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Clinical Reviews in Allergy and Immunology Volume 22, 2002 149 Clinical Reviews in Allergy and Immunology © Copyright 2002 by Humana Press Inc. 1080-0549/01/149–160/$13.00 The Diverse Effects of Mast Cell Mediators Colleen Hines University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0635 Introduction Paul Ehrlich first identified mast cells (MCs) because of their unique staining pattern to basic dyes, which is now known to be caused by the presence of cytoplasmic granules (1). Emptying of these gran- ules is the prominent physiological characteristic of MCs, a process that is elicited by numerous chemical stimuli including basic compounds (polymyxin B, compound 48/80), cytokines, and activation of the high- affinity IgE receptor, Fc ε RI (2,3). Substances that cause MC degranula- tion all share the ability to increase intracellular calcium levels, triggering fusion of the granule membrane to the plasma membrane and causing subsequent release of granule contents (3). MCs can also degranulate through mechanical forces, such as injury to the skin. Degranulation results in the release of specific MC products that medi- ate some of the diverse effects of mast cells within the body. Mast cell mediators that are stored in granules, or preformed mediators, are not the only products produced and released by MCs. There are also mediators that are generated de novo upon MC stimula- tion including adenosine, lipid mediators that are generated from the cell membrane, and proteins that are newly transcribed and translated, such as cytokines and chemokines. Mediators from these origins fol- low different time-courses for their release and action. The preformed mediators are released immediately and act quickly, adenosine and lipid mediators are made and act within a few minutes, and cytokines are synthesized over several hours and can be released long after degranulation has occurred (4). The release of preformed and newly generated MC mediators requires activation of Fc ε RI, the high-affinity receptor for IgE. This receptor binds the Fc portion of IgE antibodies, and is activated by the binding of the appropriate antigen to the IgE antibody. Binding of anti-

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Page 1: The diverse effects of mast cell mediators

MC Mediators 149

Clinical Reviews in Allergy and Immunology Volume 22, 2002149

Clinical Reviews in Allergy and Immunology© Copyright 2002 by Humana Press Inc.1080-0549/01/149–160/$13.00

The Diverse Effects of Mast Cell Mediators

Colleen Hines

University of California, San Diego, 9500 Gilman Drive,La Jolla, CA 92093-0635

IntroductionPaul Ehrlich first identified mast cells (MCs) because of their

unique staining pattern to basic dyes, which is now known to be causedby the presence of cytoplasmic granules (1). Emptying of these gran-ules is the prominent physiological characteristic of MCs, a process thatis elicited by numerous chemical stimuli including basic compounds(polymyxin B, compound 48/80), cytokines, and activation of the high-affinity IgE receptor, FcεRI (2,3). Substances that cause MC degranula-tion all share the ability to increase intracellular calcium levels,triggering fusion of the granule membrane to the plasma membraneand causing subsequent release of granule contents (3). MCs can alsodegranulate through mechanical forces, such as injury to the skin.Degranulation results in the release of specific MC products that medi-ate some of the diverse effects of mast cells within the body.

Mast cell mediators that are stored in granules, or preformedmediators, are not the only products produced and released by MCs.There are also mediators that are generated de novo upon MC stimula-tion including adenosine, lipid mediators that are generated from thecell membrane, and proteins that are newly transcribed and translated,such as cytokines and chemokines. Mediators from these origins fol-low different time-courses for their release and action. The preformedmediators are released immediately and act quickly, adenosine andlipid mediators are made and act within a few minutes, and cytokinesare synthesized over several hours and can be released long afterdegranulation has occurred (4).

