- Email: [email protected]
Cytokine production by mast cells and basophils
Cytokine Stephen
production J. Calli,
Beth Israel Hospital
John
and Harvard
by mast cells and basophils R. Gordon Medical
and Barry
School,
Boston,
K. Wershil
Massachusetts,
USA
Mast cells and/or basophils have been implicated in the expression of a wide variety of biological responses, including immediate hypersensitivity reactions, host responses to parasites and neoplasms, angiogenesis, tissue remodeling, and immunologically non-specific inflammatory and fibrotic conditions. Recent findings suggest that an important mechanism by which mast cells influence such biological responses is through the production of a broad panel of multifunctional cytokines. In contrast, the extent to which basophils can produce cytokines is uncertain.
Current
Opinion
in Immunology
Introduction Mast cells and basophils are critical effector cells in certain forms of &E-dependent immediate hypersensitivity, and also participate in a wide variety of biological responses in which IgE has no demonstrable role (reviewed in [l-5]). Certain clinically important aspects of &E-dependent responses, such as the striking recruitment of leukocytes that occurs in some of these reactions, are incompletely understood in mechanistic terms. The functions of mast cells and basophils in responses not involving IgE are even more obscure. This review focuses primarily on evidence that indicates mast cells or basophils can produce multifunctional cytokines and that such molecules may be important mediators in biological responses associated with the activation of these cells. Space limitations preclude adequate discussion of several important, related issues, which recently have been reviewed elsewhere. These include the role of multifunctional cytokines in regulating mast-cell or basophil proliferation, maturation or phenotype [4,5], and the ability of some of the same cytokines to induce or regulate basophil or mast-cell mediator production [6,71.
Distribution basophils
and function
of mast cells and
Mammalian mast cells and basophils perform three major functions: they express the high&inky receptor for IgE (Fc,RI) [8]; upon &E-dependent or other forms of stimulation they cleave a similar, though not identical, panel of biologically active mediators [l-3]; and they participate in &E-dependent and certain &E-independent biological responses [l-5]. Although the number of tis-
AMulV-Abelson murine leukemia virus; ElAM-extracellular CM-CSF-granulocyte-macrophage colony-stimulating LPT-late-phase reaction; MIP-macrophage inhibitory TN&tumor necrosis factor; VCAM-vascular @ Current
1991,
3:8654373
sue mast cells can increase (or decrease) in association with certain biological responses, even normal vascularized tissues have a resident population of mature mast cells, whose numbers and phenotypic characteristics vary according to anatomical site [5]. Many of these cells reside in close proximity to such potential targets of mediator/cytokine action as vascular endothelial cells, iibroblass, epithelial cells, or nerves [ 51. Mature basophils, unlike mature mast cells, circulate in the blood, albeit in very low numbers, but normally do not reside in the peripheral tissues [2,5]. However, a wide variety of biological responses are associated with elevated levels of circulating basophils and/or the recruitment of basophils into the affected tissues [ 21.
Mast cells as a source cytokines
of multifunctional
The first direct evidence that mast-cell populations can produce a well characterized cytokine was the demonstration that certain Abelson murine leukemia virus (A-MuLV)-transformed tumorlgenic mouse mast-cell lines constitutively produced granulocyte-macrophage colonystimulating factor (GM-CSF) mRNA and released GM-CSF [9]. Brown et al [lo] subsequently reported that nine of 15 spontaneously or A-MuLV-transformed mouse mastcell lines constitutively expressed mRNA for interleukln (IL)-4 and some constitutively released IL.-4 bioactivity. Only a few of these mast-cell lines contained mRNA for IL-3 or GM-CSF. Brown et al [lo] also detected low levels of IL-4 mRNA in each of five IL+dependent mouse mastcell lines, but these cells did not release detectable IL-4 bioactivky, Humphries et al [ 1 l] showed that some AMuLV-transformed mast cells constitutively produced IL-3
Abbreviations leukocyte adhesion molecule; Pc,RI-high-affinity receptor for I& factor; ICAM-intercellular adhesion molecule; IL-interleukin; basophilic leukemia; protein; PCDa-prostaglandin D2, . RRL-rat cell-adhesion molecule; VIA-very late antigen.
Biology
Ltd ISSN
0952-7915
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allergy and other hypersensitivities
and GM-CSF mRIU4.s and products, and also produced a bioactivity similar to that of IL-~. The first cytokine bioactivity to be clearly associated with normal mast cells was tumour necrosis factor (TNF)&ache&n. Several groups demonstrated that in vitro derived IL-3-dependent mouse mast cells, rat basophilic leukemia (RBL) cells, or freshly isolated mouse or rat peritoneal mast cells expressed cytolytic activity against certain cellular targets, and some examples of this mastcell-dependent cytotoxicity were partially inhibited by antibodies to TNF-a (reviewed in [ I2 ] >. Young et al [13] showed that mouse peritoneal mast cells, as well as IL-3-dependent and IL3independent mouse mast cells generated in vitm, contained a cytoplasmic granule-associated cytokine with immunologic and cytotoxic activities very similar to those of TNF-a. We showed [ 140.1 that this TNP-a-like cytotoxic mediator was a product of the TNF-c&achectin gene, and that unstimulated mouse peritoneal mast cells constitutively contained approximately twice as much TNF-a bioactivity as did lipopolysaccharide-stimulated mouse peritoneal macrophages. This iinding illustrates the important point that the biology of some mast-cell-associated cytokines may differ signihcantly from that of the same cytokines in other cell types. Thus, macrophages, T cells, and B cells contain little or no preformed TNF-a bioactivity, whereas mouse peritoneal mast cells contain substantial preformed stores of TNF-a available for immediate reIease upon appropriate stimulation of the cell (reviewed in [ 12,14**]).
IgE-dependent production
regulation
of mast-cell cytokine
Stimulation through the Fc,IU induces mast cells to accumulate increased levels of mRNA for cytokines and to release cytokine products. Richards et al [ 151 showed that RBL cells released a TNF-a-like cytotoxlc activity upon challenge with anti-IgE. Plaut et al [16] demonstrated that &E-dependent stimulation of long-term IL+dependent mouse mast-cell lines resulted in increased levels of mRNA for IL-3, IL4, IL-5, and IL-6 and the release of bioactivity for IL-3, IL-4 and IL-6. Wodnar-FiIipowicz et al [ 171 reported that primary cultures of IL-3-dependent, bone marrow-derived cultured mast cells stimulated with 1g8 and specific antigen exhibited increased levels of IL-3 and GM-CSF mRNA and released IL-3 and GM-CSF bioactivity. Burd et al [ 181 showed that long-term IL-3-dependent or -independent mouse mast-cell lines activated by 1gE and antigen exhibit Increased levels of ~RNA for IL-la, IL-~, IL-5, IL-6, GM-CSF, and four members of the macrophage in8ammatory protein (MIP)-1 gene family TCA3, JE, MIPla, and MIP-18. ‘Iwo of the four mast-cell lines tested exhibited &E-dependent augmentation of levels of ~I?NA for EN-y. Burd et al 1181 also showed that IgE-dependent activation of mast-cell lines or primary cultures of bone-marrow-derived cultured mast cells resulted in release of bioactivity for IL-l, IL-4 and IL-6. In contrast to mRNA for other cytokines, transforming growth factor (TGF)-j3 ~RNA was readily detectable in un%imulated
cells and only slightly elevated by &E-dependent activation of mast-cell lines or bone-marrow-derived cultured mast cells [ 191. Gurish et al [20*] showed that IgP-dependent activation of these cultured mast cells resulted in a preferential increase in mRNA for cytokines compared with mRNA for secretory granule proteins.
TNF-a as an example of a new class of mast-cell-associated mediators
Conventionally, mast-cell-associated mediators are divided into the preformed mediators such as histamine and the proteases, which are stored in the cells’ cytoplasmic granules and are released upon cell activation, and the newly synthesized mediators, such as prostaglandin Dz (PGDz) and the sulftdopeptide leukotrienes, which are not stored but are produced and only secreted upon appropriate stimulation of the cells [2,3]. We have proposed [21**] that TNP-a may be representative of a new class of mast-cell-associated mediators, because IgE-dependent activation of the mast cell results in the rapid release of preformed stores of TNF-a bioactivity, as well as the induction of increased levels of TNF-a mRNA associated with the sustained release of large quantities of newly synthesized TNF-a bioactivity (Fig. 1). Thus, for both in vitroderived cultured mast cells and puriiied peritoneal mast cells, the total amount of TNF-a bioactivity present in the cells and their supematant l-2 h after &$-dependent activation exceeds that present in the unstimulated cells [ 14”,21**]. The sustained release of newly synthesized TNF-a by appropriately stimulated mast cells represents a mechanism bywhich mast-cell-derived TNF-a can exert its actions on leukocyte emigration and activation, and have other effects, for prolonged periods during &E-dependent and perhaps other biological responses.
IgE-dependent leukocyte recruitment in mouse skin requires mast cells and is dependent on
TNFa Much of the interest in the clinical significance of mastcell cytokine production has focused on late-phase reactions (LPRs). In LPRs, &E-dependent mast-cell activation is associated with leukocyte infiltration that develops within hours of antigen challenge [2,3,22]. Notably, the leukocyte infiltration associated with LPRs, rather than the immediate consequences of mast-cell activation per se, is thought to be largely responsible for the tissue damage associated with asthma and other allergic conditions [2,3,22]. We have reported several lines of evidence indicating that mast cells and TNF-a contribute significantly to the expression of &E&dependent inflammation elicited in mouse skin. First, mast cells are essential for the leukocyte infiltration associated with &E-dependent cutaneous reactions, which do not occur in the absence of this cell type [23**]. Second, the amount of TNF-a mR1%4 detectable in skin challenged with IgE and anti-
Cytokine
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90'
TNF Stimulation time Cl. MUC57.1
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Stimulation time Cl. MCIC57.1
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30'
5-HT
BMCMC
30' -
90'
TNF
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S-H1
PMC
1. Kinetics of the release of preformed and newly synthesized tumor necrosis factor fTNF)-a from mouse mast cells stimulated through the high-affinity receptor for IgE, Fc,RI. Mast cells were sensitized with a monoclonal mouse anti-DNP IgE and then challenged with DNP ~s~-HSA in the presence f+) or absence f-1 of the transcription inhibitor actinomycin D (Act. D) at 10 pgml-1. In some experiments, the cells were incubated with 3H-5HT (1pCi ml-l) during the IgE-sensitization period, to permit the cells to incorporate 3H-5HT into their cytoplasmic granules prior to washing and challenge with specific anti en (see [210*1). (a) Kinetics of secretion of sH5HT and TNF-a from CI.MCJC57.1 cells in the absence of Act.D. (b) Kinetics of secretion of 9 H-SHT and TNF-a from CI.MC/C57.1 cells in the presence of Act.D. fc) Effect of transcription inhibiton with Act.D on the secretion of )H-5HT and TNF-a from primary cultures of mouse bone-marrow-derived mast cells (BMCMC) and from purified, freshly isolated mouse peritoneal mast cells (PMCs). Data for TNF-a are mean f SEM (n = 4/paint); data for sH-5HT are mean f SEM fn = 2-4/paint). Values for TNF-a release in the absence of Act.D are significantly different (P < 0.01) from values for the same cell types in the presence of Act.D at all intervals 2 30 min after initiation of stimulation for CI.MUC57.1 cells and at 90 min after initiation of stimulation for BMCMC and PMC. Reproduced, with permission, from Fig.
