch as IL-3 and IL-4 are expressed prominently by lymphocytes in inflamed mucosal surfaces, these studies suggest a mechanism by which endogenously produced cytokines may coordinately regulate cys-LT generation by MCs in the effector phase of the mucosal inflammation that accompanies helminth infection and allergic disease.

Genetic variants of 5-LO and LTC4S have been described in humans. Allelic variants in the 5-LO core promoter result in the addition or deletion of consensus binding sites for the zinc-finger DNA binding proteins SP1 and early growth response-1, and diminished 5-LO promoter reporter activity compared with the wild-type allele (23). The lung function of individuals with asthma carrying these variant alleles improved substantially less in response to an orally administered 5-LO inhibitor than did the lung function of similarly treated individuals with asthma who were homozygous for the wild-type allele (24). A common polymorphism in the human LTC4S gene results from an A-C substitution 444 bases upstream of the translational start site. The presence of this polymorphism correlates with increased levels of LTC4 generation by calcium ionophore-stimulated peripheral blood eosinophils (25), diminished lung function in asthmatic children (26), increased clinical responses to CysLT1 receptor antagonists (25, 27), and an increased incidence of aspirin sensitivity in some (28), but not all, human ethnic populations (29). Thus polymorphisms in cys-LT-generating enzymes may modify drug responses and certain phenotypic features in patients with asthma.


   Molecular biology of the CysLT1 and CysLT2 receptors
Top
 Abstract
 Introduction
 cys-LT biosynthesis
 Molecular biology of the...
Involvement of cys-LTs and...
 Functions of the cys-LTs...
 Roles of cys-LTs and...
 Summary
 References
 
Early pharmacologic profiling studies of mammalian tissues predicted the existence of at least two types of receptors for the cys-LTs (30, 31). Subsequently, the CysLT1 and CysLT2 receptors were cloned in the mouse (32, 33, 34) and human (35, 36, 37). Both receptors are members of the G protein-coupled receptor family, which use both pertussis toxin (PTX)-sensitive and PTX-insensitive G proteins for their signaling. The different pharmacologic profiles and incompletely overlapping tissue distributions of the CysLT1 and CysLT2 receptors (Table I) correlate well with their pharmacology predicted from tissue profiling studies (38).


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  		Table I. Human and mouse cys-LT receptorsa

 
The sequences of the human CysLT1 and CysLT2 receptors are highly divergent (38% amino acid identity). Human and mouse CysLT1 receptors are 87% identical, whereas the CysLT2 receptors are 74% identical. The mouse gene encoding the CysLT1 receptor consists of four exons and three introns, giving rise to two transcripts that result in long and short respective isoforms of the receptor (33). Exons I and IV encode the short isoform, whereas the long isoform also incorporates the small exons II and IV. Exon III of the mouse CysLT1 receptor gene contains an in-frame start codon (ATG) that is 39-bp upstream of the ATG translation start site reported for the human CysLT1 receptor. This sequence permits a 13-aa extension at the N terminus, resulting in a long receptor isoform with 352 deduced amino acid residues and a calculated mass of 40,715. The N-terminal extension is missing in the human CysLT1 receptor because of a stop codon six nucleotides upstream of the ATG start codon within the coding exon; thus, only one isoform of the CysLT1 receptor exists in the human (35). Both isoforms of the CysLT1 receptor are expressed at the mRNA level in a variety of mouse tissues, including lung, skin, and small intestine. The gene for the mouse CysLT1 receptor maps to band XD, and the human gene maps to a syntenic region of chromosome X. Both isoforms of the mouse CysLT1 receptor and its single human counterpart bind LTD4 with high affinity (Kd ~ 1 nM), and bind LTC4 and LTE4 with progressively lower affinities (Table I).