The release of preformed and newly generated MC mediatorsrequires activation of FcεRI, the high-affinity receptor for IgE. Thisreceptor binds the Fc portion of IgE antibodies, and is activated by thebinding of the appropriate antigen to the IgE antibody. Binding of anti-

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gen causes crosslinking of the receptors and, in turn, activates a signal-ing pathway that causes degranulation, release of adenosine, synthesisof lipid mediators, and activation of transcription factors (i.e., NfκB)that cause production of various cytokines and chemokines (3,4). Indi-viduals who are atopic generate IgE antibodies to commonly inhaledsubstances, such as pet dander, mold, dust, or pollen. When these anti-bodies are made, exposure to the substance causes allergic symptomsthrough the release of MC mediators.

Mast cells are capable of inducing broad physiological responsesthrough both their location within the body and the number of media-tors they release. Anatomically, the location of mast cells allowsinteraction with multiple cells including fibroblasts, endothelium, epi-thelium, smooth muscle, and other cells of the immune system. Their

Table 1Mast Cell Mediators and Their Targets

Preformed,granule-associated mediators Target cells and/or tissues

Histamine Endothelium, nerves, smooth muscle

Proteases Eosinophils, fibroblasts, mucus-secreting(tryptase, chymase, cathepsin B, cells, extracellular matrix (ECM)carboxypeptidase A)

Proteoglycans Enzymes in the ECM(heparin and chondroitinsulfate E)

Newly synthesized mediators Target cells and/or tissues

Adenosine Vascular endothelium and smoothmuscle, mast cells

Platelet activating factor (PAF) Smooth muscle, endothelium, platelets,eosinophils, neutrophils, leukocytes,mononuclear cells

Leukotrienes C4 and D4 Airway smooth muscle, endothelium

Leukotriene B4 Neutrophils, eosinophils, polymorphonuclear cells, monocytes

Prostaglandin D2 Airway and vascular smooth muscle,neutrophils

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strategic placement throughout connective tissues and along epithelialsurfaces, including the skin, respiratory tract, and alimentary canal,allow them to respond to the external environment and transmit thisresponse to cells and tissues around them. Table 1 summarizes the typesof MC mediators and the cells and tissues they affect. As shown, MCsrelease a large repertoire of mediators with diverse targets. Each of themediators also has diverse biological activities, which is the focus ofthis chapter.

Preformed Mediators

HistamineHistamine is found in the granules of all MCs, and is the only bio-

logical amine found in human MCs. Within the granules, it is positivelycharged and found complexed to negatively charged proteoglycans andproteases (5). It is formed by decarboxylation of histidine within thegolgi of the MC, and is rapidly degraded upon release (6). Because ofrapid degradation, the actions of histamine are both local and brief.The broad effects of histamine can be seen after intravenous adminis-tration, after which subjects experience iching, flushing, headache, nau-sea, bronchoconstriction, accelerated heart rate, and decreased bloodpressure (7). Histamine is also responsible for the classical “tripleresponse” (8) or wheal and flare reaction in the skin through its abilityto dilate blood vessels and cause vascular leakage, the same actionsseen in allergic reactions such as uticaria, rhinitis, and in the asthmaticresponse. Histamine also causes contraction of smooth muscle in boththe gastrointestinal tract and the airways, causing bronchoconstrictionin the lungs and further contributing to the asthmatic response.

The effects of histamine are mediated by three receptors, the H1(9), H2 (10), and H3 (11), which are found on many cell types includingvascular and gastrointestinal smooth muscle, epithelium, neurons, andother immune cells. Allergic responses, such as bronchoconstriction,edema through capillary leakage, and vasodilation, are mediated bythe H1 receptor, to which drugs for these conditions are also aimed (9).The H2 receptor causes acid release from parietal cells in the stomachand increases mucus production in the lung (10). The H3 receptorinhibits further MC histamine release in an autocrine fashion, and isfound on neurons in the lung where they limit reflex bronchocon-striction (11,12).