[21-l.
gen is much higher at sites containing mast cells than at mast-cell-deficient sites [21-l. Third, local administration of an antiserum to TNF-a reduces the leukocyte inliltration associated with &E-dependent cutaneous inflammation by about 50% [ 23**]. These fmdings strongly suggest that the production of TNF-a by mast cells is an important contribution to the leukocyte infiltration observed in &E-dependent reactions in mice. However, it is unlikely that TNF-a represents the only mast-cell-associated mediator that influences leukocyte recruitment in this setting; moreover, mast-cell activation may also result in the recruitment of additional sources of TNF-a at these sites (reviewed below and in [23**]).
Cytokine
production
by mouse basophils
Ben-Sasson ef al [24**] reported that mouse splenic non-B, non-T cells can produce IL-4 and IL-3 in response to cross-linkage of high-aIRnity Fc,RI. Conrad et UC [25= ] demonstrated that the IL-4-producing potential of splenic or bone marrow non-B, non-T cells markedly increased in mice that had been infected with N@postrongylus brasiliknsis or had been injected with antibodies to mouse IgD. Recently, Seder et aL [26*] reported that the splenic or bone marrow non-B, non-Tcell populations from anti-&D-injected mice, which express high affinity Fc,R and have IL4-producing capacity, are highly enriched in mature basophils or in mature basophils and basophillc myelocytes, respectively. This
finding, and others discussed in [26=], suggest that the mouse basophil may be able to produce IL-4 and perhaps IL-3 upon IgE-dependent and other forms of activation. However, the basophil-enriched populations also contained rare immature cells in the mast-cell lineage and numerous mononuclear cells lacking cytoplasmic granules. Thus, the precise identity of the IL-4-producing cell (or cells) in these preparations remains to be determined.
Cytokine production basophils
by human mast cells and
Stefan et al [27], using in situ hybridization with a murine cDNA probe, reported that cells with properties of basophils, or mast cells that were generated in vitro from human hemopoietic cells, expressed TNF-a mRNA They also identiIied a cytotoxic factor In the supematants of these cells whose bioactivlty could be partially blocked by an anti-TNF-a antibody. However, it was not determined whether the cells identiIied by in situ hybridization with the TNF-a probe were basophils or mast cells. Using an organ culture system; Klein et al [28] demonstrated that &E-dependent activation of human foreskin mast cells resulted in the expression of a TNF-a-inducible leukocyte adherence molecule, extracellular leukocyte adhesion molecule (ELAM)-1, on adjacent vascular endothelial cells and showed that antibodies to TNF-a Inhibited the development of augmented expression of EIAM-1 In tissue fragments challenged with
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agents to induce mast-cell activation. Subsequently, this group demonstrated the presence of both immunoreactive TNF-a and TM-a mRNA in human skin mast cells j2P.l. In contrast to the iindings of Klein ef al [ 281, Leung et aL [30**] reported that inhibition of the allergeninduced augmented ELAM-1 expression, which was observed in a skin organ culture system, required simultaneous treatment with antisera to both TNF-a and IL-l. These Iindings are further evidence to support the possibility that mast-cell-derived TNF-a may contribute to the leukocyte iniiltration observed in &E-dependent cutaneous LF%s in man, but indicate that IL-1 (from mast ceU and/or other sources) may also have an important role. Mast-cell-derived TNF-a may also contribute to LPRs expressed in human lung. We reported preliminary evidence that put&d human lung mast cells can release TNF-a upon stimulation through the Fc,RI [31]. Wegner et al [32**] showed in a primate model of asthma that a monoclonal antibody to intercellular adhesion molecule (ICAM)-1, a leukocyte adherence structure whose expression on the surface of vascular endothelial cells can be augmented by IL-l, TNF-a, or IFN-y, attenuated both airway eoslnophilia and airway hyper-responsiveness.
Mast-cell leukocyte cytokine inflammation and immunity
cascades
in
When one considers the diversity of multifunctional cytokines detected in different mouse mast-cell populations, the broad spectrum of biological responsesthat can be ir&.renced by these cytokines and the possibility that the expression of cytokine bioactivity by mastceU populations can be diiferentially regulated by various stimuli of mast-cellactivation (reviewed in [12]), one might reasonably propose an enormous number of potential roles for mast-cell cytolcines in adaptive or pathological responses.Consideration of all the biological effects of each mouse mast-cell-associatedcytokine would require a separate review for each molecule. However, the known effects of these agents include regulation of IgE production (IL-4, IFN-y), regulation of mast-cellproliferation and phenotype (IL-3, IL-4, GM-CSF, IFN-y, TGFp), modulation of leukocyte (basophil, eosinophil, neutrophil and monocyte) effector function (IL-3, IL-4, GMCSF, IFN-y, TNF-a), and numerous actions in in&mmation, clotting, anglogenesis,wound repair, tissue remodeling, and the development of pathological fibrosis (reviewed in [4-7,12,3339]). As reviewed elsewhere [4,5,7,12,39,40], mast cells have been implicated in many of these responses. Most analysesof mast-cellcytokine production have been carried out in in timderived mouse mast cells. Indeed, except-in the caseof TNF-a, there is virtually no information about cytokine production by freshly isolated mast cells, which can be very phenotypically diUerent from in vimderived mast cells [4,5]. Moreover, in many biological responses,including even those dependent on IgE, mast cells or basophils will represent just one of
many potential sources of cytokines, and many of their products will have complex activities that overlap, synergize, and/or antagonize those of other cytokine or inflammatory mediators (reviewed in [4,12]). As a result, a clear picture of the actual roles of mast-cell(or basophil) cytokine production in the diverse biological responses thought to be influenced by these cells will require much additional study (see below). Data derived from both murine and human studies strongly suggeststhat mast-cell-derivedTNF-a has an important role in the expression of &E-dependent intlammation and leukocyte recruitment. In the mouse, IgE-dependent cutaneous reactions predominantly contain neutrophils [ 23*-l, yet another cell type that can produce TNF-a [41~*,42**]. In humans, &E-dependent cutaneous reactions, and the infiltrates associatedwith asthma,also contain large numbers of eosinophils. Eosinophils represent a potential source of some cytokines that may also be produced by mast cells, such as IL-1 [43**] and TGFj3 [44**], and at least one cytokine that apparently is not produced by mast cells, TGF-a [45**,46**]. On the basisof thesefindings, we have proposed that the expression of many &E-dependent reactions, and probably other responsesin which mast cells play an important role, reflect the activities of a ‘mast cell-leukocyte cytokine cascade’ [4,12]. This hypothesis proposes that mast-cellactivation initiates the response,in part, through the releaseof M-a and other cytokines that can intluence the recruitment and/or function of additional effector cells (neutrophils, eosinophils, basophils, lymphocytes, monocytes, and platelets); these recruited cells influence the progression of the responseby providing additional sources of certain cytokines also produced by mastcells, and new sourcesof somecytokines (e.g., TGFa) that are not produced by the mast ceU (Fig. 2). As the reactions progress further, cytokines from mast cells and other resident cells, and from recruited (leukocyte) sources, exert complex paracrine and autocrine effects on resident cells (vascular endothelial cells, iibroblasts, epithelial cells, nerves, mastcells) that may contribute importantly to the vascular and epithelial changes, and to the tissue remodeling and fibrosis, which are so prominent in many disorders associatedwith mast-cell activation and leukocyte infiltration.
Mast-cell cytokine understanding
production:
gaps in our
Many important questions concerning the mechanisms that regulate the production, intraceUulardistribution and release of mast-cell cytokines remain. Furthermore, the extent to which different naturally occurring stlrnuli generated in association with immunological, physiological, or pathological responsesin viva can elicit distinct patterns of mast-cell(or basophil) cytokine releaseis uncertain. Much more work is required to determine the extent to which iindings obtained in the mouse apply to human mastcells, to evaluate possibleanatomicalvariation in the ability of mast cells to produce specific cytokines, and to
Cytokine
production
by mast
cells
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basophils
Galli, Gordon,
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(a) Mast-cell activation
(b)
Resident
[o
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(4
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Recruited
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Fig. 2. The mast cell-leukocyte cytokine cascade. (a) Mast cells are activated via IgE and specific antigen or by other mechanisms. fb) Mastcell-derived cytokines initiate direct effects on nearby cellular targets already present in the tissue, including epithelial cells/keratinocytes, fibroblasts and other stromal cells, vascular endotheial cells, mast cells, and, in some tissues, resident mononuclear cells, lymphocytes, and eosinophils. These cytokine-dependent effects will occur together with many important effects of mast-cell-derived mediators other than cytokines. fc) Some of the effects of mast-cell-derived cytokines, such as the induction of leukocyte adherence structures on vascular endothelial cells and/or epitheliai cells, contribute to the recruitment of leukocytes, including neutrophils, eosinophils, basophils, mononuclear cells, and platelets. (d) Certain mast-cell-derived cytokines may also enhance the effector function of some of these recruited cells. fe) The recruited leukocytes also contribute to the amplification/progression of the reaction, in part by increasing local concentrations of some cytokines also produced by mast cells (e.g., IL-l, TNF-a) (see text). Continued production of cytokines by activated mast cells contributes to the progression of the reaction. Local expansion of mast-cell populations, via autocrine factors produced by mast cells or by products of stromal cells or recruited leukocytes, may also contribute to the amplification/progression of the response.
define the basophil’s spectrum of cytokine production. Although these issuescan be addressedinitially using in vi&oderived cell populations, they ultimately will have to be evaluatedwith freshly isolated mature cells and in mast-cell or basophil populations present at sites of immune responsesor diseaseprocesses in vivo. For example, Bochner et al [47= ] demonstrated that IL-1 production occurred at sites of allergic responseselicited in human skin. However, the cellular source(s) of IL-1 in these responsesis not clear yet.
Conclusions Despite the current gaps in our understanding of mastcell cytokine production, particularly in humans,we feel that studiesperformed with mouse mastcells provide evidence for a few broad conclusions or generalizations. First, it is likely that the predominant actions of mastcell-derived cytokines will be manifestedwithin rejatively short distances (reviewed in [12]). However, effects of mast-cell-derived cytokines might become widespread
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under certain conditions, such as after parenteral exposure to specilic antigen or during systemic mastocytosis
1121. Second, the extent to which mast cells, as opposed to other cell types, are an important source of a parricular cytokine may vary greatly depending on the characteristics of the biological response under investigation. Clearly, the mast cells’ role will be most significant when the type and/or anatomical distribution of the relevant stimuli generated during individual biological responses favor(s) activation of mast cells over other sources of cytokines. In LPRs, mast cells may represent by far the most important initial source of TNF-or and other proMlammatory cytokines. Indeed, mast-cell-derived cytokines may directly or indirectly regulate the type of leukocyte recruited to these reactions (e.g., see [48**]), as well as influence many other important features of these responses. However, in other biological responses, which generate stimuli capable of activating multiple sources of cytokines, the specific contribution of mastcell-derived cytokines may be relatively unimportant or diflicult to discern. For example, TIT-a appears to be essential for the expression of contact sensitivity responses in mouse skin [49-l, but most analyses have detected no impairment of contact sensitivity reactions in genetically mast-cell-deficient mice (reviewed in [4,5]). Third, even in responses influenced by mast cell cytokine production significantly, full development of the reactions may depend on the generation of cytokines from additional cell types. One of the most important consequences of mast-cell activation may be the initiation of a mast cell-leukocyte cytokine cascade in which mast-cellderived cytokines contribute to an influx of neutrophils, eosinophils, and mononuclear cells that in turn provide additional cytokine activities important to the progression of the response. Fourth, the appreciation that certain of the biologically and clinically significant consequences of mast-cell (and perhaps basophil and eosinophil) activation reflect the production of multifunctional cytokines by these cells may suggest new insights into the therapy of disorders inlluenced by these cell types. The &E-dependent induction of increased levels of cytokine mRNAs in in vitroderived mouse mast cells can be inhibited by cyclosporin A [ 181 or dexarnethasone [ 501. Although corticosteroids can markedly diminish many of the clinical and histological manifestations of cutaneous LPRs and other allergic responses in the skin and other organs, and can inhibit mediator release from human basophils, corticosteroids do not inhibit &$-dependent release of histamine from human mast cells (reviewed in [2,6]). In light of these findings, it will be interesting to evaluate the possibility that one of the mechanisms by which corticosteroids interfere with the expression of allergic responses (and perhaps other pathological reactions) is by suppressing cytokine production by mast cells, as well as by interfering with cytokine production and the release of other mediators by cells recruited to sites of mast-cell activation. This hypothesis proposes that corticosteroids, and perhaps cyclosporln A and related compounds, can interfere with both the mast-cell-dependent
initiation, and the mast-cell- and leukocyte-dependent amplification/progression of disorders intluenced by the mast cell-leukocyte cytokine cascades.
