The Journal of Allergy and Clinical Immunology
Volume 111, Issue 1 , Pages 24-32, January 2003

Mast cells: Beyond IgE☆☆☆

Division of Rheumatology, Immunology, and Allergy, Harvard Medical School, Brigham and Women's Hospital, Boston. Boston, Mass

Received 7 October 2002; accepted 16 October 2002.

Article Outline

Abstract 

Continuing Medical Education examination

CONTINUING MEDICAL EDUCATION ARTICLE Credit can now be obtained, free for a limited time, by reading the following review. Please note the instructions listed below. Method of Physician Participation in Learning Process: The core material for this activity can be read in this issue of the Journal or online at the JACI Web site: www.mosby.com/jaci . The accompanying test may only be submitted online at www.mosby.com/jaci . Fax or other copies will not be accepted. Date of Original Release: January 2003. Credit may be obtained for this course until December 31, 2003. Copyright Statement: Copyright © 2003-2004. All rights reserved. List of Design Committee Members: Authors: Donald Y. M. Leung, MD, PhD, FAAAAI, John W. Bloom, MD Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Activity Objectives (a) To understand the molecular mechanisms of glucocorticoid action. (b) To recognize potential mechanisms of glucocorticoid resistance. (c) To review evaluation and management of patients with glucocorticoid resistance. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma and Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this educational activity for up to 1.0 hour in Category I credit towards the AMA Physician's Recognition Award. Each physician should claim only those hours of credit he or she actually spent in the educational activity. Recognition of Commercial Support: This activity has been funded through an unrestricted educational grant from GlaxoSmithKline.

Keywords:  Mast cells, IL-4, cysteinyl leukotrienes, cysteinyl leukotriene 1 receptor, uridine diphosphate

Abbreviations:  AA , Arachidonic acid, CysLT , Cysteinyl leukotriene, FLAP , 5-Lipoxygenase activating protein, GPCR , G protein-coupled receptor, 5-LO , 5-Lipoxygenase, LT , Leukotriene, LTC4S , Leukotriene C4 synthase, PG , Prostaglandin, TLR , Toll-like receptor, UDP , Uridine diphosphate

 

Mast cells, historically known for their involvement in type I hypersensitivity, also serve critical protective and homeostatic functions. They directly recognize the products of bacterial infection through several surface receptor proteins, releasing proteases, cytokines, and eicosanoid mediators that recruit neutrophils, limit the spread of bacterial infection, and facilitate subsequent tissue repair. In vitro studies suggest that the spectrum of microbes capable of initiating mast cell activation is broad and extends to common respiratory viruses, mycoplasma, and even products of tissue injury, such as nucleotides. TH2-polarized inflammation elicits a reactive hyperplasia of mast cells at the involved mucosal surfaces in both mice and human subjects. Several recombinant TH2 cytokines (IL-3, IL-4, IL-5, and IL-9) act synergistically with stem cell factor to facilitate proliferation of nontransformed human mast cells in vitro. IL-4 induces the expression of critical inflammation-associated genes by human mast cells, such as those encoding leukotriene C4 synthase, FcϵRI, and several cytokines. Consequently, priming with IL-4 not only amplifies classical FcϵRI-dependent mast cell activation but also dramatically alters the product profile of mast cells activated by innate signals and by chemical mediators of inflammation. Strikingly, IL-4 induces an activation response by mast cells to cysteinyl leukotrienes, which act through a receptor shared with uridine diphosphate to induce cytokine generation without exocytosis. It is possible that alterations in mast cell phenotype by the TH2 milieu of allergy permits otherwise trivial infections or homeostatic chemical signals to initiate harmful inflammatory cascades and sustain tissue pathology. Drug development must take these nonclassical mast cell activation pathways into account without compromising the beneficial and protective functions of mast cells. (J Allergy Clin Immunol 2003;111:24-32.)

Mast cells are distributed widely throughout mammalian tissues, especially the perivascular spaces and connective tissues of the skin, gut, and respiratory and gastrointestinal tracts.1 Cross-linkage of FcϵRI elicits the release of preformed inflammatory mediators from mast cell secretory granules (including histamine, neutral proteases, preformed cytokines, and proteoglycans).2 The same stimulus triggers rapid synthesis and release of lipid mediators that are the products of endogenous arachidonic acid (AA) metabolism, such as prostaglandin (PG) D2, leukotriene (LT) B4, and LTC4, the parent molecule of the cysteinyl LTs (cysLTs) LTC4, LTD4, and LTE4.3, 4, 5, 6, 7 Activated mast cells also synthesize and secrete several proinflammatory, chemoattractive, and immunomodulatory cytokines over a period of several hours.8, 9, 10 The diverse profile of chemical mediators generated and released by activated mast cells leads to plasma extravasation, tissue edema, bronchoconstriction, leukocyte recruitment, and mucosal inflammation, which result from allergen exposure in sensitized hosts. IgE-dependent mast cell activation is a prominent mechanism in a substantial number of diseases treated by allergists, including anaphylaxis, urticaria, angioedema, and acute exacerbations of asthma and rhinoconjunctivitis.

The firmly established role of mast cells and their products in allergic (type I) hypersensitivity contrasts with the comparatively sparse knowledge, until recently, of their physiologic functions and their role in nonallergic diseases. The prominence of lesional mast cells in multiple sclerosis,11 cardiomyopathy,12 rheumatoid arthritis,13, 14 and a number of other chronic inflammatory and fibrotic diseases in human subjects15, 16, 17 suggested mast cell involvement. The critical importance of mast cells in many of these diseases has recently been validated by animal models (Table I).11, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27

Table I. Physiologic and pathophysiologic roles of mast cells
PhysiologicPathophysiologic
Antibacterial21, 22Allergy, asthma27
Antihelminthic25, 26Fibrosis16, 17
Wound healing24Rheumatoid arthritis13, 14, 18
Angiogenesis23Multiple sclerosis11, 20
Congestive heart failure19

Involvement in both normal host defense and in the indicated diseases are strongly inferred by animal models, by human studies, or both.

It is now clear that mast cells receive and integrate a wide array of non–IgE-driven chemical signals from their environment, permitting mobilization of their effector properties. Moreover, mast cells use these same activation mechanisms and effector properties to serve protective and homeostatic functions. The extent of mast cell involvement in both allergic and nonallergic disease, as well as host defense, is likely far greater than would be predicted strictly on the basis of studies of classical IgE-dependent immune responses. This article will review recent progress in mast cell biology, as well as the potential implications for disease pathophysiology and therapy.

