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The Journal of Immunology, 2006, 177: 2755-2759.
Copyright © 2006 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Interleukin 4-Dependent Mast Cell Proliferation Requires Autocrine/Intracrine Cysteinyl Leukotriene-Induced Signaling1

Yongfeng Jiang*,{dagger}, Yoshihide Kanaoka*,{dagger}, Chunl Feng{dagger}, Karl Nocka§, Sudhir Rao§ and Joshua A. Boyce2,*,{dagger},{ddagger}

* Departments of Medicine and Pediatrics, Harvard Medical School, Boston, MA 02115; {dagger} Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA 02115; {ddagger} Partners Asthma Center, Boston, MA 02115; and § UCB Pharma, Cambridge, MA 02140


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Reactive mastocytosis (RM) in epithelial surfaces is a consistent Th2-associated feature of allergic disease. RM fails to develop in mice lacking leukotriene (LT) C4 synthase (LTC4S), which is required for cysteinyl leukotriene (cys-LT) production. We now report that IL-4, which induces LTC4S expression by mast cells (MCs), requires cys-LTs, the cys-LT type 1 receptor (CysLT1), and Gi proteins to promote MC proliferation. LTD4 (10–1000 nM) enhanced proliferation of human MCs in a CysLT1-dependent, pertussis toxin-sensitive manner. LTD4-induced phosphorylation of ERK required transactivation of c-kit. IL-4-driven comitogenesis was likewise sensitive to pertussis toxin or a CysLT1-selective antagonist and was attenuated by treatment with leukotriene synthesis inhibitors. Mouse MCs lacking LTC4S or CysLT1 showed substantially diminished IL-4-induced comitogenesis. Thus, IL-4 induces proliferation in part by inducing LTC4S and cys-LT generation, which causes CysLT1 to transactivate c-kit in RM.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Mast cells (MCs)3 are central to allergy and host mucosal defense (1). They develop in tissues from circulating committed progenitor cells (MCps) and require the c-kit receptor tyrosine kinase (RTK) and its ligand, stem cell factor (SCF) (2, 3). Constitutive stromal expression of SCF ensures that MCs thrive in normal connective tissues. In contrast, normal intestinal and respiratory epithelial surfaces contain few MCs, although MCs selectively accumulate in these mucosal surfaces with inflammation (reactive mastocytosis (RM)). RM is required for the clearance of intestinal helminths (4). The MCs arising in such circumstances generate large quantities of cysteinyl (cys) leukotrienes (LTs) (cys-LTs) (5), lipid mediators that induce vascular leak, smooth muscle constriction, and intracrine signaling (6). Asthma, rhinitis, and allergic esophagitis in humans all are associated with RM in the involved mucosal epithelia (reviewed in Ref. 1) and high levels of cys-LTs. The effector role of MCs in both mucosal defense and allergy makes the mechanisms controlling RM and its relationship to cys-LT generation of considerable importance.

RM requires both c-kit (7) and T cells (8). Abs against IL-3 and IL-4 in vivo block RM but not constitutive MC development (9). Each T cell-derived cytokine implicated in RM amplifies SCF-dependent proliferation of MC and/or MCp in vitro (comitogenesis) (10, 11). IL-4 is comitogenic with SCF for human MCs (hMCs) isolated from the human intestine (12) or derived in vitro from peripheral blood (13). IL-4 induces the expression of LTC4 synthase (LTC4S), an enzyme obligate for the generation of cys-LTs, by cord blood-derived hMCs (14) and enhances calcium flux and ERK phosphorylation (15, 16) by hMCs through the type 1 cys-LT receptor (CysLT1), one of two cys-LT-specific G protein-coupled receptors (17). By regulating both cys-LT synthesis and CysLT1 function, IL-4 may induce unique cys-LT-dependent autocrine/intracrine signaling events in MCs.

In a MC-dependent model of allergic airway disease, mice lacking LTC4S showed diminished Th2 cytokine generation and airway inflammation as compared with identically treated wild-type controls (18). The numbers of MCs in the tracheal epithelia of allergen-challenged Ltc4s–/– mice were decreased by ~90% compared with wild-type control mice but were normal in the adjacent submucosa. These findings implied a previously unrecognized requirement for cys-LTs in T cell-dependent RM, a process that involves in situ proliferation of MCs and/or MCp. In this study, we demonstrate that cys-LTs are autocrine/intracrine regulators of IL-4-driven comitogenesis. RM, a pathogenetically relevant feature of all allergic mucosal diseases, may involve a novel IL-4-mediated signaling mechanism requiring the induction of LTC4S and the transactivation of c-Kit by CysLT1.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Reagents

LTs, MK886 (an inhibitor of 5-lipoxygenase-activating protein and LTC4S), and the CysLT1-selective antagonist MK571 were purchased from Cayman Chemical. Pertussis toxin (PTX) (Sigma-Aldrich), the c-kit inhibitor STI571 (Novartis Pharmaceuticals), the 5-lipoxygenase inhibitor zileuton (Critical Therapeutics), and UO126 (Promega), an inhibitor of MEK, were purchased from the indicated vendors. Recombinant cytokines were purchased from R&D Systems.