Acknowledgment This work was supported by grants from the NIH.
References and recommended
reading
Papers of special interest, published within the annual period of review, have been highlighted as: . of interest of outstanding interest .. 1.
ISHUAKAT: Mechanisms of IgE-Mediated Hypersensitivity. In and Practice, 3rd edn. edited by Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, YningerpJV. St Louis, Missouri: Mosby, 1988, pp 71-93. GAIA SJ, LICHTENSTEIN LM: Biology of Mast CeIIs and Basophils. In Allerg)l: Principles and PracticeV 3rd edn edited by Middleton E Jr, Reed CE, EIIis EF. Adkinson NF Jr, Yuninger JW. St Louis, Missouri: Mosby, 1988, pp 10&134. Ailerg)~: Principles
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HOLGATEST, ROBINWNC, CHURCHMK: Mediators of Immediate Hypersensitivity. In Allerm: Principles and Practice, 3rd edn. edited by Middleton E Jr, Reed CE, EIIis EF. Adkinson NF Jr, Yuninger JW. St Louis, Missouri: Mosby 1988, pp 135163.
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GALUSJ.GEI~SLEREN, WER~HILBK, GORDONJR,TSAI M, HAMMEL I: Insights into Mast CeII Development and Function Derived from Analyses of Mice Carrying Mutations at beige, W/c-kit or SUSCF (c-kit Ligand) Loci. In 7?x Role of the Mast Cell in Health and Disease edited by KaUner MA, MetcaIfe DD. New York: Marcel Dekker, in press.
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GALU SJ: New Insights into ‘the Riddle of the Mast CeUs’: Microenvironmental Regulation of Mast CeII Development and Phenotypic Heterogeneity. Lub Invest 1990, 62:5-33. SCHLEIMERRP, DERSECP, FRIEDMANB, Guus S, PLAUI’ M, LICHTENSTEIN LM, MACGU\SHANDW JR: Regulation of Human BasophU Mediator Release by Cytokines. 1. Interaction with Antiinflammatory Steroids. J Immunol 1989, 143:131&1317.
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COSTAJJ, BURD PR, METCAIXE DD: Mast CeU Cytokines. In 7he Role of the Mast Cell in Health and Disease edited by KaIIner MA, MetcaIfe DD. New York: Marcel Dekker, in press.
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KINET J-P: The High AfI?nity Receptor for IgE. Curr Opin Immunol 1990, 2~499-505. CHUNGSW, WONG PMC, SHEN-ONGG, Ruscnn S, ISHUAKAT, EAVESCJ: Production of Granulocyte-Macrophage ColonyStimulating Factor by Abelson Virus-Induced Tumorigenic Mast CeII Lines. Blood 1986, 68:1074-1081. BROWN MA, PIERCEJH, WATSON CJ, FALCOJ, IH~E JN, PAUL WE: B CeU Stimulatory Factor-l/Interleukin-4 rnRh’A Is Expressed by Normal and Transformed Mast CeIIs. Cell 1987, 508Op-818.
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HUMPHRLESK, ABRAHAMS, KRYSTALG, IANSDORPP, LEMOINE F, EAT CJ: Activation of Multiple Hemopoietic Growth Factor Genes in Abelson Viis-Transformed MyeIoid CeUs. Eq Hematol 1988, 16:774-781.
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Cytokine ciated Cytolytic Factor Related to Tumor Pros Nat1 Acad Sci USA 1987, 85~91759179.
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&mDON JR, GALU JS: Mast Ceils as a Source of Both Preformed and Immunologically Inducible TNP-a/Cachectin. Nature 1990, 346~274-276. The mouse maSt cell is the first cell type to be identified that contains signilicant preformed stores of TNF-a bioactivity avaiiable for immedi ate release. IgE.dependent activation of in vitroderivecl or freshly isolated peritoneal mast cells results in increz.ed levels of TNF-a mRNA and release of TNF-a bioactivity. This study presents the first direct ev idence that mature, freshly purified mast ceUs contain both mRNA and bioactlvity for a well characterized cytokine. 15.
RIcm AL, OKUNO T, TAKAGAK~ Y, DJEU JY: Natural Cy totoxic CelI-Specihc Cytotoxic Factor Produced by IL-3. Dependent BasophiIIc/Mast CeIIs. Relationship to TNF. J Immunol 1988, 141:306-3066.
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PLWT M, PIERCE JH, WAGON CJ. HANLEY-HYDE J, NORDAN RP, PAUL WE: Mast Ceil Limes Produce Lymphokines in Response to Cross-Linkage of FceRI or to Calcium Ionophores. Nature 1909, 3396467.
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WODNAR-FIUPOWICZ A, HEU~~ER CH, MORONI C: Production of the Haemopoietic Growth Factors GM-CSF and Interleukin3 by Mast Cells In Response to I@ Receptor-Mediated Activation. Nature 1989, 339:15G152.
18.
BURD PR, RICERS HW, GOR~~N JR, MARTIN CA, JAYWILSON SD, DVORAK AM, GALU SJ, Dear ME: Interleukin Dependent and -Independent Mast CeIIs Stimulated 1gE and Antigen Express Multiple Cytokines. J &J 1989, 170:245-257.
19.
TSAI M, GORooN JR, GNU SJ: Mast Express Transforming Growth Factor FRSEB J 1990, 4zAI944.
S, 3with Med
Ceils Constitutively g mRNA [abstract].
20. .
GURLSH MF, GHUDYAL N, ARM J, AUSTEN KF, ABRAHAM S, RE?‘NOLDS D, SEVENS RL Cytokhte mRNAs are Preferentially Increased Relative to Secretory Granule Protein mRNA in Mouse Bone Marrow-Derived Mast Ceils that have Undergone @E-Mediated Activation and Degranulation. J Immunol 1991, 146:1527-1533. Reports that the substantial increases in levels of TNF-a, IL-~, and GMCSF mRNA observed l-2 h after &E-dependent activation of in r&o derived mouse mast ceils is not associated with significant changes in levels of mRNA for Fc,RIa or several constituents of the cells’ secretory granule. 21. ..
ChXDON JR GALLI SJ: Release of Both Preformed and Newly Synthesized Tumor Necrosis Factor a (TNF-a)/Cachectin by Mouse Mast Cells StimuIated by the Fc,RI. A Mechanism for the Sustained Action of Mast Cell-Derived TNF-a During &E-Dependent Biological Responses. J EQ Med 1991, 174:103107. Presents evidence derived from both in vitro and in vivo experiments indlcatlng that mouse mast cells represent a biologicaUy significant source of TNF-a during &E-dependent responses, and demonstrates that &E-dependent mast-cell activation results in the sustained release of newiy synthesized TNF-a. First demonstration of a signUicant difference in the &E-dependent augmentation of levels of a cytokine mRNA at tissue sites containhtg or essentially devoid of mast ceils. 22.
23. ..
I~ANSKE RF JR, KAUNER MA Late Phase AIlergic Reactions. In Allergy, Princ@ks and Practie, 3rd edn edited by Middleton E Jr, Reed CE, EUIs DF, Adkinson NF Jr, YunInger JW. St Louis, MISSOU~: Mosby, 1988, pp 224-226.
WERSHIL BK, WANG 2, GORDON JR, G~tu SJ: Recruitment of NeutrophiIs During &E-Dependent Cutaneous Late Phase Responses in the Mouse is Mast Cell Dependent: Partial Inhibition of the Reaction with Antiserum Against Tumor Necrosis Factor-Alpha J Clin Invest 1991, 87:44ti53. First demonstration, using geneticaUy mast-cell-deficient mice In which the deIiciency is overcome IocaUy and selectively by adoptive transfer of in uitroderived mast cells, that mast cells are essential for virtually ail of the earIy and late phases of tissue swelling and leukocyte in&ation a.ssocIated with &E-dependent reactions in the skin, and local admIn-
production
by mast
cells
istration of antibodies leukocyte inliitration evidence that a well candy inlluences the biological response
and
basophils
Galli,
Gordon,
Wershil
to TNF-a can inhibit such mast-ceil-dependent by about 50%. This study presents the first direct characterized mast-cellassociated cytokine signiiiexpression of an IgE- and/or mast-cell-dependent in oirto.
BENSASSON SZ, LEGROS G, CONRAD DH, F~NKELMAN FD, PAUL WE: Cross-Linking Fc Receptors StImuIate Splenic NonB, Non-T CeIIs to Secrete Interleukin 4 and Other Lymphokines. Proc Natl Acud Sci USA 1990, 87:1421-1425. Demonstration that spleen cells depleted of both B and T iymphocytes, and containing no detectable alcianblue positive mature mast ceUs, produce IL-4 and IL-3 in vitrowhen stimulated with plate-bound 1gE in the presence or absence of IL-3. Furthermore, they produce IL-4 when stimulated with plate-bound IgGl, IgG2a or IgG2b in the presence of IL-3. These lindings suggest that ‘non-B, non-T cells’ might represent an important source of cytokines in allergic diseases, heirninth infections, and disorders associated with immune complex deposition.
24. ..
25. .
CONRAD DH, BEN-SMSON SZ, LEGROS G, FINKELMAN FD, PAUL WE: Infection with Nippostrongyfus brasiliensis or Injection of Anti-IgD Antibodies Markedly Enhances FcReceptor-Mediated Interleukin 4 Production by Non-B, Non-T CeUs. J Exp Med 1990, 171:1497-1508. Demonstration that infection of mice with N. brasik?nsis, or injection of mice with anti-IgD antibodies, greatly increases the number and IL-4producing capacity of splenk non-B, non-T cells and gready increases the IL-4.producing capacity of bone marrow non-B, non-T cells. The IL-4-producing capacity of splenic non-B. non-T cells from anti-IgD-injetted mice is less dependent on IL-3 than that of ceils from naive mice, and antigen can induce IL-4 production from non-B, non-T cells derived from N brasi(iens&infected mice. 26. .
SEDER R4, PAUL WE, DVORAK AM, SHARI~S SJ, KAGEY-SOBOTKA A NIV Y, FU‘IKELMAN FD, BAREIIEIU SA, GALU SJ, PLAUT M: Mouse Splenic and Bone Marrow Cell Populations that Express High-ARInity Fc, Receptors and Produce Interleukin 4 are Highly Enriched in BasophiIs. Prcc Nat1 Aud Sci USA 1991, 88:2835-2839. Reports that basophils or basophilic myelocytes represent the vast majority ( >90%) of granulated cells present in Fc,R+ splenic or bone marrow non-B, non-T cells of anti-&D-injected mice. However, these populations also contain many non-granulated mononuclear ceUs and rare cells (3-l%) that may represent immature mast ceils. These data raise the possibility, but do not prove, that basophils represent a source of the IL-4 and IL-3 produced by Fc,R+ non-B, non-T cells. 27.