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Divergent pathways of mast cell development: The concept of T cell–dependent and T cell–independent populations belonging to a single lineage 

Mast cells are unique among granulated hematopoietic cells for their exclusive and normal residence in all vascularized tissues. Unlike other such cells, mast cells exit the bone marrow as committed progenitors with sparse secretory granules.28, 29, 30 The subsequent development of these progenitors into mature mast cells requires input from constitutive signals that dictate their trafficking from the circulation, their survival, and their maturation. The basal homing of these progenitors to the gut, but not to other tissues, is profoundly deficient in mice lacking the β7 integrin subunit,31 which pairs with the α4 integrin subunit to form a heterodimer that interacts with both mucosal addressin cell adhesion molecule 1 and vascular cell adhesion molecule 1 (Fig 1).

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  • Fig. 1. 

    Constitutive versus reactive tissue mast cell development on the basis of the prototype of the intestine. Basal homing of blood-borne committed mast cell progenitors (PrMC) depends on the intact function of the β7 integrin subunit forming a heterodimer with the α4 integrin subunit that interacts with mucosal adressin cell adhesion molecule 1 (MadCAM1) and vascular cell adhesion molecule 1 (VCAM1) . Differentiation of all mast cells requires the input of SCF and its receptor, c-kit. Development of the reactive subtype, observed in the epithelial compartment in mucosal inflammation, requires additional cytokines derived from activated T cells. The subtypes differ in protease content and effector profile. CPA, Carboxypeptidase A.

The most critical viability and differentiation signal for mast cells is provided by the interaction between the membrane-associated receptor tyrosine kinase c-kit,32 which is strongly expressed by mast cells throughout their life cycle, and its ligand, stem cell factor (SCF),33 a growth factor that is expressed constitutively by endothelial cells, fibroblasts, and other stromal cells. Tissue mast cells frequently juxtapose with the stromal cells that produce SCF, likely reflecting the SCF/c-kit interaction in vivo. Under experimental circumstances, membrane-bound SCF, its soluble isoform, or both are chemotactic for mast cells and their progenitors,34 elicit their adhesion,35 facilitate their proliferation,36 and sustain their survival, differentiation, and maturation.37, 38 The critical requirement for the SCF/c-kit interaction in normal mast cell development is confirmed by the mast cell deficiencies manifested by mouse strains lacking the normal function of either c-kit (W/Wv strain)39 or the membrane-bound isoform of SCF (Sl/Sld strain).40 Thus the widespread constitutive expression of SCF and the presence of the c-kit receptor at all stages of mast cell development ensure the presence of mast cells in tissues under normal conditions.

What is the evolutionary purpose of constitutive populations of mast cells? Mast cells likely normally serve both protective and homeostatic functions under basal conditions. Compared with normal congenic control mice, mast cell–deficient W/Wv mice exhibit poor survival rates when experimentally subjected to septic peritonitis or gram-negative pneumonia because they lack the capacity to efficiently recruit neutrophils to the infected tissue.21, 22 Both survival and neutrophil recruitment are restored to normal levels by means of transplantation of histocompatible mast cells into the W/Wv mice. These observations prompted studies revealing that mast cells express several receptors (toll-like receptor [TLR] 4, TLR2, CD48, and complement receptor 1)41, 42, 43, 44 that recognize microbes and their products through direct pattern recognition. Such receptors can activate mast cells without requirements for antibody or immunologic education (ie, innate immunity). In innate immune responses mast cells generate several mediators (TNF-α, tryptases, and LTB4) that recruit neutrophils by means of distinct mechanisms.21, 22, 41, 42, 45, 46, 47 Recently, mouse mast cells were activated in vitro by the Stapylococcus aureus peptidoglycan in a TLR2-dependent manner,22 as well as by Mycoplasma pneumoniae 48 and the cutaneous parasites Leishmania major or Leishmania infantum ,49 for which the respective responsible receptor or receptors on mast cells are not yet identified. It is noteworthy that β tryptases, which are among the mast cell products likely involved in neutrophil recruitment,45 also stimulate angiogenesis,23 epithelial cell proliferation,47 type I collagen production by fibroblasts,50 and bronchial smooth muscle proliferation.51 These properties might relate to a role for mast cells in wound healing, as implicated in some experimental models,24, 52 and in fibrosis and tissue remodeling in various diseases. Thus constitutive mast cells are specialized to receive danger signals through pattern recognition and to generate mediators involved both in the protective neutrophil response and in subsequent repair and healing. Such functions are teleologically consistent with the apparent strategic localization of mast cells in the skin and the gastrointestinal, respiratory, and genitourinary tracts, which are subject to both frequent trauma and potential infectious insults.

Although the SCF/c-kit interaction maintains relatively stable numbers of mast cells within connective tissue matrices, mast cell numbers in gastrointestinal, genitourinary, and respiratory mucosal epithelial surfaces (commonly referred to as mucosal or reactive mast cells, Fig 1) can fluctuate widely. Under normal conditions, there are few mast cells in these locations, but their numbers increase markedly in mucosal inflammation. Intestinal helminthic infections, which elicit a prototypical TH2-polarized adaptive immune response, give rise to a profound intraepithelial mastocytosis.53 This mastocytosis is critical to the elimination of most helminthic worms and resolves after worm clearance. As with constitutive mast cell development, reactive mast cell hyperplasia at mucosal surfaces requires the normal interaction of c-kit and SCF.39 However, reactive intraepithelial mast cells differ from their constitutive counterparts in their additional requirement for T-lymphocyte function.25 Athymic nude mice, which lack functional T cells, lack the capacity to mount a reactive intraepithelial mast cell hyperplasia in response to helminth infections.25 Similarly, human subjects with profound lymphopenia caused by HIV infection lack mast cells in the intestinal epithelium.54 In both human subjects and mice, T-cell deficiency has no effect on constitutive and connective tissue-associated mast cells. Thus mast cell development, at least in the intestine, can be viewed as a dichotomous process that occurs in T cell–dependent (reactive) and T cell–independent (constitutive) compartments (Fig 1). On the basis of selective antibody blockade or gene knockout strategies, IL-3 and IL-4 are especially critical in supporting helminth-induced reactive mast cell hyperplasia in the mouse intestine.26, 55 Another TH2 cytokine, IL-9, induces profound intraepithelial mast cell hyperplasia when overexpressed in the lungs or guts of mice.56 Thus reactive intraepithelial mast cell hyperplasia, which is required for the elimination of helminthic parasites, reflects T cell–dependent modulation of mast cell development through several cytokines. The fact that the reactive mast cells arising during helminth infection exhibit striking alterations in their granule ultrastructure and protease content57 suggests that T-cell cytokines induce alterations in the expression of genes that are involved in the mast cell–dependent elimination of helminths.

