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Roles of IL-18 in Basophils and Mast Cells


Tomohiro Yoshimoto and Kenji Nakanishi [About this authors]


Basophils and mast cells are effecter cells in allergen/IgE-mediated immune responses. They induce type 1 immediate immune response in airway or other organ, resulting in bronchial asthma and other allergic diseases. However, they also play a critical role in host defense against infection with helminthes. Upon linkage of FcεRI with a complex of allergen and IgE, basophils and mast cells release a large amount of Th2 cytokines and chemical mediators. Therefore these responses are "acquired allergic responses" and induce allergic diseases, such as bronchial asthma. However, basophils and mast cells derived from cultured bone marrow cells with IL-3 for 10 days express IL-18Rα chain and produce Th2 cytokines in response to the stimulation with IL-3 and IL-18 without FcεRI cross-linkage. Furthermore, they produce Th2 cytokines upon stimulation with several TLR ligands, such as LPS. This finding may suggest the presence of allergen/IgE-independent allergic responses, which we would like to designate as "innate allergic response". However, in vivo treatment with IL-18 and IL-2 protects against gastrointestinal nematode infection by activating intestinal mucosal mast cells in STAT6-independent manner, suggesting the importance of innate allergic response against helminth infection. Here we discuss the functional role of IL-18-induced "innate allergic response" in disease and host defense.

basophils, IL-18, mast cells, nematode infection, Th2 cytokines

Received: 13 January 2006.

Allergology International 2006; 55: 105-113


IL-18 was discovered as a potent IFN-γ -inducing factor that is produced by macrophages and dendritic cells upon stimulation with microbes or microbe products.1 Thus, IL-18 has been categorized in an innate immune cytokine. There are several pathways to induce IFN-γ, a crucial factor for inflammatory responses. Th1 cells produce abundant IFN-γ in response to the appropriate antigen. We now know that a large amount of IFN-γ is also produced by a wide variety of cell types in response to the innate immune cytokines, such as IL-12, IL-15 and IL-18.2-8 IL-18 is the first cytokines demonstrated to activate T cells to produce plentiful IFN-γ without T cell receptor (TCR) engagement.3, 4 Resultant IFN-γ then activates macrophages to produce nitritic oxide,9 leading to eradication of intracellular pathogens,10-12 or tissue injuries (Fig. 1).13 However, our recent studies also clarified that IL-18 induce Th2 cytokines production from T cells or mast cells/basophils.14, 15 Without TCR engagement, IL-18 with IL-2 induces T cells to produce IL-4 and IL-13 and to express CD40 ligand, which in combination induce B cell IgE response (Fig. 1). Indeed, administration of IL-18 or IL-18 plus IL-2 into nave mice induces IgE in a CD4+ T cell-, IL-4- and STAT6-dependent manner.15, 16 Moreover, transgenic mice over-expressing IL-18 in their keratinocytes, spontaneously produce IgE and develop atopic dermatitis.15-17 Intriguingly, this dermatitis develops even in the absence of STAT6 activation, which is required for Th2 cell development and IgE responses.18 Thus, IL-18 induces dermatitis in an IgE-independent manner. Antigen plus IgE induces allergic response by activation of basophils and mast cells.19 However, IL-18 induces allergic inflammation without Th2/IgE. Therefore, we proposed to designate the former type as "acquired allergic response" and the latter as "innate allergic response"(Fig. 2).8


It is well documented that basophils and mast cells release a large amount of Th2 cytokines (IL-4, IL-5, IL-9 and IL-13) after cross-linkage of their FcεRI by antigen and antigen-specific IgE.19 IL-4 initiates and promotes Th2 responses and is the most important determinant of Ig class switching to IgE.20, 21 IL-5 induces maturation and activation of eosinophils.22 IL-13 induce mucus production by causing goblet cell hyperplasia.23, 24 Furthermore, IL-13 induces airway hyperresponsiveness (AHR).25-28 Basophils and mast cell also produce various bioactive chemical mediators such as histamine and lipid metabolites.19 Thus, cross-linkage of FcεRI induces the development of "acquired type allergic response". However, we found that cultured bone marrow-derived basophils and mast cells express IL-18Rα chain and produce IL-4/IL-13 and histamine in response to the stimulation with IL-3 and IL-18 even without FcεRI cross-linkage.14 Thus, IL-3 and IL-18 induce "innate allergic response" by direct activation of basophils and mast cells (Fig. 2).