STEFFEN M, ABBOUD M, POTI-ER GK, YUNG YP, MOORE MAS: Presence of Tumor Necrosis Factor or a Related Factor in Human BasophiI/Mast Ceils. Immunology 1989, 66:44%50.
28.
KLEIN LM, IA~KER RM, MA’rts WI, MURPHY GF: DegranuIation of Human Mast CelIs Induces an EndotheliaI Antigen CentraI to Leukocyte Adhesion. Proc Nat1 Acad Sci USA 1989, 86~0972-8976.
WAlSH LJ, TRINCHIERI G, WAIDOW HA, WHlTAKER D, MURFWY GE Human Dental Mast Cells Contain and Release Tumor Necrosis Factor a which Induces Endothelial Leukocyte Adhesion Molecule-l. Proc Natl Acud Sci USA 1991, 88:4220-4224. Demonsttation using in situ hybridhation d-tat human dermaI mast cells represent the only ceU type in the normal dermis with detectable TNF-a immunoreactivity. Furthermore, some mast ceUs at sites of delayed hypersensitivity response express TNF-a mRNq and sdrnulation of purified dermal mast cells with morphine sulfate results In loss of T’NF-u immunoreacdvity in the cells and the appearance of TNF-a Immunoreactivity in the ceils’ supematant. Such mast-cell-derived TNF-a can Induce I&AM-l expression by vascular endothelial cells.
29. ..
IEUNG DYM, POBER JS, COTRAN RS: Expression of EndotheIialLeukocyte Adhesion Molecule-l in Elicited Late Phase Allergic Reactions. J Clin Inuest 1991, 87:180>1809. Documents that injection of allergen into the skin of allergic subjects Induces both EIAM-1 expression on vascular endotheiiai ceUs and leukocyte infJmtion. Allergen also induces ELAM-1 expression on vzcular endothelial cells in skin organ culture~~ in vitq and this EIAM-1 exptession can be inhibited by combined treatment with antisera to TNF-a and IL-l, but not by antisera to either cytokine alone. These Iindings sup
30. ..
871
872
Atopic
allergy and other hypersensitivities
port the conclusion that allergen-induced cytokine release by in skin (probably mast cells), rather than by recruited cells, for the augmented EL4M1 expression observed during early these responses. The relevant cytokines are likely to be TNF-a 31.
GORDON
32.
WECNER ROTHIEIN
cells iixed accounts phases of and 1L.l.
JR, Pos’r T, Sc~uw ES, G~lll SJ: Characterization of Mouse Mast Cell TNF-a Induction In Vitro and In Viuo, and Demonstration that Purifted Human Lung Mast Cells contain TNF-a FdEB J 1991, 5:1009. CD, GUNDEL R: Intracellular
RH,
REILLY
P, W~NE.~
N,
Lm-13
LG,
Adhesion Molecule-l (RAM-l) in the Pathogenesis of Asthma Science 1990, 2473456-159. Presents evidence derived from both in vifro and in c+uo studies indicating that tissue inliltration of eosinophils in a monkey model of asthma is mediated, in part, by adhesion of eosinophils to ICAM-I. lCAM-1 is upregulated on both vascular endothellal cells and bronchial epithelial cells in this model, and in vit~oadministration of a monoclonal antibody to ICAMl markedly diminishes both airway eosinophilia and hyper-responsiveness. ..
33.
BEIJTUR B, CERMU A The Biology of Cachectin/TNF - a Primary Mediator of the Host Response. Annu Rev Immunot 1989, 1625-655.
34.
ARAI
K-I,
LEE F, MNAJ~MA
A, M~YATAKE
S, ARAI
N, YOKOTA
Cytokines: Coordinators of Immune and Inflammatory sponses. Annu Rev Birxbem 1990, 59~783-836.
SL, HOLGATX ST: Cellular and Chemical Mediators - Their Roles in Allergic Diseases. Cur-r @in Immunol 1990. 2:513-524.
36.
SD, CERAMI A: Macrophage lntlammatory Proteins 1 and 2: Members of a novel Superfamily of Cytokines. F+l.S.!Z,!l J 1989, 3:2565-2573.
37.
FD, KATONA LM, URBAN JF JR, PAUL WE: Control of In Vito IgE Production in the Mouse by lnterleukin 4. In I@, Mast C-elk and ibe AIIagic Re$nwse. Ciba Foundah’on S’um Na 147 edited by Chadwick D, Evered D, Whelan J. Chichester: John Wiley and Sons Ltd, 1989, pp 3-22.
38.
B~UKW~LL FR, BURKE F: The Cytokine day 1989, 10:299-304.
39.
CV~MAN HN: Mast Cells. T Cells munol Today 1985, 6:192-194.
40.
SELVE H: The Mast
WOLPE
FINKELMAN
Cells [book].
Washington
fmmunol
To
Fibrosis.
Im
DC: Butterworths,
1%5. 41.
DLIBRA~EC DB, SPIUGGS DR, MANNICK J& RODIUCK ML Circulatlng Human Peripheral Blood Granulocytes Synthesize and Secrete Tumor Necrosis Factor a. Proc Nafl Acud Sci USA 1990, 87:675ti761. Reports that highly purilied preparations of human neutrophils (98% neutrophils, 1% eosinophils and approximately 1% monocytes) stimulated with lipopolysaccharide contain TNF-a mRNA and release approximately the same amount of TFN-a bioactivlty per cell as do lipopolysaccharide-stimulated monocytes isolated from the same donors. The results suggest that neutrophils may represent a significant source of TNF-a during inflammatory responses and TNF-a can function as an autocrine factor influencing neutrophil function.
..
42. ..
DJEU JY, SEREOUSEK D, B~CHARD DK: Release of Tumor Necrosis Factor by Human Polymorphonuclear Leukocytes. B&ud 1990, 76:1405-1409. Documents that human peripheral blood neutrophils ( > 99% purity) stimulated in uihw by co-culture with Candida albicans or by lipopolysaccharide release TNF-a bioactivity, which is inhibitable by antibodies to TNF-a but not by antibodies to lymphotoxin. Such TNF-a production by neutrophils is markedly reduced by inhibitors of RNA or protein synthesis. These results indicate that most, or all, of the TNFa produced by neuttophils, like that of monocytes, is synthesized in response to appropriate stimulation of the cells.
43. ..
WONG DTW, J, CHOU MY,
ELOVIC A, MATOSSIAN K, NACURA N, MCBR~E GORDON JR, RAND TH, Gw SJ, WEUER PF:
Eosinophils from Patients with Blood Eosinophilia Express Transforming Growth Factor 81. Blood 1991, in press. Demonstration using in sifu hybridization that 100% of the peripheral blood eosinophils from patients with hypereosinophilia associated with the idiopathic hypereosinophilic syndrome, Job’s syndrome, or a drug hypersensitivity reaction, contain TGF-Bl mRNA and, using immunohistochemistry techniques, TGF-81 product. In contrast, the blood eosinophils of normal donors contain little or no TGF-Bl mRNA and no detectable product. These findings suggest that eosinophil production of TGF.81 may contribute to the pathogenesis of the striking alteration in connective tissue observed in many disorders associated with hypereosinophilia and/or eosinophil infiltration of tissues. 45. ..
JOHNSTON
and Abnormal
44. ..
T:
Re-
35.
Network.
Reports that peritoneal eosinophils purifted (94%) from mice infected with Mesocesloides corfi and then stimulated with lipopolysaccharide are positive for IL.1 mRNA according to in silu hybridization nith a cDNA probe, and release IL-1 bioactivlty when stimulated with lipo polysaccharide. In contrast, no IL.1 is detected in lysates of unstimulated eosinophiis. tipopolysaccharide-induced IL-I production is greatly increased by indomethacin. Although many other cell types can also pro. duce IL-I, this is the first report that eosinophils can produce mRNA and the product of a well characterized cytokine.
DEL Pozo V, DE ANDRES B, M~ttrt~ E, MARUIU N, ZUBELD~A JM, PALXXINO P, moz C: Mu&e Eosinophils and IL-l: aIL1 mRNA Detection by In Situ Hybridization. J Immunol 1990, 144:3117-3122.
ELOVIC A, GAUI SJ, WEUER PF, CHANG ALC, CHIANG T, CHOU MY, DONOFF RB, GAUAGHER GT, MATOSS~AN K, MCBRIDE J, TSN M, TODD R, WONG DTW: Production of Transforming
Growth FActorAlpha by Hamster Eosinophils. Am J Pafbol 1990, 137:14251434. Demonstration using in si?u hybridization immunohistochemistry that infiltrating eosinophils, but not resident mast cells, represent a major source of TGF-a mRNA in hamster cheek pouch carcinomas and that about 40% of these eosinophils also contain TGF-a product. Bone marrow eosinophils are also positive for TGF-a mRNA (approximately 70%) and product (approximately 20%). These findings suggest that expression of TGF-a by eosinophils may be regulated during eosinophil maturation and/or by factors at sites of eosinophil inliltration. and suggest unique roles for the eosinophil in health and disease. 46. ..
WONG DTW. WEUR PF, GALU SJ, ELOVIC 4 RAND TH, GAUAGHER GT, CHUG T, CHOU MY, MATOSSWU K. MCBRIDE J, TODD R Human Eosinophils Express Transforming Growth
Factor-Alpha J Ez+!J Med 1990, 172:673-681. First demonstration that human eosinophils represent a source of a multifunctional cytokine. TGF-a mRNA was detected by in sifu hybridization in eosinophils infiltrating colonic adenocarcinomas and by in siru hybridization, polymerase chain reaction or northern analysis, in eosinophils from a patient with the idiopathic hypereosinophillc syndrome: these eoslnophils also expressed the mature, biologically active form of TGF-a according to polymerase chain reaction restriction enzyme analysis, immunohistochemistry, and radioimmunoassay of the cells’ supematants. In contrast, none of the blood eosinophils of normal donors contained detectable TGF-a product and most of them lacked TGF-a mNRA 47.
BOCHNER
GILLIS leased Allergy Demonstration duced at sites Immunoreactive phases of the at late (IO-12
.
BS, C HNUSWORTH
EN,
LICHTENSTELN
LM,
DERSE
CP,
S, DINAR!Z~.~I CA, S~HLEIMER RP: lnterleukin-1 is Reat Sites of Human Cutaneous Allergic Reactions. J CIin Immunol 1990, 86:83&839. using a skin-chamber challenge model, that RI is proof antigen-induced late phase reactions in human skin. IL-1 B was generated during early (peak at 1 h) and late response, but detectable IL-1 bioactlvity was present only h) intervals.
48.
BOCHNER
..
STERBINSKY
BS, LUSCINSKAS FW, G~RONE SA, DERSE-ANIXONY
CP,
KLUNK
JA JR, NEWMAN D, SCHIJZIMER
W, RF?
Adhesion of Human Basophils, Eosinophils, and Neutrophils to lnterleuldns I-Activated Human Vascular Endothelial Cells: Contributions of Endothelial Cell Adhesion Molecules. / E3qb Med 1991, 173:15531556. In uifro assays of binding of human granulocytes to human umbiical vein endothelial cells, and Bow cytometric detection of gtanulocyte counter-receptors for endothelial-ceU adhesion molecules, were used to suggest distinct roles for ICAM-1, EIAM-1 and VCAM-1 during granulocyte adhesion to vascular endothelium. Basophils and eoslnophils, unlike neutrophils, expressed very late antigen-4, the counter-receptor
Cytokine for VCAMI, suggesting that preferential induction thelial cells at sites of allergic responses might selective recruitment of basophils and eosinophils
of VCAM-I on endopromote the relatively to these reactions.