Is the paradigm of constitutive versus T cell–dependent reactive mast cell development pertinent to human allergic diseases? Immune responses to helminth infection share mechanistic and histologic features in common with human allergic diseases, including prominent expression of TH2 cytokines, IgE synthesis, and local eosinophilia. Asthma, allergic rhinitis, and allergic esophagitis are each also associated with increased numbers of mast cells within the involved mucosal epithelial surfaces.58, 59, 60, 61 The histopathology of asthma is also characterized by an additional increase in the numbers of mast cells within the bronchial smooth muscle layer.27 The numbers of mast cells in this layer correlate with indices of airway hyperresponsiveness and distinguish the histopathology of asthma from that of eosinophilic bronchitis, a disease process with an otherwise similar pattern of mucosal inflammation. Several human TH2 cytokines (IL-3, IL-4, IL-5, IL-6, and IL-9) can support the survival of human mast cells in vitro,62 synergistically stimulate their proliferation when provided in combination with SCF,63, 64, 65 or both. Conversely, the TH1 cytokine IFN-γ inhibits SCF-dependent proliferation of cultured human mast cells,63, 66 while inducing their expression of the high-affinity receptor for IgG, FcγRI.67 These observations support the hypothesis that in human allergic mucosal inflammation, mast cell numbers (and very likely key aspects of their function) are under T-cell control, just as they are in the mouse intestine during helminth infection.

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AA metabolism: A marker of mast cell phenotype and T-cell modulation? 

The cysLTs and PGD2 secreted by mast cells act through specific 7 transmembrane–spanning G protein–coupled receptors (GPCRs)68, 69, 70, 71 to elicit powerful vasoactive and bronchoactive effects. CysLTs are especially powerful bronchoconstrictors72, 73 and elicit bronchial eosinophilia,74 edema,75 and mucous hypersecretion76 when instilled into the human lung in vivo. Recent experimental evidence from a mouse model of allergic airway disease implicates the cysLTs in the development of bronchial smooth muscle hyperplasia and submucosal collagen deposition,77 2 features of airway remodeling in asthma. CysLTs act through at least 2 GPCRs, termed the CysLT1 and CysLT2 receptors, respectively.70, 71 Both the 5-lipoxygenase (5-LO) inhibitor zileuton, which interferes with cysLT synthesis,78 and CysLT1 receptor antagonists79 improve lung function in asthmatic subjects compared with placebo. CysLT1 receptor antagonists also attenuate both early- and late-phase pulmonary responses to inhaled allergen in asthmatic subjects.80 These clinical studies confirm the involvement of cysLTs and at least one of their receptors in human asthma.

Although mast cells from all human tissues studied generate abundant PGD2 after FcϵRI cross-linkage, there is striking tissue-to-tissue heterogeneity in the quantity of cysLTs generated. For example, mast cells isolated from normal human skin (which are immunohistochemically similar to the constitutive mast cell subset in intestine and lung) generate an average of 3.5 ng of cysLTs/106 cells when stimulated by means of IgE receptor cross-linking,81 whereas those isolated from the human lung, intestine, or uterus generate roughly 10 times more.82, 83, 84, 85 These observations suggest that the cysLT-producing ability of human mast cells is regulated by tissue-specific factors. Perturbations in these regulatory processes could underlie the observation that endobronchial allergen challenge results in 10- to 20-fold higher levels of cysLTs from subjects with asthma than from subjects with allergic rhinitis alone86 and could be a key determinant of the development and severity of asthma and other diseases.

CysLT generation by mast cells and other immune cell types depends on the intact function of the 5-LO/LTC4 synthase (LTC4S) metabolic pathway. Calcium influx subsequent to cell activation permits phospholipase A2 to liberate AA from cell membrane phospholipids.87 AA is then converted sequentially to 5-hydroperoxyeicosatetraenoic acid and then to LTA4 by 5-LO, which is reversibly translocated to the perinuclear envelope88 and requires the additional presence of 5-LO activating protein (FLAP)89 for its catalytic function. LTA4 is then either converted through an LTA4 hydrolase to LTB490 (as occurs dominantly in neutrophils) or is conjugated to reduced glutathione by LTC4S,91 an integral membrane protein with homology to FLAP, forming LTC4 (as occurs dominantly in mast cells, basophils, and eosinophils). LTC4, the parent compound of the cysLTs, is then exported to the extracellular space by a distinct, carrier-mediated step92 and is sequentially converted to the receptor-active metabolites LTD4 and LTE4 by extracellular enzymes.93 The gene encoding the terminal enzyme, LTC4S , is located on chromosome 5q35,94 telomeric to the sites containing the TH2 cytokine gene cluster, the β2 adrenergic receptor, and the glucocorticoid receptor. A commonly occurring single-nucleotide polymorphism consisting of an A to C substitution at base −444 in the 5′ untranslated region of the gene encoding LTC4S gives rise to a consensus binding sequence for the histone H4 transcription transcription factor.95 Heterozygosity for this polymorphism is overrepresented among individuals with aspirin-sensitive asthma in some,95, 96 but not all,97 ethnic populations. In one study peripheral blood eosinophils from asthmatic subjects who were heterozygous for the polymorphic LTC4S allele exhibited greater ionophore-induced cysLT synthesis than did eosinophils from subjects who were homozygous for the wild-type allele.98 In this study the presence of the polymorphic LTC4S allele also predicted a more favorable clinical response to CysLT1 receptor antagonists.