The cytoplasmic portion of IL-18R is homologous to that of Toll-like receptors (TLRs), which have been identified as signaling receptor of the innate immune system and recognize corresponding pathogen-associated molecular patterns (PAMP).7, 29 Myeloid differentiation factor 88 (MyD88) is an adapter molecule essential for signaling through either IL-18R or TLRs.30, 31 Eleven mammalian TLRs have been described so far and microbial ligands corresponding each member have been identified.29 Upon entry of invading pathogens, DCs recognize them through TLRs and maturate to express co-stimulatory molecules CD80 and CD86 and to produce IL-12.29 It is widely accepted that IL-12 induces Th1 responses but inhibits Th2 responses to achieve the efficient inflammatory responses.

IL-18 is secreted from various cells via activation of TLRs after stimulation with microorganisms and their products in a caspase-1-dependent manner.32 Notably, upon stimulation via TLRs, IL-18 as well as other proinflammatory cytokines including IL-12 are released.7 However, IL-12 does not block the activity of IL-18-stimulated basophils or mast cells to produce IL-4/IL-13.14 Thus, basophils and mast cells produce Th2 cytokines even under Th1-inducing condition.

Basophils and mast cells also produce Th2 cytokines via activation of TLRs on their cell surface with PAMP. Mast cells produce Th2 cytokines when stimulated with ligands for TLR2 or TLR4, suggesting their role in induction of Th2 response.33-36 TLR2 recognizes Gram-positive bacterial components, including peptidoglycan (PGN) and lipoprotein, and TLR4 recognizes lipopolysaccharide (LPS), a component of Gram-negative bacteria.29, 37, 38 Human basophils were recently found to express high levels of TLR2 and TLR4.39 More recently, it has been reported that human basophils produce Th2 cytokines when stimulated with ligands for TLR2 but not TLR4, suggesting that basophils can play an important role in promoting and amplifying the Th2 responses.40 Although roles of TLRs on mast cells and human basophils have been fully examined, expression and functional roles of TLRs on murine basophils remain unclear. We have recently revealed that bone marrow-derived murine basophils selectively express TLR1, 2, 4 and 6 and produce significant amounts of Th2 cytokines (IL-4, IL-6 and IL-13) in response to IL-3 plus PGN or to IL-3 plus LPS via TLR2 or TLR4, respectively, even without FcεRI cross-linkage (un-published observation). Consistent with the previous reports,35 PGN- or LPS-stimulated mast cells produce small amounts of IL-6 and IL-13, which are significantly increased when additionally stimulated with IL-3. However, notably, compared with basophils, mast cells are poor producers of IL-4 even when they were stimulated with IL-3 and TLR ligands. Co-stimulation with IL-12 fails to attenuate these responses, substantiating further that basophils favor induction of Th2 response. It is known that allergic inflammatory responses are also induced under some infectious condition.41, 42 Thus, our study suggests that bacterial components-stimulated basophils may play a key role for induction of "innate allergic responses", providing a clue to understanding the mechanisms of allergic diseases triggered by bacterial infection (Fig. 3)


It is well known the expulsion of some types of gastrointestinal nematodes depends on the action of Th2 responses. There are two types of Th2-mediated host protective immunity against gastrointestinal nematode infections. One is worm expulsion by activated intestinal mast cells.43 Strongyloides venezuelensis is expelled by activated intestinal mast cells. The other types of worm expulsion is mediated by mucus derived from activated goblet cells stimulated by IL-13.44 Nippostrongy brasiliensis is expelled by this mucous product (Fig. 4).