The CysLT2 receptor arises from a single exon gene on human chromosome 13q14. The mouse orthologue arises from a gene containing 6 exons on chromosome 14, with the entire coding sequence in exon 6 (34). Two splice variants of the receptor exist in mice, whereas a single variant is described in humans (37). The mouse and human CysLT2 receptors both bind LTC4 and LTD4 with equal affinity (Kd ~10 nM). The human CysLT2 receptor mRNA is expressed in peripheral blood leukocytes, lymph nodes, spleen, heart, and several CNS regions (37, 39), a tissue distribution similar to that reported for the mouse CysLT2 receptor (34). In situ hybridization localized CysLT2 receptor mRNA to the adrenal medulla, as well as the cardiac Purkinje cells. Especially strong hybridization was noted in interstitial macrophages in the lung (37). Both HUVEC (40) and coronary smooth muscle cells (41) both express high levels of the CysLT2 receptor protein and mRNA, suggesting a prominent function for this receptor in vascular responses. A single nucleotide polymorphism in the human CysLT2 receptor was reported that results in the substitution of methionine for valine at amino acid residue 202. The resultant polymorphic receptor, when cloned and expressed heterologously, binds to LTD4 and the receptor-selective partial agonist, BAY-u9773, at 4-fold lower affinity than the wild-type receptor (42). The presence of this polymorphic CysLT2 variant conferred a substantially increased risk of atopy in inhabitants of Tristan da Cunha, a population characterized by both a founder effect and a high prevalence of atopy. The incompletely overlapping distributions and distinct ligand-binding properties of CysLT1 and CysLT2 receptors strongly suggest that they serve different functions in vivo. The existence of a third receptor for cys-LTs has been proposed on the basis of pharmacologic profiling studies of human pulmonary artery (43) and guinea trachea (30), although such a receptor has yet to be isolated and cloned.

When transfected into Xenopus oocytes, both CysLT1 and CysLT2 receptors use PTX-resistant Gq family proteins to initiate calcium flux (35, 37). HUVEC express both CysLT1 (44) and CysLT2 receptor transcripts (40), but CysLT2 receptors dominate and are exclusively responsible for LTC4-mediated calcium flux in this cell type (40). In contrast, CysLT2 receptors fail to contribute to the robust cys-LT-mediated calcium fluxes in human MCs, even though these cells also express both receptors (45, 46). Blockade of CysLT1 receptors also prevents cys-LT-mediated phosphorylation of ERK in human MCs, but does not affect p38 kinase phosphorylation or IL-8 secretion; the latter is inhibited by PTX (46). Stimulation of CysLT1 receptors in human bronchial smooth muscle cells initiates calcium flux and translocation of both calcium-dependent protein kinase C{alpha}, as well as calcium-independent protein kinase C{gamma}. Interestingly, sustained contraction of these smooth muscle cells in response to LTD4 does not require extracellular calcium, even though it is CysLT1 receptor-dependent (47). Thus, both CysLT1 and CysLT2 receptors can initiate signaling through more than one class of G proteins, and can induce both calcium-dependent and -independent events. These properties may vary depending on their relative levels of expression and the cell type involved.


   Involvement of cys-LTs and their receptors in acute asthma and the allergic response
Top
 Abstract
 Introduction
 cys-LT biosynthesis
 Molecular biology of the...
 Involvement of cys-LTs and...
Functions of the cys-LTs...
 Roles of cys-LTs and...
 Summary
 References
 
Historically, cys-LTs have been recognized for their powerful bronchoconstricting effects and their role in asthma exacerbations. When administered by inhalation to human subjects, LTE4 is substantially more potent than histamine in eliciting a decrease in airflow (48). Cys-LTs are present in bronchoalveolar lavage (BAL) fluid collected from atopic human subjects after endobronchial challenge with allergen (49), and levels of LTE4 were elevated in urine samples collected from patients presenting to the emergency room for treatment of asthma exacerbations (50). Both an orally administered inhibitor of 5-LO (51) and CysLT1 receptor-selective antagonists (52) were clinically efficacious in the treatment of humans with asthma. Pranlukast, one of the CysLT1 receptor antagonists, substantially attenuated both the early- and late-phase decrements in airflow in allergic asthmatic individuals challenged with allergen by inhalation (53). Orally administered CysLT1 receptor antagonists also attenuate bronchoconstrictive responses to challenges with exercise (54), cold air (55), and inhalation of adenosine (56). Intravenous administration of montelukast, a CysLT1 receptor-selective antagonist, substantially increased measures of airflow compared with placebo in a group of patients presenting to the emergency room with acute asthma who also received standard treatment with bronchodilators and glucocorticoids (57). Taken together, these observations confirm the involvement of cys-LTs in the development of airflow obstruction in both experimentally induced and naturally occurring asthma in humans, and with a prominent role for the CysLT1 receptor in exacerbations.


   Functions of the cys-LTs and their receptors in human inflammation
Top
 Abstract
 Introduction
 cys-LT biosynthesis
 Molecular biology of the...
 Involvement of cys-LTs and...
 Functions of the cys-LTs...
Roles of cys-LTs and...
 Summary
 References
 
Recruitment of effector leukocytes and in situ expression of CysLT1 and CysLT2 receptors.