Could the heterogeneity of cysLT-generating capacity in mast cells reflect T-cell control of the 5-LO/LTC4S pathway? Such control is suggested by studies of primary cultured human mast cells derived in vitro from umbilical cord blood mononuclear cells in medium supplemented with SCF, IL-6, and IL-10. When stimulated by means of FcϵRI cross-linkage, such mast cells generate few cysLTs but produce nanogram quantities of PGD2. Exposure of these mast cells for 5 days to IL-4 resulted in a 27-fold increase in cysLT production, with only a 2-fold increase in PGD2 generation. The selective enhancement of cysLT-producing ability likely reflected 2 events. First, IL-4 priming upregulates the expression of FcϵRI on the surface of cord blood–derived mast cells,99 enhancing the strength of the activation signal in response to FcϵRI cross-linkage. Second, priming with IL-4 profoundly and rapidly (within hours) induces the expression of LTC4S mRNA and protein by human mast cells,100 thus increasing the available activity of the terminal enzyme necessary for the conversion of LTA4 to LTC4. Additional cytokine control of the 5-LO/LTC4S pathway is introduced by priming with either IL-3 or IL-5, which each induce a nuclear import of pre-existing cytosolic 5-LO stores.100 The combination of either IL-3 or IL-5 with IL-4 markedly augments FcϵRI-mediated cysLT generation by cord blood–derived mast cells (to approximately 30 ng/106 cells), without a corresponding effect on PGD2 generation. Thus TH2 cytokines act nonredundantly at proximal (5-LO) and distal (LTC4S) control points of the 5-LO/LTC4S pathway to amplify the capacity of mast cells to generate cysLTs in response to FcϵRI cross-linkage. IL-4 and IL-5 both also prime mast cells for enhanced FcϵRI-dependent cytokine generation.101 It thus seems likely that cytokines prominently expressed in asthma not only control mast cell numbers but can also alter several mast cell effector properties, which in turn could regulate the magnitude of IgE-dependent early and late asthmatic responses and the clinical severity of asthma.

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Cyslts, nucleotides, and IL-4: convergence at the mast cell and a novel activation mechanism 

The CysLT1 and CysLT2 receptors map to different chromosomes (X and 13 in human subjects, respectively), bear essentially no nucleotide sequence homology, and have only 37% amino acid identity. These 2 receptors also differ in their respective ligand-binding preferences. The CysLT1 receptor binds LTD4 approximately 10-fold more avidly than it binds LTC4, whereas the CysLT2 receptor has equal affinity for both ligands.70, 71 LTE4, the least potent cysLT in vivo, binds weakly to both cysLT receptors. On the basis of ex vivo pharmacologic profiling of guinea pig lung tissues, the existence of a third, LTC4-preferring cysLT receptor has been proposed,102, 103 although such a receptor has not yet been isolated or cloned. Both of the known cysLT receptors are loosely homologous (24%-32% amino acid sequence identity) to the purinergic (P2Y) receptors, a family of widely expressed GPCRs that bind extracellular nucleotides.104 Nucleotide ligands are released from cells as a result of cellular injury and microbial invasion and could thus serve as innate danger signals. Proved functions for P2Y receptors consistent with their roles in responses to tissue injury include ADP-induced platelet activation (through the P2Y2 and P2Y12 receptors),105 ATP-dependent amplification of pain perception to tissue trauma (through the P2Y1 receptor),106 and uridine diphosphate (UDP)–induced macrophage activation (through the P2Y6 receptor).107 The UDP-selective P2Y6 receptor shares several regions of sequence identity with the CysLT1 receptor, including 8 of 10 identical amino acids in their respective first extracellular domains.108 Like the cysLT receptors, the distribution of P2Y6 includes smooth muscle.109 Evolutionary and functional relationships between the cysLT and P2Y receptor classes is supported by the surprising observation that the mouse CysLT1 receptor, like the P2Y6 receptor, binds and transduces a calcium flux in response to UDP when expressed in a heterologous cell line. This UDP response was blocked by the competitive CysLT1 receptor antagonist MK571, which does not interfere with the P2Y6 receptor.108 UDP-induced activation of both immune and nonimmune cells bearing CysLT1 or P2Y6 receptors could thus provide part of the cellular danger-sensing system operative in circumstances of infection or tissue injury.

Although pharmacologic studies of the cysLT receptors have traditionally focused on smooth muscle, the fact that several blood-borne cells71, 110 also express these receptors suggests potential immune functions. Cultured cord blood–derived human mast cells express CysLT1 receptor mRNA and the corresponding membrane protein and respond to both LTD4 and LTC4 with the anticipated dose-dependent calcium response (with a median effective concentration of approximately 10−9 and 10−8 for LTD4 and LTC4, respectively).108 Priming of these mast cells with IL-4 shifted the dose-response curve for LTD4 by 10-fold but enhanced the sensitivity to both LTC4 and UDP by 1000-fold; the latter 2 agonists exhibited complete cross-desensitization in a calcium flux assay, confirming their use by a shared receptor.108 Additionally, LTC4, LTD4, and UDP each induced TNF-α, macrophage inflammatory protein 1β, and IL-5 production by IL-4–primed mast cells through a mechanism dependent on nuclear factor of activated T cells transcription factors and extracellular regulated kinase (Fig 2).111

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  • Fig. 2. 

    Regulatory effects of IL-4 on biosynthesis and reception of cysLTs by mast cells. Human mast cells express the CysLT1 receptor constitutively, which transduces a calcium flux to both cysLTs and UDP. With IL-4 priming, both LTC4 and UDP elicit mast cell activation at 3 log-fold lower doses and elicit cytokine generation through a nuclear factor of activated T cells– and extracellular regulated kinase–dependent pathway, without exocytosis. The priming effect occurs without changes in CysLT1 receptor expression. IL-4 priming also upregulates FcϵRI-dependent generation of cysLTs by inducing LTC4S expression. Autocrine actions of cysLTs are indicated by partial antagonism of FcϵRI-dependent cytokine generation by the CysLT1 receptor selective antagonist MK571 and by MK886, a biosynthetic inhibitor. MIP, Macrophage inflammatory protein.

Importantly, cysLT- and UDP-induced cytokine generation occurred without morphologic or biochemical evidence of degranulation. Pretreatment of the primed mast cells with either MK571 or MK886 (an inhibitor of FLAP and LTC4S) also attenuated the generation of IL-5 and TNF-α in response to FcϵRI cross-linkage by approximately 30%, indicating an autocrine function for cysLTs in classical IgE-dependent mast cell activation. Despite its striking priming effect for cysLT-mediated mast cell activation, IL-4 did not alter the levels of CysLT1 receptor protein or mRNA; moreover, the complete inhibition by the selective CysLT1 receptor antagonist MK571 indicated no involvement of the CysLT2 receptor. Whether IL-4 induces expression of a novel, MK571-senstive third CysLT receptor (“CysLT3” receptor, Fig 2) or works by an alternate mechanism to enhance the sensitivity of mast cells to cysLTs and UDP is not presently known. The overlapping purinergic-cysLT receptor system is thus an example of a TH2-modulated pathway for mast cell activation. The fact that IL-4 priming permits human intestinal mast cells to generate IL-5 in response to stimulation by Escherichia coli 112 suggests that the TH2 milieu alters mast cell function downstream of additional innate activation mechanisms. Cytokine-dependent amplification of innate receptor-mediated mast cell activation pathways would thus facilitate tissue inflammation during infections or tissue injury. In such a context mast cells could elicit these tissue changes with no morphologic evidence of degranulation. Indeed, given their capacity to secrete cytokines without undergoing exocytosis, it is possible that traditional light microscopy underestimates the true contribution of mast cells in tissue pathology.