The role of intestinal mucosal mast cells (MMC) in worm expulsion has been studied extensively in various experimental host-parasite systems. In the case of infection with Strongyloides venezuelensis (S. venezuelensis) third-stage larvae (L3), host mice complete parasite expulsion within 2 weeks, which is tightly associated with level of intestinal mastocytosis.45, 46 Therefore, mast cell-deficient W/Wv mice infected with S. venezuelensis L3 show a significant delay in parasite expulsion.45 Furthermore, parasite expulsion is more severely impaired in W/Wv mice that are deficient for IL-3 gene expression. In these mice, MMC responses are almost completely absent and S. venezuelensis continue to parasitize in the intestine for >50 days.45 In the case of infection of mice with Trichinella spiralis (T. spiralis) or Trichuris muris (T. muris), IL-9 expression correlates well with the resistant phenotype and its elevation in vivo results in the enhancement of intestinal mastocytosis and parasite expulsion.47, 48 Furthermore, IL-9 transgenic mice that display increased intestinal MMC more rapidly expel T. muris or T. spiralis than wild-type mice.47, 49 Therefore, both IL-3 and IL-9 are deeply involved in recruitment and activation of MMC in mice infected with gastrointestinal nematode.

It is well-established evidence that mouse mast cell protease-1 (mMCP-1), selectively expressed by intestinal MMC, participates in the effecter phase response to intestinal nematodes expulsion.43, 50-53 Indeed, mMCP-1-deficient mice fail to expel gastrointestinal nematode.50 Miller et al. reported that mMCP-1 is not detectable in the culture of bone marrow-derived mast cells stimulated with IL-3 alone.9 However, mast cells begin to produce mMCP-1 when additionally stimulated with IL-9, SCF and TGF-β.9 Thus, it has been speculated that IL-3 and IL-9 from Th2 cells in mice infected with gastrointestinal nematode induce precursor cells to develop into mMCP-1+MMC together with SCF and TGF-β from gut epithelium.


As mentioned above, without TCR engagement, IL-18 with IL-2 can induce IL-4 and IL-13 production by CD4+ T cells in vitro (Fig. 1).15 In addition to IL-4/IL-13, IL-18 plus IL-2 stimulates CD4+ T cells to produce IL-3 and IL-9.16 Furthermore, administration of IL-18 plus IL-2 into nave mice induces increases in serum levels of IL-3, IL-4, IL-9 and IL-13.16 As, IL-3, IL-4 and IL-9 are well-known potent mast cell growth factors54-56 and essential to induce intestinal mMCP-1+MMC,9 we tested whether daily administration of IL-2 and/or IL-18 induces accumulation of MMC in intestines of the mice, and found that IL-18 and IL-2 dose-dependently increase the number of intestinal MMC.57 Furthermore, these intestinal MMC express mMCP-1, suggesting that they are activated.57 Taken together, these results clearly indicate that treatment with IL-18 and IL-2 induces accumulation, maturation and activation of intestinal MMC, namely intestinal mastocytosis (Fig. 5).

The cellular and molecular bases for IL-18 plus IL-2-induced mMCP-1+MMC have been examined. Wild-type mice depleted of CD4+ T cells by the pretreatment with anti-CD4 antibody or RAG-2 deficient (RAG-2-/-) mice, lacking both T cells and B cells, exhibit poor accumulation of MMC in response to administration of IL-18 plus IL-2, indicating a requirement of CD4+ T cells.57 Interestingly, STAT6-/- mice display intestinal mastocytosis when injected with IL-2 and IL-18, suggesting STAT6-independent mastocytosis.57 IL-18 plus IL-2-stimulated CD4+ T cells produce IL-3 and IL-9, well-known potent mast cell growth factors.54, 55 Indeed, administration of IL-3 and IL-9 into naïve mice for 2 weeks dose-dependently induce mMCP-1+MMC in the intestine.57 Thus, IL-2 plus IL-18 treatment seems to induce mMCP-1+MMC by virtue of IL-3 and IL-9 from CD4+ T cells and IL-3 seems to be most critical for mMCP-1+MMC induction (Fig. 5)