ProteasesMost of the protein content in MC granules is accounted for by the

presence of proteases, and the major proteases found in human MCsare tryptase, chymase, cathepsin G, and carboxypeptidase A. Within

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the granules, proteases are found bound to proteoglycans (i.e., heparin),which keeps them inactivated until release (13). Association withproteoglycans also prevents inactivation by protease inhibitors oncedegranulation occurs (14,15). The protease profile has been useful inthe classification of human MCs as it has been found that MCs contain-ing both tryptase and chymase predominate in the skin and other con-nective tissues, whereas those in the mucosa of the intestinal tract andwithin the alveolar spaces contain only tryptase (16).

Tryptase is a serine protease expressed by nearly all human MCs,and is the most abundant MC mediator (17). Upon release, it cleavesmultiple proteins, which results in promoting bronchoconstriction andanticoagulation, as well as the remodeling of the extracellular matrix(ECM). Bronchoconstriction occurs through enhancement of the effectsof histamine and the cleavage of bronchodilators such as vasoactiveintestinal peptide (VIP) (18–20). Tryptase also cleaves proteins in theclotting cascade, such as fibrinogen, thereby preventing clot formation.It also promotes anticoagulation through its association with theanticoagulent heparin. Trypase contributes to remodeling of the ECMby activating proteases (i.e., stromelysin) that activate collagenase (21),and acting synergistically with mitogens to promote fibroblast growth(22,23).

Chymase and cathepsin G are related serine proteases, and cathe-psin G is expressed only in MCs also expressing chymase (24–27). Theyare capable of promoting bronchoconstriction through degradation ofVIP, similar to the activity of tryptase (18,28). Promotion of broncho-constriction contributes to the asthmatic response, as does their abilityto induce mucus secretion by airway gland cells (29). Chymase andcathepsin G are also capable of remodeling the ECM through degrada-tion of matrix components, specifically proteoglycans, and release ofmatrix-bound transforming growth factor-beta1 (TGF-β1) (30–33). Onceliberated, TGF-β1 stimulates fibroblast and smooth muscle growth. Likehistamine, chymase and cathepsin G have also been shown to cause edemaand wheal formation in the skin by increasing vascular permeability(34,35).

Carboxypeptidase A is also found complexed to proteoglycanswithin the MC granule. Its substrates are similar to those of chymase,including bronchodilators (VIP) and various proteins in the ECM, andis thought to complement the actions of chymase (36). Like cathepsinG, it appears carboxypeptidase A is found only in MCs where chymaseis also present (37).

ProteoglycansProteoglycans function within the MC granule to package other

mediators and prevent their action until released from the MC. Hep-

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arin and chondroitin sulfate E are found in human MCs, and arecomplexed to proteases (38,39). Proteoglycan binding to proteases isnecessary to prevent their activation before release and inactivationfrom extracellular proteases. Binding of tryptase and chymase to hep-arin is also necessary for transformation into their active forms (40–42).Both heparin and chondroitin sulfate E also bind proteins present inthe EMC, which can alter the activity of matrix enzymes. For example,anticoagulation by heparin is caused by its ability to bind antithrombinand thrombin, which increases the rate of inactivation of thrombinby antithrombin. Recently, it was shown that release of MC proteo-glycans is required to prevent attachment of an intestinal nematode ina mouse model, showing their importance in the MC’s response to para-sitic infection (43).

Newly Formed Mediators

AdenosineAdenosine has gained attention through its ability to cause broncho-

constriction in asthmatic individuals (44). Although not thought of as atraditional MC mediator, it is released from stimulated MCs and has abroad range of effects once released (45). Adenosine has been shown topotentiate antigen-stimulated release of preformed mediators fromMCs, resulting in a higher level of release (46,47). Adenosine also actsas an antiinflammatory agent, inhibiting phagocytosis and disruptingneutrophil adhesion (48). In addition, adenosine acts as a vasodilator,especially on the coronary arteries, and is used as an antiarrhythmicagent (49–51).

Lipid MediatorsOne of the signaling molecules produced after activation of FcεRI

is phopholipase A2, which causes the formation of platelet activatingfactor and arachidonic acid by cleavage of cell membrane phospholip-ids. Arachidonic acid is the substrate for cyclooxygenases, which formprostaglandins and thromboxanes, and lipoxygenases, which generateleukotrienes. These lipid mediators are potent proinflammatory agentsthat are released into the extracellular space within minutes of MC acti-vation (52–54).