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Implications of mast cells for health and disease 

The unique anatomic distribution of mast cells, their diverse effector repertoire, their ability to multiply and undergo functional changes in response to T cell–derived signals, and the expanding list of microbes and natural agonists for their activation presents a therapeutically relevant interface between innate and adaptive immunity. The constitutive SCF/c-kit axis provides basal populations of mature mast cells in connective tissues, as well as an ongoing supply of committed mast cell progenitors (Fig 1). The normal function of mast cells as sensors of infection and injury through innate recognition receptors and their response to these signals both limits the potential spread of infection (by recruiting neutrophils) and facilitates wound healing (through actions on fibroblasts and other connective tissue elements, Fig 3).

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  • Fig. 3. 

    Hypothetic consequences of non–IgE-dependent activation of constitutive and reactive mast cell phenotypes. Under baseline conditions, mast cell activation by microbes, toxins, and humoral factors elicits neutrophil recruitment, contains invasive pathogens, and facilitates tissue healing. Under conditions of T-cell priming (particularly IL-4) in asthma and allergic diseases, the same activating stimuli produce an amplified mast cell response, resulting in sustained inflammation, tissue dysfunction, and remodeling.

In the context of TH2-polarized mucosa inflammation, cytokines transduce growth and survival signals to mast cells and their progenitors and alter their profile of gene expression. These alterations both expand the repertoire of mast cell effector mediators (cytokines and cysLTs) and lower their threshold for activation by both IgE-dependent and non–IgE-dependent mechanisms. These mechanisms for phenotypic modification of mast cells might have evolved as a result of pressures exerted by helminth infection. They very likely contribute to functional alterations in mast cells in the tissues of allergic individuals. It is possible that these alterations render mast cells capable of triggering sustained or deleterious inflammatory responses in response to otherwise innocuous stimuli. Indeed, the potential for microbes to elicit or exacerbate allergic mucosal inflammation directly through direct activation of reactive phenotypically altered mast cells is a fascinating possibility that requires further investigation. Under such circumstances, the mast cell effector systems normally specialized to protect against pathogens and heal tissue could lead instead to perpetuation of inflammation, fibrosis, angiogenesis, and tissue remodeling (Fig 3). The potential to modify mast cell phenotypes and attenuate their disease-related activation without compromising their beneficial protective and housekeeping functions would appear to be one of the challenges in future drug development.