PICUET PF, GRALI GE, HA~ISER C. VA%SAU.I P: Tumor Necrosls Factor is a Critical Mediator in Hapten-Induced Irritant and Contact Hypersensitivity Reactions. J Exp Med 1991, 173673-679. Demonstration that antibodies to TNF.a markedly inhibit the development of contact sensitivity responses in sensitized mice and irritant reactions in non-sensitized mice, and also interfere with the augmenta tion of TNFa mRNA levels obsetved at sites of contact sensitivity or irritant reactions, Using in situ hybridization, TNF-a mRNA was found to be present in several cell types in these reactions, especially basal keratinocytes and dermal cells thought to be neutrophils. 49. ..
production
50.
by
mast
WERSHIL
cells
BK,
Dexamethasone tion by Mouse Mast Cell and stract). FXSEB
and
GORDON
basophils
Calli, Gordon,
Wershil
JR,
Zs,
GALU
Inhibits the Mast CeUs TNF-a-Dependent J, in press.
WANG
LAVICNE
&E-Dependent In Vitro and 1nRammation
SJ Galli, BK Wershil, Division of Experimental of Pathology, Beth Israel Hospital, 330 Brookline sachusetts 02215, USA JR Gordon, The Department of Veterinary lege of Veterinary Medicine, University Saskatchewan S7NOW0, Canada.
JA,
SJ:
TNF-a RoducSuppresses IgEIn l&o. (ab-
Pathology, Avenue,
Department Boston, Mas-
Microbiology, of Saskatchewan,
Western ColSaskatoon,
873
production J. Calli,
Beth Israel Hospital
John
and Harvard
by mast cells and basophils R. Gordon Medical
and Barry
School,
Boston,
K. Wershil
Massachusetts,
USA
Mast cells and/or basophils have been implicated in the expression of a wide variety of biological responses, including immediate hypersensitivity reactions, host responses to parasites and neoplasms, angiogenesis, tissue remodeling, and immunologically non-specific inflammatory and fibrotic conditions. Recent findings suggest that an important mechanism by which mast cells influence such biological responses is through the production of a broad panel of multifunctional cytokines. In contrast, the extent to which basophils can produce cytokines is uncertain.
Current
Opinion
in Immunology
Introduction Mast cells and basophils are critical effector cells in certain forms of &E-dependent immediate hypersensitivity, and also participate in a wide variety of biological responses in which IgE has no demonstrable role (reviewed in [l-5]). Certain clinically important aspects of &E-dependent responses, such as the striking recruitment of leukocytes that occurs in some of these reactions, are incompletely understood in mechanistic terms. The functions of mast cells and basophils in responses not involving IgE are even more obscure. This review focuses primarily on evidence that indicates mast cells or basophils can produce multifunctional cytokines and that such molecules may be important mediators in biological responses associated with the activation of these cells. Space limitations preclude adequate discussion of several important, related issues, which recently have been reviewed elsewhere. These include the role of multifunctional cytokines in regulating mast-cell or basophil proliferation, maturation or phenotype [4,5], and the ability of some of the same cytokines to induce or regulate basophil or mast-cell mediator production [6,71.
Distribution basophils
and function
of mast cells and
Mammalian mast cells and basophils perform three major functions: they express the high&inky receptor for IgE (Fc,RI) [8]; upon &E-dependent or other forms of stimulation they cleave a similar, though not identical, panel of biologically active mediators [l-3]; and they participate in &E-dependent and certain &E-independent biological responses [l-5]. Although the number of tis-
AMulV-Abelson murine leukemia virus; ElAM-extracellular CM-CSF-granulocyte-macrophage colony-stimulating LPT-late-phase reaction; MIP-macrophage inhibitory TN&tumor necrosis factor; VCAM-vascular @ Current
1991,
3:8654373
sue mast cells can increase (or decrease) in association with certain biological responses, even normal vascularized tissues have a resident population of mature mast cells, whose numbers and phenotypic characteristics vary according to anatomical site [5]. Many of these cells reside in close proximity to such potential targets of mediator/cytokine action as vascular endothelial cells, iibroblass, epithelial cells, or nerves [ 51. Mature basophils, unlike mature mast cells, circulate in the blood, albeit in very low numbers, but normally do not reside in the peripheral tissues [2,5]. However, a wide variety of biological responses are associated with elevated levels of circulating basophils and/or the recruitment of basophils into the affected tissues [ 21.
Mast cells as a source cytokines
of multifunctional
The first direct evidence that mast-cell populations can produce a well characterized cytokine was the demonstration that certain Abelson murine leukemia virus (A-MuLV)-transformed tumorlgenic mouse mast-cell lines constitutively produced granulocyte-macrophage colonystimulating factor (GM-CSF) mRNA and released GM-CSF [9]. Brown et al [lo] subsequently reported that nine of 15 spontaneously or A-MuLV-transformed mouse mastcell lines constitutively expressed mRNA for interleukln (IL)-4 and some constitutively released IL.-4 bioactivity. Only a few of these mast-cell lines contained mRNA for IL-3 or GM-CSF. Brown et al [lo] also detected low levels of IL-4 mRNA in each of five IL+dependent mouse mastcell lines, but these cells did not release detectable IL-4 bioactivky, Humphries et al [ 1 l] showed that some AMuLV-transformed mast cells constitutively produced IL-3
Abbreviations leukocyte adhesion molecule; Pc,RI-high-affinity receptor for I& factor; ICAM-intercellular adhesion molecule; IL-interleukin; basophilic leukemia; protein; PCDa-prostaglandin D2, . RRL-rat cell-adhesion molecule; VIA-very late antigen.
Biology
Ltd ISSN
0952-7915
865.
866
Atopic
allergy and other hypersensitivities
and GM-CSF mRIU4.s and products, and also produced a bioactivity similar to that of IL-~. The first cytokine bioactivity to be clearly associated with normal mast cells was tumour necrosis factor (TNF)&ache&n. Several groups demonstrated that in vitro derived IL-3-dependent mouse mast cells, rat basophilic leukemia (RBL) cells, or freshly isolated mouse or rat peritoneal mast cells expressed cytolytic activity against certain cellular targets, and some examples of this mastcell-dependent cytotoxicity were partially inhibited by antibodies to TNF-a (reviewed in [ I2 ] >. Young et al [13] showed that mouse peritoneal mast cells, as well as IL-3-dependent and IL3independent mouse mast cells generated in vitm, contained a cytoplasmic granule-associated cytokine with immunologic and cytotoxic activities very similar to those of TNF-a. We showed [ 140.1 that this TNP-a-like cytotoxic mediator was a product of the TNF-c&achectin gene, and that unstimulated mouse peritoneal mast cells constitutively contained approximately twice as much TNF-a bioactivity as did lipopolysaccharide-stimulated mouse peritoneal macrophages. This iinding illustrates the important point that the biology of some mast-cell-associated cytokines may differ signihcantly from that of the same cytokines in other cell types. Thus, macrophages, T cells, and B cells contain little or no preformed TNF-a bioactivity, whereas mouse peritoneal mast cells contain substantial preformed stores of TNF-a available for immediate reIease upon appropriate stimulation of the cell (reviewed in [ 12,14**]).
IgE-dependent production
regulation
of mast-cell cytokine
Stimulation through the Fc,IU induces mast cells to accumulate increased levels of mRNA for cytokines and to release cytokine products. Richards et al [ 151 showed that RBL cells released a TNF-a-like cytotoxlc activity upon challenge with anti-IgE. Plaut et al [16] demonstrated that &E-dependent stimulation of long-term IL+dependent mouse mast-cell lines resulted in increased levels of mRNA for IL-3, IL4, IL-5, and IL-6 and the release of bioactivity for IL-3, IL-4 and IL-6. Wodnar-FiIipowicz et al [ 171 reported that primary cultures of IL-3-dependent, bone marrow-derived cultured mast cells stimulated with 1g8 and specific antigen exhibited increased levels of IL-3 and GM-CSF mRNA and released IL-3 and GM-CSF bioactivity. Burd et al [ 181 showed that long-term IL-3-dependent or -independent mouse mast-cell lines activated by 1gE and antigen exhibit Increased levels of ~RNA for IL-la, IL-~, IL-5, IL-6, GM-CSF, and four members of the macrophage in8ammatory protein (MIP)-1 gene family TCA3, JE, MIPla, and MIP-18. ‘Iwo of the four mast-cell lines tested exhibited &E-dependent augmentation of levels of ~I?NA for EN-y. Burd et al 1181 also showed that IgE-dependent activation of mast-cell lines or primary cultures of bone-marrow-derived cultured mast cells resulted in release of bioactivity for IL-l, IL-4 and IL-6. In contrast to mRNA for other cytokines, transforming growth factor (TGF)-j3 ~RNA was readily detectable in un%imulated
cells and only slightly elevated by &E-dependent activation of mast-cell lines or bone-marrow-derived cultured mast cells [ 191. Gurish et al [20*] showed that IgP-dependent activation of these cultured mast cells resulted in a preferential increase in mRNA for cytokines compared with mRNA for secretory granule proteins.
TNF-a as an example of a new class of mast-cell-associated mediators
Conventionally, mast-cell-associated mediators are divided into the preformed mediators such as histamine and the proteases, which are stored in the cells’ cytoplasmic granules and are released upon cell activation, and the newly synthesized mediators, such as prostaglandin Dz (PGDz) and the sulftdopeptide leukotrienes, which are not stored but are produced and only secreted upon appropriate stimulation of the cells [2,3]. We have proposed [21**] that TNP-a may be representative of a new class of mast-cell-associated mediators, because IgE-dependent activation of the mast cell results in the rapid release of preformed stores of TNF-a bioactivity, as well as the induction of increased levels of TNF-a mRNA associated with the sustained release of large quantities of newly synthesized TNF-a bioactivity (Fig. 1). Thus, for both in vitroderived cultured mast cells and puriiied peritoneal mast cells, the total amount of TNF-a bioactivity present in the cells and their supematant l-2 h after &$-dependent activation exceeds that present in the unstimulated cells [ 14”,21**]. The sustained release of newly synthesized TNF-a by appropriately stimulated mast cells represents a mechanism bywhich mast-cell-derived TNF-a can exert its actions on leukocyte emigration and activation, and have other effects, for prolonged periods during &E-dependent and perhaps other biological responses.