Platelet activating factor (PAF) is named for its ability to aggregateand degranulate platelets, although it has many more biological activi-ties. PAF causes bronchoconstriction, most likely through contractionof airway smooth muscle (55). It also constricts blood vessels, causesvascular leakage, and increases endothelial cell permeability (56–58).PAF acts in a proinflammatory manner by functioning as a chemo-attractant for immune cells including eosinophils, neutrophils, and

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lymphocytes (59-63). In addition to immune cell recruitment, PAF acti-vates eosinophils and neutrophils, stimulating them to release granule-associated and newly formed mediators (64–68). PAF is also known tomodulate cytokine production in mononuclear cells (69).

Leukotrienes (LT) produced by MCs include LTB4 and LTC4, whichis converted into LTD4 and LTE4 in the extracellular space (70–72). LTC4and LTD4 cause effects similar to those of histamine, although they are1000 times more potent. They cause vascular leakage from postcapillaryvenules and stimulate mucus secretion in the lungs. They are alsopotent bronchoconstrictors through their action on airway smoothmuscle. LTB4 is a chemoattractant for neutrophils, eosinophils, poly-morphonuclear leukocytes, and monocytes, and also promotes degran-ulation of eosinophils and neutrophils (73,74).

The action of cyclooxygenase on arachidonic acid produces pros-taglandins (PG) G2 and H2, which are converted into numerous endproducts by terminal synthetases, whose expression is cell-specific (75).The prostaglandin produced by MCs is PGD2 (53). It acts as a bronchoc-onstrictor and has the ability to increase airway responsiveness to otherbronchoconstricting agents (76,77). PGD2 also causes vasoconstrictionin the pulmonary circulation, whereas in other areas causes vasodila-tion (78,79). Like LTD4, PGD2 is a chemoattractant for neutrophils, andtogether these eicosanoids mediate accumulation of neutrophils in theskin (80,81).

Cytokines and ChemokinesCytokines and chemokines are proteins or glycoproteins secreted

by cells and include the interleukins (IL), interferons (IFN), and colony-stimulating factors (CSF). Mast cells have been shown to produce aplethora of cytokines and chemokines including IL-1, IL-2, IL-3, IL-4,IL-5, IL-6, IL-8, IL-9, IL-13, IL-16, tumor necrosis factor (TNF) α, IFNγ,granulocyte/macrophage colony-stimulating factor (GM-CSF), MCP-1, regulated on activation, normal T-cell expressed and secreted(RANTES), and macrophage inflammatory proteins (MIP) α and β (82–87). Mast cells are heterogeneous in their expression of cytokines andchemokines, and the cytokine/chemokine profile has been shown tovary with the protease phenotype. IL-4 is expressed primarily in MCspossessing tryptase and chymase (MCTC), although those producingonly tryptase (MCT) tend to express IL-5 and IL-6 (88). In general,cytokines and chemokines are newly transcribed after MC stimulation,however, some may be stored in granules, including TNFα (89).Although most cytokines and chemokines are generated and releasedafter degranulation occurs, their production can be induced by factorsthat do not cause degranulation, including lippolysaccharide, stem cellfactor, substance P, thrombin, and nerve growth factor (NGF) (90–92).