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References 

  1. Stevens RL, Austen KF. Recent advances in the cellular and molecular biology of mast cells. Immunol Today. 1989;10:381–386
  2. Castells M, Schwartz LB. Tryptase levels in nasal lavage fluid as an indicator of the immediate allergic response. J Allergy Clin Immunol. 1988;82:348–355
  3. O'Sullivan S, Dahlen B, Dahlen SE, Kumlin M. Increased urinary excretion of the prostaglandin D2 metabolite 9 alpha, 11 beta-prostaglandin F2 after aspirin challenge supports mast cell activation in aspirin-induced airway obstruction. J Allergy Clin Immunol. 1996;98:421–422
  4. Casale TB, Wood D, Richerson HB, Zehr B, Zavala D, Hunninghake GW. Direct evidence of a role for mast cells in the pathogenesis of antigen-induced bronchoconstriction. J Clin Invest. 1987;80:1507–1511
  5. Schulman ES, Kagey-Sobotka A, MacGlashan DW, et al.  Heterogeneity of human mast cells. J Immunol. 1983;131:1936–1941
  6. Mencia-Huerta JM, Razin E, Ringlet WE, et al.  Immunologic and ionophore-induced generation of leukotriene B4 from mouse bone marrow-derived mast cells. J Immunol. 1983;130:1885–1890
  7. Lewis RA, Austen KF, Drazen JM, Clark DA, Marfat A, Corey EJ. Slow-reacting substance of anaphylaxis: identification of leukotrienes C-1 and D from human and rat sources. Proc Natl Acad Sci U S A. 1980;77:3710–3714
  8. Okayama Y, Petit-Frere C, Kassel O, et al.  IgE-dependent expression of mRNA for IL-4 and IL-5 in human lung mast cells. J Immunol. 1995;155:1796–1808
  9. Toru H, Pawankar R, Ra C, Yata J, Nakahata T. Human mast cells produce IL-13 by high-affinity IgE receptor cross-linking: enhanced IL-13 production by IL-4-primed human mast cells. J Allergy Clin Immunol. 1998;102:491–502
  10. Kobayashi H, Okayama Y, Ishizuka T, Pawankar R, Ra C, Mori M. Production of IL-13 by human lung mast cells in response to Fcϵ receptor cross-linkage. Clin Exp Allergy. 1998;28:1219–1227
  11. Ibrahim MZ, Reder AT, Lawand R, Takash W, Sallouh-Khatib S. The mast cells of the multiple sclerosis brain. J Neuroimmunol. 1996;70:131–138
  12. Arbustini E, Gavazzi A, Dal Bello B, et al.  Ten-year experience with endomyocardial biopsy in myocarditis presenting with congestive heart failure: frequency, pathologic characteristics, treatment and follow-up. Gior Ital Cardiol. 1997;27:209–223
  13. Gotis-Graham I, McNeil HP. Mast cell responses in rheumatoid synovium. Association of the MCTC subset with matrix turnover and clinical progression. Arthritis Rheum. 1997;40:479–489
  14. Woolley DE, Tetlow LC. Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion. Arthritis Res. 2000;2:65–74
  15. Algermissen B, Hermes B, Feldmann-Boeddeker I, Bauer F, Henz BM. Mast cell chymase and tryptase during tissue turnover: analysis on in vitro mitogenesis of fibroblasts and keratinocytes and alterations in cutaneous scars. Exp Dermatol. 1999;8:193–198
  16. Pesci A, Bertorelli G, Gabrielli M, Olivieri D. Mast cells in fibrotic lung disorders. Chest. 1993;103:989–996
  17. Matsunaga Y, Kawasaki H, Terada T. Stromal mast cells and nerve fibers in various chronic liver diseases: relevance to hepatic fibrosis. Am J Gastroenterol. 1999;94:1923–1932
  18. Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science. 2002;97:1689–1692
  19. Hara M, Ono K, Hwang MW, et al.  Evidence for a role of mast cells in the evolution to congestive heart failure. J Exp Med. 2002;195:375–381
  20. Secor VH, Secor WE, Gutekunst CA, Brown MA. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J Exp Med. 2000;191:813–822
  21. Echtenacher B, Mannel DN, Hultner L. Critical protective role of mast cells in a model of acute septic peritonitis. Nature. 1996;381:75–79
  22. Malaviya R, Ikeda T, Ross E, Abraham SN. Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature. 1996;381:77–80
  23. Blair RJ, Meng H, Marchese MJ, et al.  Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor. J Clin Invest. 1997;99:2691–2700
  24. Noli C, Miolo A. The mast cell in wound healing. Vet Dermatol. 2001;12:303–313
  25. Ruitenberg EJ, Elgersma A. Absence of intestinal mast cell response in congenitally athymic mice during Trichinella spiralis infection. Nature. 1976;264:258–260
  26. Lantz CS, Boesiger J, Song CH, et al.  Role for interleukin-3 in mast cell and basophil development and in immunity to parasites. Nature. 1998;392:90–93
  27. Brightling CE, Bradding P, Symon FA, Holgate ST, Wardlaw AJ, Pavord ID. Mast-cell infiltration of airway smooth muscle in asthma. N Engl J Med. 2002;346:1699–1705
  28. Rottem M, Okada T, Goff JP, Metcalfe DD. Mast cells cultured from the peripheral blood of normal donors and patients with mastocytosis originate from a CD34+/FcER1- population. Blood. 1994;84:2489–2496
  29. Kirshenbaum AS, Kessler SW, Goff JP, Metcalfe DD. Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol. 1991;146:1410–1415
  30. Kirshenbaum AS, Goff JP, Semere T, Foster B, Scott LM, Metcalfe DD. Demonstration that mast cells arise from a progenitor cell population that is CD34+, c-kit+, and expresses aminopeptidase N (CD13). Blood. 1999;94:2333–2342
  31. Gurish MF, Tao H, Abonia JP, et al.  Intestinal mast cell progenitors require CD49d/β7 (α4β7 integrin) for tissue-specific homing. J Exp Med. 2001;194:1243–1252
  32. Geissler EN, Ryan MA, Housman DE. The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. Cell. 1988;55:185–192
  33. Huang E, Nocka K, Beier DR, et al.  The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell. 1990;63:225–233
  34. Nilsson G, Butterfield JH, Nilsson K, Siegbahn A. Stem cell factor is a chemotactic factor for human mast cells. J Immunol. 1994;153:3717–3723
  35. Lorentz A, Schuppan D, Gebert A, Manns MP, Bischoff SC. Regulatory effects of stem cell factor and interleukin-4 on adhesion of human mast cells to extracellular matrix proteins. Blood. 2002;99:966–972
  36. Yee NS, Paek I, Besmer P. Role of kit -ligand in proliferation and suppression of apoptosis in mast cells: basis for radiosensitivity of white spotting and steel mutant mice. J Exp Med. 1994;179:1777–1787
  37. Irani A-MA, Nillson G, Miettinen U, et al.  Recombinant human stem cell factor stimulates differentiation of mast cells from dispersed human fetal liver cells. Blood. 1992;80:3009–3021
  38. Mitsui H, Furitsu T, Dvorak AM, et al.  Development of human mast cells from umbilical cord blood cells by recombinant human and murine c-kit ligand. Proc Natl Acad Sci U S A. 1993;90:735–739
  39. Kitamura Y, Go S, Hatanaka K. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood. 1978;52:447–452
  40. Kitamura Y, Go S. Decreased production of mast cells in Sl/Sld anemic mice. Blood. 1979;53:492–497
  41. Malaviya R, Gao Z, Thankavel K, van der Merwe PA, Abraham SN. The mast cell tumor necrosis factor alpha response to FimH-expressing Escherichia coli is mediated by the glycosylphosphatidylinositol-anchored molecule CD48. Proc Natl Acad Sci U S A. 1999;96:8110–8115