To examine the functional role of intestinal MMC induced by IL-18 plus IL-2, we surgically implanted adult worms in the duodenum of mice pretreated with IL-2 and/or IL-18 for 13 days and recovered invading parasites at 16 h after implantation.46 IL-18 plus IL-2-treated wild-type mice reject implanted worms almost completely, while mice that received PBS, IL-2 or IL-18 alone are heavily parasitized with implanted worms (Fig. 5). However, mast cell-deficient W/Wv mice even treated with IL-2 and IL-18 fail to reject them, indicating the rapid expulsion of implanted adult worms is mediated by the function of activated intestinal MMC.57 Importantly and as expected, IL-2 and IL-18-pretreated STAT6-/- mice also gain the capacity to rapidly reject implanted parasites. These results taken together suggest that IL-18 with IL-2 protects against gastrointestinal nematode infection by activating MMC-dependent innate type 2 immunity (Fig. 5)


Wild-type mice inoculated with S. venezuelensis L3 show a significant increase in serum levels of IL-18 (days 4 to 14), and complete worm expulsion within 12 days. Thus, to address the role of endogenous IL-18 in the induction of intestinal MMC for the host defense against S. venezuelensis L3 infection, the capacity of IL-18-/- mice or IL-18Rα-/- mice to expel S. venezuelensis was examined. Comparing to infected wild-type mice, IL-18-/- or IL-18Rα-/- mice infected with S. venezuelensis L3 exhibit significantly delayed worm expulsion.57 Wild-type mice completed worm expulsion by day 12, while IL-18-/- or IL-18Rα-/- mice requested 16 days. However, they eventually expelled infected parasites, suggesting the contribution of Th2 cells that were generated by parasite infection in IL-18-/- or IL-18Rα-/- mice. Thus, we assume the possible contribution of Th2 cells to this late-phase induction of mMCP-1+MMC, namely worm expulsion. These results taken together indicate involvement of two types of intestinal MMC activation, IL-18-dependent (innate type-2) MMC activation and Th2 cells-dependent (acquired type-2) MMC activation for S. venezuelensis expulsion (Fig. 6).


Although it is well known that IL-4 is critical to polarization of CD4+ T cells to a Th2 phenotype, mainly in vivo system, initial IL-4 producing cells in vivo are poorly understood. Several cell types have been reported to produce IL-4, including conventional CD4+ T cells,58, 59 NKT cells60 and mast cells.61 It has been reported that infection with gastrointestinal nematode, Nippostrongylus brasiliensis (Nb) resulted in an increase in the number of splenic FcεRI+, non-B, non-T cells.62 Most of these FcεRI+ cells were basophils morphologically and produced IL-4 in response to FcεRI cross-linkage, suggesting that basophil-derived IL-4 may play a physiologically important role in IgE production.63 Recently, Paul and his colleagues have more clearly demonstrated that Nb infection induces substantial IL-4+ basophils in the lung, liver and spleen in a STAT6 independent manner.64 Recruitment of basophils into these tissues is dependent on CD4+ T cells.64 We have also observed that S. venezuelensis infection induces substantial IL-4+ basophils in the liver and spleen in a STAT6 independent manner (unpublished data).

Nb-induced basophil recruitment and IL-4 production has been partially inhibited by the treatment with anti-IL-3 Ab.64 Glli and his colleagues have demonstrated that IL-3 does enhance basophil accumulation during S. venezuelensis infection.45 We suggested in vivo IL-2 plus IL-18 treatment induces mMCP-1+MMC via IL-3 and IL-9 production from CD4+ T cells.57 Thus, infection with a parasite that induces a "Th2-type response" resulted in accumulation of tissue basophils in the tissues, where basophils may act as major IL-4-producing cells and protect host against various pathogens by augmenting Th2 response (Fig. 5).


Okamura H, Tsutsui H, Komatsu T et al. Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 1995; 378: 88-91.
Medline Chemport

Yoshimoto T, Okamura H, Tagawa YI, Iwakura Y, Nakanishi K. Interleukin 18 together with interleukin 12 inhibits IgE production by induction of interferon-gamma production from activated B cells. Proc. Natl. Acad. Sci. U.S.A. 1997; 94: 3948-3953.
Medline Chemport

Yoshimoto T, Takeda K, Tanaka T et al. IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production. J. Immunol. 1998; 161: 3400-3407.
Medline Chemport

Robinson D, Shibuya K, Mui A et al. IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFkappaB. Immunity 1997; 7: 571-581.
Medline Chemport