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Cytokines and chemokines released by MCs possess a broad, yetsomewhat overlapping, range of activities that are summarized in Table2. One of their important effects is promotion of development andmaturation of immune cells, including T cells, B cells, and eosinophils.IL-4 allows mast cells to present antigen to T cells and triggers theirdevelopment into Th2 cells. Upon maturation, Th2 cells release cytokinesnecessary for B-cell production of IgE (93,94). It has been shown thatIL-13 can function in a similar capacity as IL-4, and may be more impor-tant in the development of allergic asthma (95,96). IL-4 also stimulatesproduction of IL-6, which functions similarly to IL-4 and IL-13 in its

Table 2Subset of Cytokines/Chemokines Produced by Mast Cells

and Their Functions

Cytokine/Chemokine Biological Activity

IL-4 Proliferation of T cells and promotion of a Th2 pheno-type

Increase in IgE production from B cellsIncrease of adhesion molecule expression on endothe-

lial cellsEosinophil chemotaxis

IL-5 Eosinophil growth, activation, and chemotaxisIL-6 T-cell growth, differentiation, and activation

Increase in IgE production from B cellsIncrease in mucus secretion from airway glandular

cellsIL-8 Neutrophil chemotaxis

Eosinophil chemotaxisIL-13 Increase in IgE production from B cells

Increase of adhesion molecule expression on endothe-lial cells

Eosinophil activationIL-16 T-cell chemotaxisTNFα T-cell growth

Enhanced cytotoxicity of eosinophilsNeutrophil chemotaxis and enhanced cytotoxicityMast cell mediator releaseFibroblast growth and chemotaxisIncrese in mucus secretion from airway glandular cellsIncrease of adhesion molecule expression on endothe-

lial cellsMacrophage chemotaxis and increased cytotoxicity

GM-CSF Eosinophil growth, activation, and chemotaxisMCP-1 T-cell chemotaxis

MIP α & β Macrophage differentiationNeutrophil chemotaxis and cytotoxicity

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ability to induce growth and differentiation of T cells and increase IgEproduction from B cells. Other cytokines/chemokines that are impor-tant in growth and development of immune cells are IL-5 and GM-CSF,which are needed for growth and activation of eosinophils.

Another important activity of cytokines and chemokines is theirability to influence leukocyte trafficking, either by acting directly aschemoattractants or indirectly by upregulation of adhesion moleculeson vascular endothelium. Chemoattractants for eosinophils includeIL-4, IL-5, IL-8, GM-CSF; IL-8, TNFα, and MIP-1α are chemoattracttantsfor neutrophils; and IL-16 and MCP-1 are chemoattractants for T cells(97). Expression of adhesion molecules, including VCAM-1, ICAM-1,and E-selectin, on vascular endothelium is necessary for binding of cir-culating immune cells and their eventual transmigration from the bloodto the site of inflammation. TNFα increases expression of E-selectin,ICAM-1, and VCAM-1 on vascular endothelium, whereas IL-4 andIL-13 increase the expression of VCAM-1 (98).

Cytokines and chemokines are also capable of enhancing the bio-logical functions of various cells. As aforementioned, IL-4, IL-6, andIL-13 increase antibody production from B cells. Enhancement of thecytotoxic activity of eosinophils, neutrophils, and macrophages ismediated by TNFα, as well as increased mediator release from MCs.TNFα is also capable of increasing mucus production from airway glan-dular cells, as is IL-6 (97).

ConclusionsInterest in MCs is usually aimed at understanding their role in

pathological states they are known to be involved in, including allergicdiseases (rhinitis, asthma) and chronic inflammatory diseases (Chrohn’sdisease, systemic sclerosis). Mast cell mediators are usually looked uponin the same manner, focusing on their role in the disease process. Thus,MCs and the mediators they release are seen primarily as producingnegative effects, and are not recognized as an integral and necessarypart of the innate immune response. Many studies have exemplifiedthe importance of MCs to the proper functioning of the immune sys-tem. Mast cell-deficient mice have shown that MCs are necessary forclearance of bacterial infections, and MCs have long been recognizedas critical for the removal of parasitic organisms (99–101). Mast cellsare also important in fibrosis, which is necessary when tissues are dam-aged beyond their capability to regenerate. The broad distribution ofMCs and their placement close to the external environment makes themcritical in the initial response to injury and invading organisms, andtheir heterogeneity allows them to respond in a manner that is mostuseful for their anatomical location.

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