IgE-dependent leukocyte recruitment in mouse skin requires mast cells and is dependent on
TNFa Much of the interest in the clinical significance of mastcell cytokine production has focused on late-phase reactions (LPRs). In LPRs, &E-dependent mast-cell activation is associated with leukocyte infiltration that develops within hours of antigen challenge [2,3,22]. Notably, the leukocyte infiltration associated with LPRs, rather than the immediate consequences of mast-cell activation per se, is thought to be largely responsible for the tissue damage associated with asthma and other allergic conditions [2,3,22]. We have reported several lines of evidence indicating that mast cells and TNF-a contribute significantly to the expression of &E&dependent inflammation elicited in mouse skin. First, mast cells are essential for the leukocyte infiltration associated with &E-dependent cutaneous reactions, which do not occur in the absence of this cell type [23**]. Second, the amount of TNF-a mR1%4 detectable in skin challenged with IgE and anti-
Cytokine
Without Act. D
(a) TNF-a _. secretion (U/l 0 cells)
With Act. D
(b) 100 -40
100~40
production
by mast cells and basophils
0
(cl
+ Act.D
0
Galli, Gordon,
Wershil
- Act.D
1207
40
Specific serotonin release (%)
30
10
0
20
40
60
120
0
20
40
60
30' --
90'
TNF Stimulation time Cl. MUC57.1
(min)
Stimulation time Cl. MCIC57.1
(min)
30'
5-HT
BMCMC
30' -
90'
TNF
-30
S-H1
PMC
1. Kinetics of the release of preformed and newly synthesized tumor necrosis factor fTNF)-a from mouse mast cells stimulated through the high-affinity receptor for IgE, Fc,RI. Mast cells were sensitized with a monoclonal mouse anti-DNP IgE and then challenged with DNP ~s~-HSA in the presence f+) or absence f-1 of the transcription inhibitor actinomycin D (Act. D) at 10 pgml-1. In some experiments, the cells were incubated with 3H-5HT (1pCi ml-l) during the IgE-sensitization period, to permit the cells to incorporate 3H-5HT into their cytoplasmic granules prior to washing and challenge with specific anti en (see [210*1). (a) Kinetics of secretion of sH5HT and TNF-a from CI.MCJC57.1 cells in the absence of Act.D. (b) Kinetics of secretion of 9 H-SHT and TNF-a from CI.MC/C57.1 cells in the presence of Act.D. fc) Effect of transcription inhibiton with Act.D on the secretion of )H-5HT and TNF-a from primary cultures of mouse bone-marrow-derived mast cells (BMCMC) and from purified, freshly isolated mouse peritoneal mast cells (PMCs). Data for TNF-a are mean f SEM (n = 4/paint); data for sH-5HT are mean f SEM fn = 2-4/paint). Values for TNF-a release in the absence of Act.D are significantly different (P < 0.01) from values for the same cell types in the presence of Act.D at all intervals 2 30 min after initiation of stimulation for CI.MUC57.1 cells and at 90 min after initiation of stimulation for BMCMC and PMC. Reproduced, with permission, from Fig.
[21-l.
gen is much higher at sites containing mast cells than at mast-cell-deficient sites [21-l. Third, local administration of an antiserum to TNF-a reduces the leukocyte inliltration associated with &E-dependent cutaneous inflammation by about 50% [ 23**]. These fmdings strongly suggest that the production of TNF-a by mast cells is an important contribution to the leukocyte infiltration observed in &E-dependent reactions in mice. However, it is unlikely that TNF-a represents the only mast-cell-associated mediator that influences leukocyte recruitment in this setting; moreover, mast-cell activation may also result in the recruitment of additional sources of TNF-a at these sites (reviewed below and in [23**]).
Cytokine
production
by mouse basophils
Ben-Sasson ef al [24**] reported that mouse splenic non-B, non-T cells can produce IL-4 and IL-3 in response to cross-linkage of high-aIRnity Fc,RI. Conrad et UC [25= ] demonstrated that the IL-4-producing potential of splenic or bone marrow non-B, non-T cells markedly increased in mice that had been infected with N@postrongylus brasiliknsis or had been injected with antibodies to mouse IgD. Recently, Seder et aL [26*] reported that the splenic or bone marrow non-B, non-Tcell populations from anti-&D-injected mice, which express high affinity Fc,R and have IL4-producing capacity, are highly enriched in mature basophils or in mature basophils and basophillc myelocytes, respectively. This
finding, and others discussed in [26=], suggest that the mouse basophil may be able to produce IL-4 and perhaps IL-3 upon IgE-dependent and other forms of activation. However, the basophil-enriched populations also contained rare immature cells in the mast-cell lineage and numerous mononuclear cells lacking cytoplasmic granules. Thus, the precise identity of the IL-4-producing cell (or cells) in these preparations remains to be determined.
Cytokine production basophils
by human mast cells and
Stefan et al [27], using in situ hybridization with a murine cDNA probe, reported that cells with properties of basophils, or mast cells that were generated in vitro from human hemopoietic cells, expressed TNF-a mRNA They also identiIied a cytotoxic factor In the supematants of these cells whose bioactivlty could be partially blocked by an anti-TNF-a antibody. However, it was not determined whether the cells identiIied by in situ hybridization with the TNF-a probe were basophils or mast cells. Using an organ culture system; Klein et al [28] demonstrated that &E-dependent activation of human foreskin mast cells resulted in the expression of a TNF-a-inducible leukocyte adherence molecule, extracellular leukocyte adhesion molecule (ELAM)-1, on adjacent vascular endothelial cells and showed that antibodies to TNF-a Inhibited the development of augmented expression of EIAM-1 In tissue fragments challenged with
867
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allergy
and
other
hypersensitivities
agents to induce mast-cell activation. Subsequently, this group demonstrated the presence of both immunoreactive TNF-a and TM-a mRNA in human skin mast cells j2P.l. In contrast to the iindings of Klein ef al [ 281, Leung et aL [30**] reported that inhibition of the allergeninduced augmented ELAM-1 expression, which was observed in a skin organ culture system, required simultaneous treatment with antisera to both TNF-a and IL-l. These Iindings are further evidence to support the possibility that mast-cell-derived TNF-a may contribute to the leukocyte iniiltration observed in &E-dependent cutaneous LF%s in man, but indicate that IL-1 (from mast ceU and/or other sources) may also have an important role. Mast-cell-derived TNF-a may also contribute to LPRs expressed in human lung. We reported preliminary evidence that put&d human lung mast cells can release TNF-a upon stimulation through the Fc,RI [31]. Wegner et al [32**] showed in a primate model of asthma that a monoclonal antibody to intercellular adhesion molecule (ICAM)-1, a leukocyte adherence structure whose expression on the surface of vascular endothelial cells can be augmented by IL-l, TNF-a, or IFN-y, attenuated both airway eoslnophilia and airway hyper-responsiveness.
Mast-cell leukocyte cytokine inflammation and immunity
cascades
in
When one considers the diversity of multifunctional cytokines detected in different mouse mast-cell populations, the broad spectrum of biological responsesthat can be ir&.renced by these cytokines and the possibility that the expression of cytokine bioactivity by mastceU populations can be diiferentially regulated by various stimuli of mast-cellactivation (reviewed in [12]), one might reasonably propose an enormous number of potential roles for mast-cell cytolcines in adaptive or pathological responses.Consideration of all the biological effects of each mouse mast-cell-associatedcytokine would require a separate review for each molecule. However, the known effects of these agents include regulation of IgE production (IL-4, IFN-y), regulation of mast-cellproliferation and phenotype (IL-3, IL-4, GM-CSF, IFN-y, TGFp), modulation of leukocyte (basophil, eosinophil, neutrophil and monocyte) effector function (IL-3, IL-4, GMCSF, IFN-y, TNF-a), and numerous actions in in&mmation, clotting, anglogenesis,wound repair, tissue remodeling, and the development of pathological fibrosis (reviewed in [4-7,12,3339]). As reviewed elsewhere [4,5,7,12,39,40], mast cells have been implicated in many of these responses. Most analysesof mast-cellcytokine production have been carried out in in timderived mouse mast cells. Indeed, except-in the caseof TNF-a, there is virtually no information about cytokine production by freshly isolated mast cells, which can be very phenotypically diUerent from in vimderived mast cells [4,5]. Moreover, in many biological responses,including even those dependent on IgE, mast cells or basophils will represent just one of
many potential sources of cytokines, and many of their products will have complex activities that overlap, synergize, and/or antagonize those of other cytokine or inflammatory mediators (reviewed in [4,12]). As a result, a clear picture of the actual roles of mast-cell(or basophil) cytokine production in the diverse biological responses thought to be influenced by these cells will require much additional study (see below). Data derived from both murine and human studies strongly suggeststhat mast-cell-derivedTNF-a has an important role in the expression of &E-dependent intlammation and leukocyte recruitment. In the mouse, IgE-dependent cutaneous reactions predominantly contain neutrophils [ 23*-l, yet another cell type that can produce TNF-a [41~*,42**]. In humans, &E-dependent cutaneous reactions, and the infiltrates associatedwith asthma,also contain large numbers of eosinophils. Eosinophils represent a potential source of some cytokines that may also be produced by mast cells, such as IL-1 [43**] and TGFj3 [44**], and at least one cytokine that apparently is not produced by mast cells, TGF-a [45**,46**]. On the basisof thesefindings, we have proposed that the expression of many &E-dependent reactions, and probably other responsesin which mast cells play an important role, reflect the activities of a ‘mast cell-leukocyte cytokine cascade’ [4,12]. This hypothesis proposes that mast-cellactivation initiates the response,in part, through the releaseof M-a and other cytokines that can intluence the recruitment and/or function of additional effector cells (neutrophils, eosinophils, basophils, lymphocytes, monocytes, and platelets); these recruited cells influence the progression of the responseby providing additional sources of certain cytokines also produced by mastcells, and new sourcesof somecytokines (e.g., TGFa) that are not produced by the mast ceU (Fig. 2). As the reactions progress further, cytokines from mast cells and other resident cells, and from recruited (leukocyte) sources, exert complex paracrine and autocrine effects on resident cells (vascular endothelial cells, iibroblasts, epithelial cells, nerves, mastcells) that may contribute importantly to the vascular and epithelial changes, and to the tissue remodeling and fibrosis, which are so prominent in many disorders associatedwith mast-cell activation and leukocyte infiltration.
Mast-cell cytokine understanding
production:
gaps in our
Many important questions concerning the mechanisms that regulate the production, intraceUulardistribution and release of mast-cell cytokines remain. Furthermore, the extent to which different naturally occurring stlrnuli generated in association with immunological, physiological, or pathological responsesin viva can elicit distinct patterns of mast-cell(or basophil) cytokine releaseis uncertain. Much more work is required to determine the extent to which iindings obtained in the mouse apply to human mastcells, to evaluate possibleanatomicalvariation in the ability of mast cells to produce specific cytokines, and to
Cytokine
production
by mast
cells
and
basophils
Galli, Gordon,
Wershil
(a) Mast-cell activation
(b)
Resident
[o
10
(4
cells
Recruited
cells
Epithelial cells/ keratinocytes
10
-
@
@J
@
Cran”loo/tes
.g 0 @
McIzIsts
6
Eosllh:&
Q
Monocytes
#:
Platelets
* :*.:. .
’
00
o Lymphocytes
Lymphocytes
(d
Fig. 2. The mast cell-leukocyte cytokine cascade. (a) Mast cells are activated via IgE and specific antigen or by other mechanisms. fb) Mastcell-derived cytokines initiate direct effects on nearby cellular targets already present in the tissue, including epithelial cells/keratinocytes, fibroblasts and other stromal cells, vascular endotheial cells, mast cells, and, in some tissues, resident mononuclear cells, lymphocytes, and eosinophils. These cytokine-dependent effects will occur together with many important effects of mast-cell-derived mediators other than cytokines. fc) Some of the effects of mast-cell-derived cytokines, such as the induction of leukocyte adherence structures on vascular endothelial cells and/or epitheliai cells, contribute to the recruitment of leukocytes, including neutrophils, eosinophils, basophils, mononuclear cells, and platelets. (d) Certain mast-cell-derived cytokines may also enhance the effector function of some of these recruited cells. fe) The recruited leukocytes also contribute to the amplification/progression of the reaction, in part by increasing local concentrations of some cytokines also produced by mast cells (e.g., IL-l, TNF-a) (see text). Continued production of cytokines by activated mast cells contributes to the progression of the reaction. Local expansion of mast-cell populations, via autocrine factors produced by mast cells or by products of stromal cells or recruited leukocytes, may also contribute to the amplification/progression of the response.
define the basophil’s spectrum of cytokine production. Although these issuescan be addressedinitially using in vi&oderived cell populations, they ultimately will have to be evaluatedwith freshly isolated mature cells and in mast-cell or basophil populations present at sites of immune responsesor diseaseprocesses in vivo. For example, Bochner et al [47= ] demonstrated that IL-1 production occurred at sites of allergic responseselicited in human skin. However, the cellular source(s) of IL-1 in these responsesis not clear yet.