In addition to bronchconstriction, endobronchial instillation of LTE4 into human subjects resulted in the subsequent influx of eosinophils, and to a lesser extent, neutrophils, into the BAL fluid (58), suggesting the capacity for cys-LTs to either directly or indirectly attract leukocytes to initiate inflammatory responses in vivo. A subsequent functional study revealed the expression of CysLT1 receptors, but not CysLT2 receptors, by human CD34+ peripheral blood-derived progenitor cells (59). cys-LTs induced transendothelial migration of these cells in vitro, suggesting a possible role for CysLT1 receptors in the regulation of hemopoietic progenitor cell trafficking. Importantly, while cys-LT-mediated calcium fluxes were completely blocked by pretreatment of the CD34+ progenitor cells with montelukast, this pretreatment with antagonist failed to block calcium fluxes in mature peripheral blood leukocytes, indicating that the CysLT2 receptor is acquired by leukocytes during hemopoietic development in vivo. Human peripheral blood monocytes (37, 60), eosinophils (61), and lung macrophages (35, 37) all express both CysLT1 and CysLT2 mRNA or protein. Priming of either human peripheral blood monocytes or monocyte-derived macrophages with recombinant human IL-4 or IL-13 increased their levels of CysLT1 receptor mRNA and protein expression, and enhanced their chemotactic responses to LTD4 in vitro (62). Similarly, CysLT1 receptor expression and chemotaxis to LTD4 in an eosinophilic subline of the human granulocytic leukemia cell line, HL60, were both enhanced by priming with rIL-5 (63). Both CysLT1 and CysLT2 receptors localized to eosinophils, mononuclear cells, and resident MCs in nasal biopsy tissue from humans with seasonal allergic rhinitis (64). In this study, the CysLT1 receptor, but not the CysLT2 receptor, also localized to a subset of lesional neutrophils. In another study, expression of the CysLT1 receptor was up-regulated on CD45+ leukocytes in nasal biopsy specimens obtained from subjects with aspirin-sensitive chronic rhinitis and nasal polyposis, compared with the same leukocyte subsets in biopsy specimens from non-aspirin-sensitive subjects with rhinitis and nasal polyposis (65). Taken together, these observations support the hypothesis that cys-LTs may serve as chemotactic mediators and/or activating ligands for human effector leukocytes, and that the cys-LT receptor expression profiles of certain leukocytes are modified by available cytokines and other microenvironmentally derived factors in inflammation. In vitro studies support the capacity for cys-LTs to serve as eosinophil chemoattractants through a CysLT1 receptor-dependent mechanism (66).

Induction of cytokine generation by eosinophils and MCs.

Although human eosinophils derived in vitro from umbilical cord blood mononuclear cells secrete IL-4 in response to cys-LTs in a CysLT1 receptor-dependent manner (67), this response was not observed in freshly isolated peripheral blood eosinophils (68). Instead, peripheral blood eosinophils secreted IL-4 in response to cys-LTs only after permeabilization. The secretion of IL-4 by permeabilized eosinophils in response to cys-LTs was sensitive to PTX, and occurred at log-fold lower doses of LTC4 than LTD4. This response profile is not compatible with the function of either the CysLT1 or CysLT2 receptor. Moreover, the pretreatment of peripheral blood eosinophils with MK886, an inhibitor of both FLAP and LTC4S, or with the 5-LO inhibitor AA861, inhibited their release of IL-4 in response to other transmembrane stimuli, such as IL-16, RANTES, or eotaxin. This study indicates an intracrine role for the cys-LTs, acting through an unidentified intracellular receptor, in activation-dependent signaling in eosinophils.