  42. Supajatura V, Ushio H, Nakao A, Okumura K, Ra C, Ogawa H. Protective roles of mast cells against enterobacterial infection are mediated by toll-like receptor 4. J Immunol. 2001;167:2250–2256
  43. Gommerman JL, Oh DY, Zhou X, et al.  A role for CD21/CD35 and CD19 in responses to acute septic peritonitis: a potential mechanism for mast cell activation. J Immunol. 2000;165:6915–6921
  44. Supajatura V, Ushio H, Nakao A, et al.  Differential responses of mast cell toll-like receptors 2 and 4 in allergy and innate immunity. J Clin Invest. 2002;109:1351–1359
  45. Huang C, De Sanctis GT, O'Brien PJ, et al.  Evaluation of the substrate specificity of human mast cell tryptase beta I and demonstration of its importance in bacterial infections of the lung. J Biol Chem. 2001;276:26276–26284
  46. Malaviya R, Abraham SN. Role of mast cell leukotrienes in neutrophil recruitment and bacterial clearance in infectious peritonitis. J Leukoc Biol. 2000;67:841–846
  47. Cairns JA, Walls AF. Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. J Immunol. 1996;156:275–283
  48. Hoek KL, Cassell GH, Duffy LB, Atkinson TP. Mycoplasma pneumoniae -induced activation and cytokine production in rodent mast cells. J Allergy Clin Immunol. 2002;109:470–476
  49. Bidri M, Vouldoukis I, Mossalayi MD, Debre P, Guillosson JJ, Mazier D, et al.  Evidence for direct interaction between mast cells and Leishmania parasites. Parasite Immunol. 1997;19:475–483
  50. Cairns JA, Walls AF. Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest. 1997;99:1313–1321
  51. Brown JK, Jones CA, Rooney LA, Caughey GH, Hall IP. Tryptase's potent mitogenic effects in human airway smooth muscle cells are via nonproteolytic actions. Am J Physiol Lung Cell Mol Physiol. 2002;282:L197–L206
  52. Garbuzenko E, Nagler A, Pickholtz D, et al.  Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis. Clin Exp Allergy. 2002;32:237–246
  53. Finkelman FD, Shea-Donohue T, Goldhill J, et al.  Cytokine regulation of host defense against parasitic gastrointestinal nematodes. Ann Rev Immunol. 1997;15:505–533
  54. Irani AM, Craig S, DeBlois G, Elson CO, Schechter NM, Schwartz LB. Deficiency of the tryptase-positive, chymase-negative mast cell type in gastrointestinal mucosa of patients with defective T lymphocyte function. J Immunol. 1987;138:4381–4386
  55. Madden KB, Urban JF, Ziltener HJ, Schrader JW, Finkelman FD, Katona IM. Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis. J Immunol. 1991;147:1387–1391
  56. Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med. 1998;188:1307–1320
  57. Friend DS, Ghildyal N, Austen KF, Gurish MF, Matsumoto R, Stevens RL. Mast cells that reside at different locations in the jejunum of mice infected with Trichinella spiralis exhibit sequential changes in their granule ultrastructure and chymase phenotype. J Cell Biol. 1996;135:279–290
  58. Laitinen LA, Laitinen A, Haahtela T. Airway mucosal inflammation even in patients with newly diagnosed asthma. Am Rev Respir Dis. 1993;147:697–704
  59. Anderson DF, MacLeod JD, Baddeley SM, et al.  Seasonal allergic conjunctivitis is accompanied by increased mast cell numbers in the absence of leukocyte infiltration. Clin Exp Allergy. 1997;27:1060–1066
  60. Amin K, Rinne J, Haahtela T, et al.  Inflammatory cell and epithelial characteristics of perennial allergic and nonallergic rhinitis with a symptom history of 1 to 3 years' duration. J Allergy Clin Immunol. 2001;107:249–257
  61. Straumann A, Bauer M, Fischer B, Blaser K, Simon HU. Idiopathic eosinophilic esophagitis is associated with a Th2-type allergic inflammatory response. J Allergy Clin Immunol. 2002;108:954–961
  62. Yanagida M, Fukamachi H, Ohgami K, et al.  Effects of T-helper 2-type cytokines, interleukin-3 (IL-3), IL-4, IL-5, and IL-6 on the survival of cultured human mast cells. Blood. 1995;86:3705–3714
  63. Ochi H, Hirani WM, Yuan Q, Friend DS, Austen KF, Boyce JA. T helper type-2 cytokine-mediated comitogenic responses and CCR3 expression during differentiation of human mast cells in vitro. J Exp Med. 1999;190:267–280
  64. Bischoff SC, Sellge G, Lorentz A, Sebald W, Raab R, Manns MP. IL-4 enhances proliferation and mediator release in mature human mast cells. Proc Natl Acad Sci U S A. 1999;96:8080–8085
  65. Gebhardt T, Sellge G, Lorentz A, Manns MP, Bischoff SC. Cultured human intestinal mast cells express functional IL-3 receptors and respond to IL-3 by enhancing growth and IgE-dependent mediator release. Eur J Immunol. 2002;32:2308–2316
  66. Kirshenbaum AS, Worobec AS, Davis TA, Goff JP, Semere T, Metcalfe DD. Inhibition of human mast cell growth and differentiation by interferon gamma-1b. Exp Hematol. 1998;26:245–251
  67. Okayama Y, Kirshenbaum AS, Metcalfe DD. Expression of a functional high-affinity IgG receptor, Fc gamma RI, on human mast cells: up-regulation by IFN-gamma. J Immunol. 2000;164:4332–4339
  68. Noguchi E, Shibasaki M, Kamioka M, et al.  New polymorphisms of haematopoietic prostaglandin D synthase and human prostanoid DP receptor genes. Clin Exp Allergy. 2002;32:93–96
  69. Hirai H, Tanaka K, Yoshie O, et al.  Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J Exp Med. 2001;193:255–261
  70. Lynch KR, O'Neill GP, Liu Q, et al.  Characterization of the human cysteinyl leukotriene cysLT1 receptor. Nature. 1999;399:789–793
  71. Heise CE, O'Dowd BF, Figueroa DJ, et al.  Characterization of the human cysteinyl leukotriene 2 receptor. J Biol Chem. 2000;275:30531–30536
  72. Davidson AB, Lee TH, Scanlon PD, et al.  Bronchoconstrictor effects of leukotriene E4 in normal and asthmatic subjects. Am Rev Respir Dis. 1987;135:333–337
  73. Griffin M, Weiss JW, Leitch AG, et al.  Effect of leukotriene D4 on the airways in asthma. N Engl J Med. 1983;308:436–439
  74. Laitinen LA, Laitinen A, Haahtela T, Vilkka V, Spur BW, Lee TH. Leukotriene E4 and granulocytic infiltration into asthmatic airways. Lancet. 1993;341:989–990
  75. Soter NA, Lewis RA, Corey EJ, Austen KF. Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4, and LTB4) in human skin. J Invest Dermatol. 1983;80:115–119
  76. Marom Z, Shelhamer JH, Bach MK, Morton DR, Kaliner M. Slow-reacting substances, leukotrienes C4 and D4, increase the release of mucous from human airways in vitro. Am Rev Respir Dis. 1982;126:4449–4451
  77. Henderson WR, Tang LO, Chu SJ, et al.  A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am J Respir Crit Care Med. 2002;165:108–116
  78. Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group JAMA. 1996;275:931–936
  79. Altman LC, Munk Z, Seltzer J, et al.  A placebo-controlled, dose-ranging study of montelukast, a cysteinyl leukotriene-receptor antagonist. Montelukast Asthma Study Group. J Allergy Clin Immunol. 1998;102:50–56