Conclusions Despite the current gaps in our understanding of mastcell cytokine production, particularly in humans,we feel that studiesperformed with mouse mastcells provide evidence for a few broad conclusions or generalizations. First, it is likely that the predominant actions of mastcell-derived cytokines will be manifestedwithin rejatively short distances (reviewed in [12]). However, effects of mast-cell-derived cytokines might become widespread
869
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Atopic allergy and other hypersensitivities
under certain conditions, such as after parenteral exposure to specilic antigen or during systemic mastocytosis
1121. Second, the extent to which mast cells, as opposed to other cell types, are an important source of a parricular cytokine may vary greatly depending on the characteristics of the biological response under investigation. Clearly, the mast cells’ role will be most significant when the type and/or anatomical distribution of the relevant stimuli generated during individual biological responses favor(s) activation of mast cells over other sources of cytokines. In LPRs, mast cells may represent by far the most important initial source of TNF-or and other proMlammatory cytokines. Indeed, mast-cell-derived cytokines may directly or indirectly regulate the type of leukocyte recruited to these reactions (e.g., see [48**]), as well as influence many other important features of these responses. However, in other biological responses, which generate stimuli capable of activating multiple sources of cytokines, the specific contribution of mastcell-derived cytokines may be relatively unimportant or diflicult to discern. For example, TIT-a appears to be essential for the expression of contact sensitivity responses in mouse skin [49-l, but most analyses have detected no impairment of contact sensitivity reactions in genetically mast-cell-deficient mice (reviewed in [4,5]). Third, even in responses influenced by mast cell cytokine production significantly, full development of the reactions may depend on the generation of cytokines from additional cell types. One of the most important consequences of mast-cell activation may be the initiation of a mast cell-leukocyte cytokine cascade in which mast-cellderived cytokines contribute to an influx of neutrophils, eosinophils, and mononuclear cells that in turn provide additional cytokine activities important to the progression of the response. Fourth, the appreciation that certain of the biologically and clinically significant consequences of mast-cell (and perhaps basophil and eosinophil) activation reflect the production of multifunctional cytokines by these cells may suggest new insights into the therapy of disorders inlluenced by these cell types. The &E-dependent induction of increased levels of cytokine mRNAs in in vitroderived mouse mast cells can be inhibited by cyclosporin A [ 181 or dexarnethasone [ 501. Although corticosteroids can markedly diminish many of the clinical and histological manifestations of cutaneous LPRs and other allergic responses in the skin and other organs, and can inhibit mediator release from human basophils, corticosteroids do not inhibit &$-dependent release of histamine from human mast cells (reviewed in [2,6]). In light of these findings, it will be interesting to evaluate the possibility that one of the mechanisms by which corticosteroids interfere with the expression of allergic responses (and perhaps other pathological reactions) is by suppressing cytokine production by mast cells, as well as by interfering with cytokine production and the release of other mediators by cells recruited to sites of mast-cell activation. This hypothesis proposes that corticosteroids, and perhaps cyclosporln A and related compounds, can interfere with both the mast-cell-dependent
initiation, and the mast-cell- and leukocyte-dependent amplification/progression of disorders intluenced by the mast cell-leukocyte cytokine cascades.
Acknowledgment This work was supported by grants from the NIH.
References and recommended
reading
Papers of special interest, published within the annual period of review, have been highlighted as: . of interest of outstanding interest .. 1.
ISHUAKAT: Mechanisms of IgE-Mediated Hypersensitivity. In and Practice, 3rd edn. edited by Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, YningerpJV. St Louis, Missouri: Mosby, 1988, pp 71-93. GAIA SJ, LICHTENSTEIN LM: Biology of Mast CeIIs and Basophils. In Allerg)l: Principles and PracticeV 3rd edn edited by Middleton E Jr, Reed CE, EIIis EF. Adkinson NF Jr, Yuninger JW. St Louis, Missouri: Mosby, 1988, pp 10&134. Ailerg)~: Principles
2.
3.
HOLGATEST, ROBINWNC, CHURCHMK: Mediators of Immediate Hypersensitivity. In Allerm: Principles and Practice, 3rd edn. edited by Middleton E Jr, Reed CE, EIIis EF. Adkinson NF Jr, Yuninger JW. St Louis, Missouri: Mosby 1988, pp 135163.
4.
GALUSJ.GEI~SLEREN, WER~HILBK, GORDONJR,TSAI M, HAMMEL I: Insights into Mast CeII Development and Function Derived from Analyses of Mice Carrying Mutations at beige, W/c-kit or SUSCF (c-kit Ligand) Loci. In 7?x Role of the Mast Cell in Health and Disease edited by KaUner MA, MetcaIfe DD. New York: Marcel Dekker, in press.
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GALU SJ: New Insights into ‘the Riddle of the Mast CeUs’: Microenvironmental Regulation of Mast CeII Development and Phenotypic Heterogeneity. Lub Invest 1990, 62:5-33. SCHLEIMERRP, DERSECP, FRIEDMANB, Guus S, PLAUI’ M, LICHTENSTEIN LM, MACGU\SHANDW JR: Regulation of Human BasophU Mediator Release by Cytokines. 1. Interaction with Antiinflammatory Steroids. J Immunol 1989, 143:131&1317.
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COSTAJJ, BURD PR, METCAIXE DD: Mast CeU Cytokines. In 7he Role of the Mast Cell in Health and Disease edited by KaIIner MA, MetcaIfe DD. New York: Marcel Dekker, in press.
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KINET J-P: The High AfI?nity Receptor for IgE. Curr Opin Immunol 1990, 2~499-505. CHUNGSW, WONG PMC, SHEN-ONGG, Ruscnn S, ISHUAKAT, EAVESCJ: Production of Granulocyte-Macrophage ColonyStimulating Factor by Abelson Virus-Induced Tumorigenic Mast CeII Lines. Blood 1986, 68:1074-1081. BROWN MA, PIERCEJH, WATSON CJ, FALCOJ, IH~E JN, PAUL WE: B CeU Stimulatory Factor-l/Interleukin-4 rnRh’A Is Expressed by Normal and Transformed Mast CeIIs. Cell 1987, 508Op-818.
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HUMPHRLESK, ABRAHAMS, KRYSTALG, IANSDORPP, LEMOINE F, EAT CJ: Activation of Multiple Hemopoietic Growth Factor Genes in Abelson Viis-Transformed MyeIoid CeUs. Eq Hematol 1988, 16:774-781.
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Cytokine ciated Cytolytic Factor Related to Tumor Pros Nat1 Acad Sci USA 1987, 85~91759179.
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14. ..
&mDON JR, GALU JS: Mast Ceils as a Source of Both Preformed and Immunologically Inducible TNP-a/Cachectin. Nature 1990, 346~274-276. The mouse maSt cell is the first cell type to be identified that contains signilicant preformed stores of TNF-a bioactivity avaiiable for immedi ate release. IgE.dependent activation of in vitroderivecl or freshly isolated peritoneal mast cells results in increz.ed levels of TNF-a mRNA and release of TNF-a bioactivity. This study presents the first direct ev idence that mature, freshly purified mast ceUs contain both mRNA and bioactlvity for a well characterized cytokine. 15.
RIcm AL, OKUNO T, TAKAGAK~ Y, DJEU JY: Natural Cy totoxic CelI-Specihc Cytotoxic Factor Produced by IL-3. Dependent BasophiIIc/Mast CeIIs. Relationship to TNF. J Immunol 1988, 141:306-3066.
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PLWT M, PIERCE JH, WAGON CJ. HANLEY-HYDE J, NORDAN RP, PAUL WE: Mast Ceil Limes Produce Lymphokines in Response to Cross-Linkage of FceRI or to Calcium Ionophores. Nature 1909, 3396467.
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WODNAR-FIUPOWICZ A, HEU~~ER CH, MORONI C: Production of the Haemopoietic Growth Factors GM-CSF and Interleukin3 by Mast Cells In Response to I@ Receptor-Mediated Activation. Nature 1989, 339:15G152.
18.
BURD PR, RICERS HW, GOR~~N JR, MARTIN CA, JAYWILSON SD, DVORAK AM, GALU SJ, Dear ME: Interleukin Dependent and -Independent Mast CeIIs Stimulated 1gE and Antigen Express Multiple Cytokines. J &J 1989, 170:245-257.
19.
TSAI M, GORooN JR, GNU SJ: Mast Express Transforming Growth Factor FRSEB J 1990, 4zAI944.
S, 3with Med
Ceils Constitutively g mRNA [abstract].
20. .
GURLSH MF, GHUDYAL N, ARM J, AUSTEN KF, ABRAHAM S, RE?‘NOLDS D, SEVENS RL Cytokhte mRNAs are Preferentially Increased Relative to Secretory Granule Protein mRNA in Mouse Bone Marrow-Derived Mast Ceils that have Undergone @E-Mediated Activation and Degranulation. J Immunol 1991, 146:1527-1533. Reports that the substantial increases in levels of TNF-a, IL-~, and GMCSF mRNA observed l-2 h after &E-dependent activation of in r&o derived mouse mast ceils is not associated with significant changes in levels of mRNA for Fc,RIa or several constituents of the cells’ secretory granule. 21. ..
ChXDON JR GALLI SJ: Release of Both Preformed and Newly Synthesized Tumor Necrosis Factor a (TNF-a)/Cachectin by Mouse Mast Cells StimuIated by the Fc,RI. A Mechanism for the Sustained Action of Mast Cell-Derived TNF-a During &E-Dependent Biological Responses. J EQ Med 1991, 174:103107. Presents evidence derived from both in vitro and in vivo experiments indlcatlng that mouse mast cells represent a biologicaUy significant source of TNF-a during &E-dependent responses, and demonstrates that &E-dependent mast-cell activation results in the sustained release of newiy synthesized TNF-a. First demonstration of a signUicant difference in the &E-dependent augmentation of levels of a cytokine mRNA at tissue sites containhtg or essentially devoid of mast ceils. 22.
23. ..
I~ANSKE RF JR, KAUNER MA Late Phase AIlergic Reactions. In Allergy, Princ@ks and Practie, 3rd edn edited by Middleton E Jr, Reed CE, EUIs DF, Adkinson NF Jr, YunInger JW. St Louis, MISSOU~: Mosby, 1988, pp 224-226.
WERSHIL BK, WANG 2, GORDON JR, G~tu SJ: Recruitment of NeutrophiIs During &E-Dependent Cutaneous Late Phase Responses in the Mouse is Mast Cell Dependent: Partial Inhibition of the Reaction with Antiserum Against Tumor Necrosis Factor-Alpha J Clin Invest 1991, 87:44ti53. First demonstration, using geneticaUy mast-cell-deficient mice In which the deIiciency is overcome IocaUy and selectively by adoptive transfer of in uitroderived mast cells, that mast cells are essential for virtually ail of the earIy and late phases of tissue swelling and leukocyte in&ation a.ssocIated with &E-dependent reactions in the skin, and local admIn-
production
by mast
cells
istration of antibodies leukocyte inliitration evidence that a well candy inlluences the biological response
and
basophils
Galli,
Gordon,
Wershil
to TNF-a can inhibit such mast-ceil-dependent by about 50%. This study presents the first direct characterized mast-cellassociated cytokine signiiiexpression of an IgE- and/or mast-cell-dependent in oirto.
BENSASSON SZ, LEGROS G, CONRAD DH, F~NKELMAN FD, PAUL WE: Cross-Linking Fc Receptors StImuIate Splenic NonB, Non-T CeIIs to Secrete Interleukin 4 and Other Lymphokines. Proc Natl Acud Sci USA 1990, 87:1421-1425. Demonstration that spleen cells depleted of both B and T iymphocytes, and containing no detectable alcianblue positive mature mast ceUs, produce IL-4 and IL-3 in vitrowhen stimulated with plate-bound 1gE in the presence or absence of IL-3. Furthermore, they produce IL-4 when stimulated with plate-bound IgGl, IgG2a or IgG2b in the presence of IL-3. These lindings suggest that ‘non-B, non-T cells’ might represent an important source of cytokines in allergic diseases, heirninth infections, and disorders associated with immune complex deposition.