Like eosinophils, resident tissue MCs in nasal biopsies express both CysLT1 and CysLT2 receptors (64, 65). Human cord blood-derived MCs also express both receptors (45, 46), and respond to ex vivo stimulation by low nanomolar concentrations of LTC4 and LTD4 with strong, PTX-resistant calcium fluxes. As noted above, LTC4 and LTD4-mediated calcium fluxes were completely blocked by pretreatment of MCs with MK571, indicating an absolute requirement for CysLT1 receptors in this response. Priming these MCs with recombinant human IL-4 markedly shifted their dose-response curve to LTC4 (~3 log-fold enhancement) to a greater extent than their response to LTD4 (1.3 log-fold enhancement), but did not alter CysLT1 receptor mRNA or cell surface protein expression (45), and only modestly up-regulated cell surface CysLT2 protein (46). Unexpectedly, IL-4 also markedly enhanced calcium fluxes in response to UDP, a nucleotide ligand previously thought to be specific for a purinergic (P2Y) receptor termed P2Y6 (69). The calcium flux in response to UDP was MK571-sensitive and was cross-desensitized with LTC4, but only incompletely with LTD4. Chinese hamster ovary (CHO) cells stably expressing the long isoform of the mouse CysLT1 receptor also respond to UDP with an MK571-sensitive calcium flux (45). IL-4-primed MCs, but not unprimed replicates, secreted several cytokines (IL-5, TNF-{alpha}, MIP-1{beta}, and IL-8) when stimulated with either LTC4, LTD4, or UDP (46, 70). Of these cytokines, IL-8 was unique for the resistance of its secretion to blockade by MK571, indicating dependence on the CysLT2 receptor (70). Blockade of CysLT1 receptors by MK571, or inhibition of endogenous cys-LT production by MK886, significantly attenuated the generation of IL-5 and TNF-{alpha} by MCs activated by Fc{epsilon}RI cross-linkage (70). These studies indicate that the CysLT1 and CysLT2 receptors have distinct yet complementary functions for MCs, permitting cytokine generation through both autocrine and paracrine mechanisms. IL-4 could act by inducing the expression of an MK571-sensitive receptor for both LTC4 and UDP, or could alter the sensitivity and ligand specificity of constitutively expressed CysLT1 receptors by inducing posttranslational modification or heterodimerization with another receptor. Moreover, the induction of IL-5 generation by MCs is an additional mechanism by which cys-LTs could promote eosinophilia.


   Roles of cys-LTs and their receptors in animal models of inflammation
Top
 Abstract
 Introduction
 cys-LT biosynthesis
 Molecular biology of the...
 Involvement of cys-LTs and...
 Functions of the cys-LTs...
 Roles of cys-LTs and...
Summary
 References
 
Afferent limb of adaptive immunity: dendritic cell (DC) maturation and phenotype.

The role of cys-LTs and their receptors in immune responses, inflammation, and tissue repair in vivo has been assessed using both pharmacologic and genetic approaches in mice. Initial recognition that cys-LTs were involved in the maturation of DCs emerged from studies of DC migration in mice lacking MRP1, which is required for the export of LTC4 to the extracellular space after it is synthesized (15, 71). In a model of contact hypersensitivity induced by topical application of FITC, DC migration was substantially attenuated in MRP1-deficient mice as compared with that observed in wild-type controls (72). The migration defect was corrected by the injection of LTC4 or LTD4 after FITC application. Migration in wild-type controls was blocked by the local injection of MK571, which acts as an antagonist of MRP1 at 25-fold higher doses than those required to block the CysLT1 receptor (72). DCs from MRP1-deficient mice showed deficient ex vivo chemotactic responses to CCL19, a chemokine ligand specific for CCR7. Again, this defect was corrected by exogenous LTC4 and LTD4. In a subsequent study, myeloid DCs cultured ex vivo from mouse bone marrow were found to express CysLT1 receptor mRNA, as well as mRNAs encoding 5-LO, FLAP, and LTC4S (73). These DCs generated both IL-10 and IL-12 when challenged ex vivo with the dust mite Ag Der f. Treatment of these DCs with the CysLT1 receptor-selective antagonists montelukast, zafirlukast, and pranlukast significantly blunted their Der f-mediated production of IL-10, but further enhanced their production of Th1 cytokine IL-12. Moreover, whereas exogenous LTC4, LTD4, and LTE4 failed to directly elicit IL-10 or IL-12 generation by otherwise unstimulated DCs, each cys-LT amplified the Der f-mediated production of IL-10, and inhibited the generation of IL-12. Mice that received intranasal adoptive transfer of Der f-pulsed DCs that had been costimulated with LTD4 ex vivo developed enhanced eosinophilia and increased BAL fluid levels of IL-5 after inhalation challenge with Der f, compared with eosinophil counts and IL-5 levels in mice that received transfer of DCs that had been stimulated with Der f alone. Finally, mice that received Der f-pulsed DCs treated with pranlukast ex vivo and then challenged with Der f developed strikingly diminished BAL fluid levels of eosinophilia and IL-5, compared with the other groups. Taken together, these studies indicate that LTC4 produced endogenously by DCs (or provided exogenously by MCs or macrophages) during their initial exposure to Ag is a critical determinant of their homing to regional lymph nodes, and their repertoire of cytokines required to induce T cell responses. Either or both of these events, which depend at least in part on the CysLT1 receptor, may play an important role in the afferent limb of acquired immunity. These findings may help to explain the fact that DC migration in response to FITC is defective in 5-LO-deficient mice (72), which also develop significantly lower IgG and IgE responses to systemic immunization with OVA than do wild-type controls (74).