Munder M, Mallo M, Eichmann K, Modolell M. Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: A novel pathway of autocrine macrophage activation. J. Exp. Med. 1998; 187: 2103-2108.
Medline Chemport

Tominaga K, Yoshimoto T, Torigoe K et al. IL-12 synergizes with IL-18 or IL-1beta for IFN-gamma production from human T cells. Int. Immunol. 2000; 12: 151-160.
Medline Chemport

Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu. Rev. Immunol. 2001; 19: 423-474.
Medline Chemport

Tsutsui H, Yoshimoto T, Hayashi N, Mizutani H, Nakanishi K. Induction of allergic inflammation by interleukin-18 in experimental animal models. Immunol. Rev. 2004; 202: 115-138.
Medline Chemport

Miller HR, Wright SH, Knight PA, Thornton EM. A novel function for transforming growth factor-beta1: upregulation of the expression and the IgE-independent extracellular release of a mucosal mast cell granule-specific beta-chymase, mouse mast cell protease-1. Blood 1999; 93: 3473-3486.
Medline Chemport

Wei XQ, Leung BP, Niedbala W et al. Altered immune responses and susceptibility to Leishmania major and Staphylococcus aureus infection in IL-18-deficient mice. J. Immunol. 1999; 163: 2821-2828.
Medline Chemport

Ohkusu K, Yoshimoto T, Takeda K et al. Potentiality of interleukin-18 as a useful reagent for treatment and prevention of Leishmania major infection. Infect. Immun. 2000; 68: 2449-2456.
Medline Chemport

Kawakami K, Kinjo Y, Yara S et al. Enhanced gamma interferon production through activation of Valpha14 (+) natural killer T cells by alpha-galactosylceramide in interleukin-18-deficient mice with systemic cryptococcosis. Infect. Immun. 2001; 69: 6643-6650.
Medline Chemport

Chikano S, Sawada K, Shimoyama T et al. IL-18 and IL-12 induce intestinal inflammation and fatty liver in mice in an IFN-gamma dependent manner. Gut. 2000; 47: 779-786.
Medline Chemport

Yoshimoto T, Tsutsui H, Tominaga K et al. IL-18, although antiallergic when administered with IL-12, stimulates IL-4 and histamine release by basophils. Proc. Natl. Acad. Sci. U.S.A. 1999; 96: 13962-13966.
Medline Chemport

Yoshimoto T, Mizutani H, Tsutsui H et al. IL-18 induction of IgE: dependence on CD4+ T cells, IL-4 and STAT6. Nat. Immunol. 2000; 1: 132-137.
Medline Chemport

Yoshimoto T, Min B, Sugimoto T et al. Nonredundant roles for CD1d-restricted natural killer T cells and conventional CD4+ T cells in the induction of immunoglobulin E antibodies in response to interleukin 18 treatment of mice. J. Exp. Med. 2003; 197: 997-1005.
Medline Chemport

Yamanaka K, Tanaka M, Tsutsui H et al. Skin-specific caspase-1-transgenic mice show cutaneous apoptosis and pre-endotoxin shock condition with a high serum level of IL-18. J. Immunol. 2000; 165: 997-1003.
Medline Chemport

Konishi H, Tsutsui H, Murakami T et al. IL-18 contributes to the spontaneous development of atopic dermatitis-like inflammatory skin lesion independently of IgE/stat6 under specific pathogen-free conditions. Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 11340-11345.
Medline Chemport

Kawakami T, Galli SJ. Regulation of mast-cell and basophil function and survival by IgE. Nat. Rev. Immunol. 2002; 2: 773-786.
Medline Chemport

Coffman RL, Seymour BW, Lebman DA et al. The role of helper T cell products in mouse B cell differentiation and isotype regulation. Immunol. Rev. 1988; 102: 5-28.
Medline Chemport

Finkelman FD, Holmes J, Katona IM et al. Lymphokine control of in vivo immunoglobulin isotype selection. Annu. Rev. Immunol. 1990; 8: 303-333.
Medline Chemport

Hamelmann E, Gelfand EW. IL-5-induced airway eosinophilia-the key to asthma? Immunol. Rev. 2001; 179: 182-191.
Medline Chemport

McKenzie GJ, Bancroft A, Grencis RK, McKenzie AN. A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Curr. Biol. 1998; 8: 339-342.

Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 1998; 188: 1307-1320.

Grunig G, Warnock M, Wakil AE. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998; 282: 2261-2263.
Medline Chemport

Kuperman DA, Huang X, Koth LL et al. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat. Med. 2002; 8: 885-889.
Medline Chemport

Wills-Karp M, Chiaramonte M. Interleukin-13 in asthma. Curr. Opin. Pulm. Med. 2003; 9: 21-27.
Medline Chemport

Wills-Karp M, Luyimbazi J, Xu X et al. Interleukin-13: central mediator of allergic asthma. Science 1998; 282: 2258-2261.
Medline Chemport

Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu. Rev. Immunol. 2003; 21: 335-376.
Medline Chemport

Adachi O, Kawai T, Takeda K et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 1998; 9: 143-150.

Kawai T, Adachi O, Ogawa T, Takeda K, Akira S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 1999; 11: 115-122.

Seki E, Tsutsui H, Nakano H et al. Lipopolysaccharide-induced IL-18 secretion from murine Kupffer cells independently of myeloid differentiation factor 88 that is critically involved in induction of production of IL-12 and IL-1beta. J. Immunol. 2001; 166: 2651-2657.
Medline Chemport

Masuda A, Yoshikai Y, Aiba K, Matsuguchi T. Th2 cytokine production from mast cells is directly induced by lipopolysaccharide and distinctly regulated by c-Jun N-terminal kinase and p38 pathways. J. Immunol. 2002; 169: 3801-3810.
Medline Chemport

Supajatura V, Ushio H, Nakao A et al. Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J. Clin. Invest. 2002; 109: 1351-1359.
Medline Chemport

Supajatura V, Ushio H, Nakao A, Okumura K, Ra C, Ogawa H. Protective roles of mast cells against enterobacterial infection are mediated by Toll-like receptor 4. J. Immunol. 2001; 167: 2250-2256.
Medline Chemport

Varadaradjalou S, Feger F, Thieblemont N et al. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. Eur. J. Immunol. 2003; 33: 899-906.
Medline Chemport

Hoshino K, Takeuchi O, Kawai T et al. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 1999; 162: 3749-3752.
Medline Chemport

Takeuchi O, Hoshino K, Kawai T et al. Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 1999; 11: 443-451.

Sabroe I, Jones EC, Usher LR, Whyte MK, Dower SK. Toll-like receptor (TLR) 2 and TLR4 in human peripheral blood granulocytes: a critical role for monocytes in leukocyte lipopolysaccharide responses. J. Immunol. 2002; 168: 4701-4710.

Bieneman AP, Chichester KL, Chen YH, Schroeder JT. Toll-like receptor 2 ligands activate human basophils for both IgE-dependent and IgE-independent secretion. J. Allergy Clin. Immunol. 2005; 115: 295-301.
Medline Chemport

Dahl ME, Dabbagh K, Liggitt D, Kim S, Lewis DB. Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells. Nat. Immunol. 2004; 5: 337-343.
Medline Chemport

Schwarze J, Gelfand EW. Respiratory viral infections as promoters of allergic sensitization and asthma in animal models. Eur. Respir. J. 2002; 19: 341-349.
Medline Chemport

Grencis RK. Th2-mediated host protective immunity to intestinal nematode infections. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 1997; 352: 1377-1384.
Medline Chemport

Urban JF Jr, Noben-Trauth N, Donaldson DD et al. IL-13, IL-4Ralpha, and Stat6 are required for the expulsion of the gastrointestinal nematode parasite Nippostrongylus brasiliensis. Immunity 1998; 8: 255-264.
Medline Chemport

Lantz CS, Boesiger J, Song CH et al. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 1998; 392: 90-93.
Medline Chemport

Maruyama H, Yabu Y, Yoshida A, Nawa Y, Ohta N. A role of mast cell glycosaminoglycans for the immunological expulsion of intestinal nematode, Strongyloides venezuelensis. J. Immunol. 2000; 164: 3749-3754.
Medline Chemport