24. ..
25. .
CONRAD DH, BEN-SMSON SZ, LEGROS G, FINKELMAN FD, PAUL WE: Infection with Nippostrongyfus brasiliensis or Injection of Anti-IgD Antibodies Markedly Enhances FcReceptor-Mediated Interleukin 4 Production by Non-B, Non-T CeUs. J Exp Med 1990, 171:1497-1508. Demonstration that infection of mice with N. brasik?nsis, or injection of mice with anti-IgD antibodies, greatly increases the number and IL-4producing capacity of splenk non-B, non-T cells and gready increases the IL-4.producing capacity of bone marrow non-B, non-T cells. The IL-4-producing capacity of splenic non-B. non-T cells from anti-IgD-injetted mice is less dependent on IL-3 than that of ceils from naive mice, and antigen can induce IL-4 production from non-B, non-T cells derived from N brasi(iens&infected mice. 26. .
SEDER R4, PAUL WE, DVORAK AM, SHARI~S SJ, KAGEY-SOBOTKA A NIV Y, FU‘IKELMAN FD, BAREIIEIU SA, GALU SJ, PLAUT M: Mouse Splenic and Bone Marrow Cell Populations that Express High-ARInity Fc, Receptors and Produce Interleukin 4 are Highly Enriched in BasophiIs. Prcc Nat1 Aud Sci USA 1991, 88:2835-2839. Reports that basophils or basophilic myelocytes represent the vast majority ( >90%) of granulated cells present in Fc,R+ splenic or bone marrow non-B, non-T cells of anti-&D-injected mice. However, these populations also contain many non-granulated mononuclear ceUs and rare cells (3-l%) that may represent immature mast ceils. These data raise the possibility, but do not prove, that basophils represent a source of the IL-4 and IL-3 produced by Fc,R+ non-B, non-T cells. 27.
STEFFEN M, ABBOUD M, POTI-ER GK, YUNG YP, MOORE MAS: Presence of Tumor Necrosis Factor or a Related Factor in Human BasophiI/Mast Ceils. Immunology 1989, 66:44%50.
28.
KLEIN LM, IA~KER RM, MA’rts WI, MURPHY GF: DegranuIation of Human Mast CelIs Induces an EndotheliaI Antigen CentraI to Leukocyte Adhesion. Proc Nat1 Acad Sci USA 1989, 86~0972-8976.
WAlSH LJ, TRINCHIERI G, WAIDOW HA, WHlTAKER D, MURFWY GE Human Dental Mast Cells Contain and Release Tumor Necrosis Factor a which Induces Endothelial Leukocyte Adhesion Molecule-l. Proc Natl Acud Sci USA 1991, 88:4220-4224. Demonsttation using in situ hybridhation d-tat human dermaI mast cells represent the only ceU type in the normal dermis with detectable TNF-a immunoreactivity. Furthermore, some mast ceUs at sites of delayed hypersensitivity response express TNF-a mRNq and sdrnulation of purified dermal mast cells with morphine sulfate results In loss of T’NF-u immunoreacdvity in the cells and the appearance of TNF-a Immunoreactivity in the ceils’ supematant. Such mast-cell-derived TNF-a can Induce I&AM-l expression by vascular endothelial cells.
29. ..
IEUNG DYM, POBER JS, COTRAN RS: Expression of EndotheIialLeukocyte Adhesion Molecule-l in Elicited Late Phase Allergic Reactions. J Clin Inuest 1991, 87:180>1809. Documents that injection of allergen into the skin of allergic subjects Induces both EIAM-1 expression on vascular endotheiiai ceUs and leukocyte infJmtion. Allergen also induces ELAM-1 expression on vzcular endothelial cells in skin organ culture~~ in vitq and this EIAM-1 exptession can be inhibited by combined treatment with antisera to TNF-a and IL-l, but not by antisera to either cytokine alone. These Iindings sup
30. ..
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..
42. ..
DJEU JY, SEREOUSEK D, B~CHARD DK: Release of Tumor Necrosis Factor by Human Polymorphonuclear Leukocytes. B&ud 1990, 76:1405-1409. Documents that human peripheral blood neutrophils ( > 99% purity) stimulated in uihw by co-culture with Candida albicans or by lipopolysaccharide release TNF-a bioactivity, which is inhibitable by antibodies to TNF-a but not by antibodies to lymphotoxin. Such TNF-a production by neutrophils is markedly reduced by inhibitors of RNA or protein synthesis. These results indicate that most, or all, of the TNFa produced by neuttophils, like that of monocytes, is synthesized in response to appropriate stimulation of the cells.
43. ..
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ELOVIC A, MATOSSIAN K, NACURA N, MCBR~E GORDON JR, RAND TH, Gw SJ, WEUER PF:
Eosinophils from Patients with Blood Eosinophilia Express Transforming Growth Factor 81. Blood 1991, in press. Demonstration using in sifu hybridization that 100% of the peripheral blood eosinophils from patients with hypereosinophilia associated with the idiopathic hypereosinophilic syndrome, Job’s syndrome, or a drug hypersensitivity reaction, contain TGF-Bl mRNA and, using immunohistochemistry techniques, TGF-81 product. In contrast, the blood eosinophils of normal donors contain little or no TGF-Bl mRNA and no detectable product. These findings suggest that eosinophil production of TGF.81 may contribute to the pathogenesis of the striking alteration in connective tissue observed in many disorders associated with hypereosinophilia and/or eosinophil infiltration of tissues. 45. ..
JOHNSTON
and Abnormal
44. ..
T:
Re-
35.
Network.
Reports that peritoneal eosinophils purifted (94%) from mice infected with Mesocesloides corfi and then stimulated with lipopolysaccharide are positive for IL.1 mRNA according to in silu hybridization nith a cDNA probe, and release IL-1 bioactivlty when stimulated with lipo polysaccharide. In contrast, no IL.1 is detected in lysates of unstimulated eosinophiis. tipopolysaccharide-induced IL-I production is greatly increased by indomethacin. Although many other cell types can also pro. duce IL-I, this is the first report that eosinophils can produce mRNA and the product of a well characterized cytokine.
DEL Pozo V, DE ANDRES B, M~ttrt~ E, MARUIU N, ZUBELD~A JM, PALXXINO P, moz C: Mu&e Eosinophils and IL-l: aIL1 mRNA Detection by In Situ Hybridization. J Immunol 1990, 144:3117-3122.
ELOVIC A, GAUI SJ, WEUER PF, CHANG ALC, CHIANG T, CHOU MY, DONOFF RB, GAUAGHER GT, MATOSS~AN K, MCBRIDE J, TSN M, TODD R, WONG DTW: Production of Transforming
Growth FActorAlpha by Hamster Eosinophils. Am J Pafbol 1990, 137:14251434. Demonstration using in si?u hybridization immunohistochemistry that infiltrating eosinophils, but not resident mast cells, represent a major source of TGF-a mRNA in hamster cheek pouch carcinomas and that about 40% of these eosinophils also contain TGF-a product. Bone marrow eosinophils are also positive for TGF-a mRNA (approximately 70%) and product (approximately 20%). These findings suggest that expression of TGF-a by eosinophils may be regulated during eosinophil maturation and/or by factors at sites of eosinophil inliltration. and suggest unique roles for the eosinophil in health and disease. 46. ..
WONG DTW. WEUR PF, GALU SJ, ELOVIC 4 RAND TH, GAUAGHER GT, CHUG T, CHOU MY, MATOSSWU K. MCBRIDE J, TODD R Human Eosinophils Express Transforming Growth
Factor-Alpha J Ez+!J Med 1990, 172:673-681. First demonstration that human eosinophils represent a source of a multifunctional cytokine. TGF-a mRNA was detected by in sifu hybridization in eosinophils infiltrating colonic adenocarcinomas and by in siru hybridization, polymerase chain reaction or northern analysis, in eosinophils from a patient with the idiopathic hypereosinophillc syndrome: these eoslnophils also expressed the mature, biologically active form of TGF-a according to polymerase chain reaction restriction enzyme analysis, immunohistochemistry, and radioimmunoassay of the cells’ supematants. In contrast, none of the blood eosinophils of normal donors contained detectable TGF-a product and most of them lacked TGF-a mNRA 47.
BOCHNER
GILLIS leased Allergy Demonstration duced at sites Immunoreactive phases of the at late (IO-12
.
BS, C HNUSWORTH
EN,
LICHTENSTELN
LM,
DERSE
CP,
S, DINAR!Z~.~I CA, S~HLEIMER RP: lnterleukin-1 is Reat Sites of Human Cutaneous Allergic Reactions. J CIin Immunol 1990, 86:83&839. using a skin-chamber challenge model, that RI is proof antigen-induced late phase reactions in human skin. IL-1 B was generated during early (peak at 1 h) and late response, but detectable IL-1 bioactlvity was present only h) intervals.
48.
BOCHNER
..
STERBINSKY
BS, LUSCINSKAS FW, G~RONE SA, DERSE-ANIXONY
CP,
KLUNK
JA JR, NEWMAN D, SCHIJZIMER
W, RF?
Adhesion of Human Basophils, Eosinophils, and Neutrophils to lnterleuldns I-Activated Human Vascular Endothelial Cells: Contributions of Endothelial Cell Adhesion Molecules. / E3qb Med 1991, 173:15531556. In uifro assays of binding of human granulocytes to human umbiical vein endothelial cells, and Bow cytometric detection of gtanulocyte counter-receptors for endothelial-ceU adhesion molecules, were used to suggest distinct roles for ICAM-1, EIAM-1 and VCAM-1 during granulocyte adhesion to vascular endothelium. Basophils and eoslnophils, unlike neutrophils, expressed very late antigen-4, the counter-receptor
Cytokine for VCAMI, suggesting that preferential induction thelial cells at sites of allergic responses might selective recruitment of basophils and eosinophils
of VCAM-I on endopromote the relatively to these reactions.
PICUET PF, GRALI GE, HA~ISER C. VA%SAU.I P: Tumor Necrosls Factor is a Critical Mediator in Hapten-Induced Irritant and Contact Hypersensitivity Reactions. J Exp Med 1991, 173673-679. Demonstration that antibodies to TNF.a markedly inhibit the development of contact sensitivity responses in sensitized mice and irritant reactions in non-sensitized mice, and also interfere with the augmenta tion of TNFa mRNA levels obsetved at sites of contact sensitivity or irritant reactions, Using in situ hybridization, TNF-a mRNA was found to be present in several cell types in these reactions, especially basal keratinocytes and dermal cells thought to be neutrophils. 49. ..
production
50.
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mast
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cells
BK,
Dexamethasone tion by Mouse Mast Cell and stract). FXSEB
and
GORDON
basophils
Calli, Gordon,
Wershil
JR,
Zs,
GALU
Inhibits the Mast CeUs TNF-a-Dependent J, in press.
WANG
LAVICNE
&E-Dependent In Vitro and 1nRammation
SJ Galli, BK Wershil, Division of Experimental of Pathology, Beth Israel Hospital, 330 Brookline sachusetts 02215, USA JR Gordon, The Department of Veterinary lege of Veterinary Medicine, University Saskatchewan S7NOW0, Canada.
JA,
SJ:
TNF-a RoducSuppresses IgEIn l&o. (ab-
Pathology, Avenue,
Department Boston, Mas-
Microbiology, of Saskatchewan,
Western ColSaskatoon,
873