Allergen-induced pulmonary inflammation.

BALB/c mice sensitized with an i.p. injection of OVA precipitated with alum were challenged with intranasal administration of OVA. Twenty-four hours later, levels of LTC4 and LTB4 had increased 5- and 3.4-fold, respectively, in the BAL fluid of the challenged mice compared with the levels in the saline controls (75). These increases were associated with widespread mucus occlusion of the airways, an influx of predominantly eosinophils in airway tissues and BAL fluid, and airway hyperresponsiveness to i.v. methacholine. The i.p. administration of leukotriene synthetic inhibitors (zileuton or MK-886) 30 min before nasal Ag challenge reduced eosinophil infiltration in tissues and BAL fluid by ~85% and significantly blocked airway mucus release and plugging. In another study, the period of intranasal administration of OVA was extended to 75 days, so as to elicit smooth muscle hyperplasia and subepithelial fibrosis, characteristic features of airway remodeling in chronic asthma (76). In the chronic protocol, treatment with montelukast starting on day 26 significantly reduced the airway eosinophil infiltration, mucus plugging, collagen deposition, and smooth muscle hyperplasia, as determined on day 76. Levels of IL-13, IL-4, IL-10, and IL-5 mRNA were dramatically reduced in the lungs of the challenged montelukast-treated mice compared with placebo-treated challenged controls. Collectively, these studies indicate that cys-LTs, acting through the CysLT1 receptor, initiate features of chronic inflammation and matrix remodeling in allergen-induced pulmonary disease, possibly by stimulating cytokine generation by resident inflammatory cells. The smooth muscle hyperplasia in the chronic model could also reflect direct proliferative effects, because LTD4 is a mitogen for human bronchial smooth muscle cells when provided in vitro in combination with TGF {beta}, IL-13 (77), or epidermal growth factor (78). It is noteworthy, however, that airway hyperresponsiveness to methacholine was not affected by inhibition of cys-LT synthesis or the CysLT1 receptor in either model. Indeed, mouse bronchial smooth muscle does not constrict in response to cys-LTs (79, 80), and the airways of transgenic mice overexpressing the human CysLT1 receptor specifically in smooth muscle were hyperresponsive to LTD4, but not to methacholine (81).

Microvascular permeability.

Mice deficient in LTC4S (19) and the CysLT1 receptor (82) were generated by targeted gene disruption. Conjugation of LTA4 to reduced glutathione to form LTC4 was abolished in the brain, tongue, lung, spleen, stomach, and colon of LTC4S-deficient mice. The activity was spared in the testis, suggesting the contribution of another enzyme with a highly restricted tissue distribution. IgE-dependent LTC4 generation by bone marrow-derived MCs from the LTC4S-deficient mice was abolished, while LTB4 and PGD2 generation were unaffected. Plasma protein leakage after i.p. challenge with zymosan or IgE-dependent passive cutaneous anaphylaxis was reduced by ~50% in LTC4S-deficient mice compared with the wild-type controls. Decrements in plasma leakage in the CysLT1-deficient mice were comparable in magnitude to those in the LTC4S knockout mice. Collectively, these studies confirm the absolute requirement for LTC4S in cys-LT biosynthesis by immune effector cells in most organs and tissues, and indicate the prominent role of cys-LTs, acting through CysLT1 receptors, in mediating increased vascular permeability in models of both innate and adaptive immunity.

Because LTC4 is rapidly converted to LTD4 in extracellular fluids by either {gamma}-GT or the more functionally specific {gamma}-GL, mouse strains lacking either or both enzymes were studied in the zymosan-induced model of peritonitis. Shi et al. showed that i.p. injection of zymosan into {gamma}-GL-deficient mice and {gamma}-GT/{gamma}-GL double-deficient mice led to the accumulation of LTC4 in the peritoneal cavity, indicating that {gamma}-GL is the enzyme responsible for the conversion of LTC4 to LTD4 in this model (83). Plasma protein extravasation was not affected 1–24 h after zymosan injection, but neutrophil infiltration was significantly reduced 2–4 h after the injection in {gamma}-GL-deficient mice. These findings suggest that LTC4 does not require conversion to LTD4 to increase vascular permeability through the CysLT1 receptor, but that LTD4 may play a role in neutrophil recruitment. Surprisingly, however, neutrophil recruitment was not affected in either LTC4S- or CysLT1 receptor-deficient mice subjected to the zymosan-induced peritonitis model (19, 82).