  80. Hamilton A, Faiferman I, Stober P, Watson RM, O'Byrne PM. Pranlukast, a cysteinyl leukotriene receptor antagonist, attenuates allergen-induced early- and late-phase bronchoconstriction and airway hyperresponsiveness in asthmatic subjects. J Allergy Clin Immunol. 1998;102:177–183
  81. Lawrence ID, Warner JA, Cohan VL, Hubbard WC, Kagey-Sobotka A, Lichtenstein LM. Purification and characterization of human skin mast cells. Evidence for human mast cell heterogeneity. J Immunol. 1987;139:3062–3069
  82. MacGlashan DW, Schleimer RP, Peters SP, et al.  Generation of leukotrienes by purified lung mast cells. J Clin Invest. 1982;70:747–751
  83. Peters SP, MacGlashan DW, Schulman ES, et al.  Arachidonic acid metabolism in purified human lung mast cells. J Immunol. 1984;132:1972–1979
  84. Fox CC, Dvorak AM, Peters SP, Kagey-Sobotka A, Lichtenstein LM. Isolation and characterization of human intestinal mucosal mast cells. J Immunol. 1985;135:483–491
  85. Massey WA, Guo C-B, Dvorak AM, et al.  Human uterine mast cells. Isolation, purification, characterization, ultrastructure, and pharmacology. J Immunol. 1991;147:1621–1627
  86. Wenzel SE, Larsen GL, Johnston K, Voelkel NF, Westcott JY. Elevated levels of leukotriene C4 in bronchoalveolar lavage fluid from atopic asthmatics after endobronchial allergen challenge. Am Rev Respir Dis. 1990;142:112–119
  87. Clark JD, Lin L-L, Kriz RW, et al.  A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell. 1991;65:1043–1051
  88. Malavia R, Malavia R, Jakschik BA. Reversible translocation of 5-lipoxygenase in mast cells upon IgE/antigen stimulation. J Biol Chem. 1993;268:4939–4944
  89. Dixon RAF, Diehl RE, Opas E, et al.  Requirement of a 5-lipoxygenase-activating protein for leukotriene biosynthesis. Nature. 1990;343:282–284
  90. Evans JF, Dupuis P, Ford-Hutchinson AW. Purification and characterization of leukotriene A4 hydrolase from rat neutrophils. Biochem Biophys Acta. 1985;840:43–50
  91. Lam BK, Penrose JF, Freeman GJ, Austen KF. Expression cloning of a cDNA for human leukotriene C4 synthase, an integral membrane protein conjugating reduced glutathione to leukotriene A4. Proc Natl Acad Sci U S A. 1994;91:7663–7667
  92. Lam BK, Xu K, Atkins MB, Austen KF. Leukotriene C4 uses a probenecid-sensitive export carrier that does not recognize leukotriene B4. Proc Natl Acad Sci U S A. 1992;89:11598–11602
  93. Raulf M, Stuning M, Konig W. Metabolism of leukotrienes by L-gamma-glutamyl-transpeptidase and dipeptidase from human polymorphonuclear granulocytes. Immunology. 1985;55:135–147
  94. Penrose JF, Spector J, Baldasaro M, et al.  Molecular cloning of the gene for human leukotriene C4 synthase: organization, nucleotide sequence, and chromosomal localization to 5q35. J Biol Chem. 1996;271:11356–11361
  95. Sanak M, Pierzchalska M, Bazan-Socha S, Szczeklik A. Enhanced expression of the leukotriene C4 synthase due to overactive transcription of an allelic variant associated with aspirin-intolerant asthma. Am J Respir Cell Mol Biol. 2000;23:290–296
  96. Kawagishi Y, Mita H, Taniguchi M, et al.  Leukotriene C4 synthase promoter polymorphism in Japanese patients with aspirin-induced asthma. J Allergy Clin Immunol. 2002;109:936–942
  97. Van Sambeek R, Stevenson DD, Baldasaro M, et al.  5′ flanking region polymorphism of the gene encoding leukotriene C4 synthase does not correlate with the aspirin-intolerant asthma phenotype in the United States. J Allergy Clin Immunol. 2000;106:72–76
  98. Sampson AP, Siddiqui S, Buchanan D, et al.  Variant LTC4 synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax. 2000;55(suppl 2):S28–S31
  99. Toru H, Ra C, Nonoyama S, Suzuki K, Yata J, Nakahata T. Induction of the high-affinity IgE receptor (FcϵRI) on human mast cells by IL-4. Int Immunol. 1996;8:1367–1373
  100. Hsieh FH, Lam BK, Penrose JF, Austen KF, Boyce JA. T helper cell type 2 cytokines coordinately regulate IgE- dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C4 synthase expression by interleukin 4. J Exp Med. 2001;193:123–133
  101. Ochi H, De Jesus NH, Hsieh F, Austen KF, Boyce JA. Interleukins 4 and 5 prime human mast cells for different profiles of IgE-dependent cytokine production. Proc Natl Acad Sci U S A. 2000;97:10509–10513
  102. Lee TH, Austen KF, Corey EJ, Drazen JM. Leukotriene E4-induced airway hyperresponsiveness of guinea pig tracheal smooth muscle to his-tamine and evidence for three separate sulfidopeptide leukotriene receptors. Proc Natl Acad Sci U S A. 1984;81:4922–4925
  103. Dahlen SE, Back M. Leukotriene receptors: functional aspects and future targets. Clin Exp Allergy Rev. 2001;2:137–141
  104. Von Kugelgen I, Wetter A. Molecular pharmacology of P2Y-receptors. Naunyn-Schmiedeberg's Arch Pharmacol. 2000;362:310–323
  105. Foster CJ, Prosser DM, Agans JM, et al.  Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest. 2001;107:1591–1598
  106. Tominaga M, Wada M, Masu M. Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc Natl Acad Sci U S A. 2001;98:6951–6956
  107. Warny M, Aboudola S, Robson SC, et al.  P2Y6 nucleotide receptor mediates monocyte interleukin-8 production in response to UDP or lipopolysaccharide. J Biol Chem. 2001;276:26051–26056
  108. Mellor EA, Maekawa A, Austen KF, Boyce JA. Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells. Proc Natl Acad Sci U S A. 2001;98:7964–7969
  109. Maier R, Glatz A, Mosbacher J, Bilbe G. Cloning of P2Y6 cDNAs and identification of a pseudogene: comparison of P2Y receptor subtype expression in bone and brain tissues. Biochem Biophys Res Commun. 1997;240:298–302
  110. Figueroa DJ, Breyer RM, Defoe SK, et al.  Expression of the cysteinyl leukotriene 1 receptor in normal human lung and peripheral blood leukocytes. Am J Respir Crit Care Med. 2001;163:226–233
  111. Mellor EA, Austen KF, Boyce JA. Cysteinyl leukotrienes and uridine diphosphate induce cytokine generation by human mast cells through an interleukin 4-regulated pathway that is inhibited by leukotriene receptor antagonists. J Exp Med. 2002;195:583–592
  112. Bischoff SC, Sellge G, Manns MP, Lorentz A. Interleukin 4 induces a switch of human intestinal mast cells from proinflammatory cells to Th2-type cells. Int Arch Allergy Immunol. 2001;124:151–154

☆ Supported by National Institutes of Health grants AI31599, HL36110, AI48802, and AI52353 and by grants from the Charles Dana Foundation and the Vinik Family Fund for Research in Allergic Diseases in Children.

☆☆ Reprint requests: Joshua A. Boyce, MD, Harvard Medical School, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Smith Research Building, Room 626, 1 Jimmy Fund Way, Boston, MA 02199.

PII: S0091-6749(02)91322-9

doi:10.1067/mai.2003.60

The Journal of Allergy and Clinical Immunology
Volume 111, Issue 1 , Pages 24-32, January 2003

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