Faulkner H, Renauld JC, Van Snick J, Grencis RK. Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris. Infect. Immun. 1998; 66: 3832-3840.
Medline Chemport

Helmby H, Grencis RK. IL-18 regulates intestinal mastocytosis and Th2 cytokine production independently of IFN-gamma during Trichinella spiralis infection. J. Immunol. 2002; 169: 2553-2560.
Medline Chemport

Faulkner H, Humphreys N, Renauld JC, Van Snick J, Grencis R. Interleukin-9 is involved in host protective immunity to intestinal nematode infection. Eur. J. Immunol. 1997; 27: 2536-2540.
Medline Chemport

Knight PA, Wright SH, Lawrence CE, Paterson YY, Miller HR. Delayed expulsion of the nematode Trichinella spiralis in mice lacking the mucosal mast cell-specific granule chymase, mouse mast cell protease-1. J. Exp. Med. 2000; 192: 1849-1856.

Scudamore CL, McMillan L, Thornton EM, Wright SH, Newlands GF, Miller HR. Mast cell heterogeneity in the gastrointestinal tract: variable expression of mouse mast cell protease-1 (mMCP-1) in intraepithelial mucosal mast cells in nematode-infected and normal BALB/c mice. Am. J. Pathol. 1997; 150: 1661-1672.
Medline Chemport

Urban JF Jr, Schopf L, Morris SC et al. Stat6 signaling promotes protective immunity against Trichinella spiralis through a mast cell- and T cell-dependent mechanism. J. Immunol. 2000; 164: 2046-2052.
Medline Chemport

Wastling JM, Scudamore CL, Thornton EM, Newlands GF, Miller HR. Constitutive expression of mouse mast cell protease-1 in normal BALB/c mice and its up-regulation during intestinal nematode infection. Immunology 1997; 90: 308-313.
Medline Chemport

Galli SJ, Hammel I. Mast cell and basophil development. Curr. Opin. Hematol. 1994; 1: 33-39.
Medline Chemport

Hultner L, Druez C, Moeller J et al. Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9). Eur. J. Immunol. 1990; 20: 1413-1416.
Medline Chemport

Madden KB, Urban JF Jr, Ziltener HJ, Schrader JW, Finkelman FD, Katona IM. Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis. J. Immunol. 1991; 147: 1387-1391.
Medline Chemport

Sasaki Y, Yoshimoto T, Maruyama H et al. IL-18 with IL-2 protects against Strongyloides venezuelensis infection by activating mucosal mast cell-dependent type 2 innate immunity. J. Exp. Med. 2005; 202: 607-616.
Medline Chemport

Bird JJ, Brown DR, Mullen AC et al. Helper T cell differentiation is controlled by the cell cycle. Immunity 1998; 9: 229-237.
Medline Chemport

Paliard X, de Waal Malefijt R, Yssel H et al. Simultaneous production of IL-2, IL-4, and IFN-gamma by activated human CD4+ and CD8+ T cell clones. J. Immunol. 1988; 141: 849-855.

Yoshimoto T, Bendelac A, Watson C, Hu-Li J, Paul WE. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science 1995; 270: 1845-1847.
Medline Chemport

Bradding P, Feather IH, Howarth PH et al. Interleukin 4 is localized to and released by human mast cells. J. Exp. Med. 1992; 176: 1381-1386.
Medline Chemport

Conrad DH, Ben-Sasson SZ, LeGros G, Finkelman FD, Paul WE. Infection with Nippostrongylus brasiliensis or injection of anti-IgD antibodies markedly enhances Fc-receptor-mediated interleukin 4 production by non-B, non-T cells. J. Exp. Med. 1990; 171: 1497-1508.
Medline Chemport

Seder RA, Paul WE, Dvorak AM et al. Mouse splenic and bone marrow cell populations that express high-affinity Fc epsilon receptors and produce interleukin 4 are highly enriched in basophils. Proc. Natl. Acad. Sci. U.S.A. 1991; 88: 2835-2839.
Medline Chemport

Min B, Prout M, Hu-Li J et al. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. J. Exp. Med. 2004; 200: 507-517.
Medline Chemport

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