Pulmonary fibrosis.

Intratracheal or systemic administration of the chemotherapeutic agent bleomycin induces chronic pulmonary inflammation and fibrosis in mice. These features were significantly blunted with respective disruptions of cPLA2 (84) and 5-LO (85), suggesting a role for leukotrienes in this model. Several features of bleomycin-induced injury, including pulmonary macrophage and neutrophil recruitment, alveolar septal thickening, fibroblast accumulation, and collagen deposition were significantly reduced in LTC4S-deficient mice compared with their wild-type littermates (86). Unexpectedly, CysLT1 receptor-deficient mice were not protected from this injury; instead, these mice showed exaggerated alveolar septal thickening with reticular fiber deposition when compared with wild-type or LTC4S-deficient mice. Additionally, cys-LT levels in the BAL fluids of the CysLT1 receptor-deficient mice were roughly 2-fold greater than the levels recovered from the wild-type mice, with no change in the levels of LTB4 or PGE2. These results suggest that the cys-LTs are crucial to this macrophage-mediated chronic inflammatory and fibrotic insult, likely working through the CysLT2 receptor. Because CysLT2 receptor-deficient mice have not been reported, the direct role for the CysLT2 receptor in bleomycin-induced pulmonary inflammation and fibrosis remains to be elucidated.


   Summary
Top
 Abstract
 Introduction
 cys-LT biosynthesis
 Molecular biology of the...
 Involvement of cys-LTs and...
 Functions of the cys-LTs...
 Roles of cys-LTs and...
 Summary
References
 
cys-LTs, initially thought to be restricted in their functions to acute, smooth muscle-mediated responses, clearly serve a diverse array of biologic functions (summarized in Fig. 2). The cloning of their two receptors, development of receptor-specific Abs, CysLT1 receptor-selective antagonists, and null mice lacking biosynthetic enzymes and the CysLT1 receptor have all expanded the scope of functions served by this mediator class. The involvement of cys-LTs in the afferent limb of adaptive immunity (particularly the induction of Th2 responses in the lung via effects on DCs and cytokine generation), the recruitment and/or activation of effector cells (especially eosinophils and MCs), inflammation, and fibrosis have all been supported by animal models and await validation in humans. Moreover, the prominent expression of the CysLT2 receptor in the brain, adrenals, heart, and vascular endothelium suggests additional unrecognized functions of cys-LTs. Studies in this area await the development of CysLT2 receptor-deficient mice. Based on these observations, the scope of therapeutic applications for agents that alter cys-LT generation or reception are likely to expand.



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  		FIGURE 2. Recognized bioactivities of the cys-LTs and the receptor(s) responsible for each.

 


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by National Institutes of Health Grants AI-48802, AI-52353, AI-31599, and HL-36110, and by grants from the Charles Dana Foundation, the Vinik Family Fund for Research in Allergic Diseases, and the Hyde and Watson Foundation. Back

2 Address correspondence and reprint requests to Dr. Joshua A. Boyce, One Jimmy Fund Way, Smith Building Room 626, Boston, MA 02115. E-mail address: jboyce{at}rics.bwh.harvard.edu Back

3 Abbreviations used in this paper: LT, leukotriene; cys-LT, cysteinyl LT; CysLT1 receptor, type 1 receptor for cys-LT; CysLT2 receptor, type 2 receptor for cys-LT; MC, mast cell; cPLA2, cytosolic phospholipase A2; 5-LO, 5-lipoxygenase; FLAP, 5-LO-activating protein; LTC4S, LTC4 synthase; MRP1, multidrug resistance protein 1; {gamma}-GT, {gamma}-glutamyl transpeptidase; {gamma}-GL, {gamma}-glutamyl leukotrienase; PTX, pertussis toxin; BAL, bronchoalveolar lavage; DC, dendritic cell. Back

Received for publication May 18, 2004. Accepted for publication May 25, 2004.


   References
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 Abstract
 Introduction
 cys-LT biosynthesis
 Molecular biology of the...
 Involvement of cys-LTs and...
 Functions of the cys-LTs...
 Roles of cys-LTs and...
 Summary
 References
 

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