Derivation of MCs

hMCs were derived from cord blood mononuclear cells using SCF (100 ng/ml), IL-6 (50 ng/ml), and IL-10 (10 ng/ml) as described (19) and harvested when >95% stained with toluidine blue (typically 6 wk). In some experiments, various concentrations of cys-LTs were added weekly to the cells from the start of the culture. hMCs were also derived from peripheral blood CD34+ cells from healthy adult volunteers using magnetic beads (Dynal Invitrogen) according to manufacturer’s protocol. Cells were seeded at 1.5 x 104/ml in StemPro-34 medium (Invitrogen Life Technologies) containing 20% charcoal-filtered FCS, SCF (100 ng/ml), GM-CSF (10 pg/ml), and 4% conditioned medium from an immortalized B cell line. After 2 wk, cells were maintained in new flasks at a density of 1 x 105/ml, and the medium was replaced weekly. hMCs grown under these conditions were ~100% toluidine blue-positive and highly c-Kit-positive (19) at 4 wk. Mouse bone marrow-derived MCs (mBMMCs) were derived from marrow in the presence of IL-3 (10 U/ml) and were studied at 4–6 wks when virtually all stained with toluidine blue. Mitogenic assays were performed in triplicate on cells suspended in fresh medium at a concentration of 0.5 x 106/ml in the presence of SCF (1–100 ng/ml) with or without LTD4 (0.01–1 µM), IL-4 (10 ng/ml), or both. LTB4 was used as a control stimulus. In some experiments, PTX (100 ng/ml), MK571 (1 µM), MK886 (1 µM), UO126 (5 µg/ml), or zileuton (1 µM) was added at the same time as the mitogens. At 72 h, the cells were pulsed overnight with thymidine, and counts were analyzed by beta counting. Apoptosis was assessed by cytofluorographic binding of annexin V (BD Pharmingen). Cys-LTs were measured in supernatants of IL-4-stimulated hMCs by ELISA (Cayman Chemical).

Mice

Ltc4s–/– mice (C.129S7-Ltc4stm1Blam; backcrossed for eight generations onto a BALB/c background), Cysltr1–/– mice (C57BL/6-Cysltr1tm1Ykn), and Cysltr2–/– mice (C57BL/6-Cysltr2tm1Ykn) were derived as described (20, 21, 22). Bone marrow from 6- to 8-wk-old male mice were used for in vitro experiments, along with littermate control cells. All animal studies were approved by the Animal Care and Use Committee of the Dana-Farber Cancer Institute (Boston, MA).

SDS-PAGE immunoblotting and c-kit transactivation

Cytokine-starved hMCs were stimulated for 5 min with LTD4 (1 µM), SCF (100 ng/ml), or medium. Some cell samples were pretreated overnight with PTX (100 ng/ml) or for 30 min with STI571 (2 µM) before stimulation. Lysates were processed for Western blotting as described previously (16). Blots were probed with a 1/1000 dilution of a rabbit polyclonal Ab that recognizes c-Kit phosphorylated at tyrosine 721 (Zymed Laboratories) or with a 1/200 dilution of an anti-total c-Kit Ab (Santa Cruz Biotechnology). Abs against MAPK (Cell Signaling Technologies) are detailed elsewhere (16). Anti-LTC4S purified antiserum (14) and recombinant mouse LTC4S protein as a positive control were provided by Dr. B. Lam (Harvard Medical School, Boston, MA). Bands were detected with ECL and quantitated by densitometry (ChemiImager; Alpha Innotech).

Statistics

Data are expressed as mean ± SEM from at least three experiments except where otherwise indicated. Data were converted to a percentage of control for each experiment where indicated. Differences between treatment groups were determined with Student’s t test.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
All nonlymphoid leukocytes of the respiratory mucosa in asthma or rhinitis express CysLT1 (23, 24). Unlike granulocytes, MCs proliferate in the peripheral tissues, which, along with MCp recruitment, results in RM. The association between RM and high levels of cys-LT generation (5) suggested a potential link between them. IL-4 is the only Th2 cytokine implicated in RM in vivo that is comitogenic for mature tissue-derived MCs and MCps from both rodents and humans in vitro (10, 12, 13, 25). The induction of LTC4S and CysLT1 function by IL-4 and the lack of RM in the airway epithelium of the Ltc4s–/– mice (18) led us to suspect a role for endogenous cys-LTs as amplifiers of MC proliferation in the context of mucosal inflammation.

Of the cys-LTs, LTD4 has the highest affinity for CysLT1 (17). We therefore tested whether LTD4 could directly induce proliferation of cord blood-derived hMCs maintained with SCF. LTD4 (1 µM) increased the proliferation of hMCs at every SCF concentration tested, most markedly at doses of SCF sufficient to sustain cell viability (1–10 ng/ml) but below the EC50 for proliferation. Even in the absence of SCF, LTD4 caused hMC proliferation in a dose-dependent manner (n = 2; data not shown). The 2–2.5-fold amplification of SCF-dependent proliferation induced by LTD4 was ~70% blocked by MK571 (as shown for one experiment; Fig. 1A; n = 5, p = 0.01; data not shown), implicating CysLT1. LTB4, an LT that is chemotactic for MCp in vitro through the BLT1 receptor (26), failed to induce proliferation of hMCs (n = 2; Fig. 1A) although it stimulated robust calcium flux (n = 3, not shown); thus, the mitogenic effect was specific to cys-LTs. The abrogation of the LTD4-mediated comitogenic signal by treatment of the cells with either PTX or the MEK inhibitor UO126 (Fig. 2A) and the loss of LTD4-mediated ERK phosphorylation in cell samples treated with PTX (not shown) imply that CysLT1 used Gi protein-dependent MEK/ERK signaling to cause proliferation.


Figure 1
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  		FIGURE 1. Comitogenic effects of cys-LTs. A, Dose-response to LTD4 for 3 days (top panel). Some samples were treated with MK571 for 30 min before the addition of LTD4. Results are the mean ± SD of triplicate samples in a single experiment representative of five performed. Bottom panel, response to LTB4 at the indicated concentrations as compared with the response to LTD4 (1 µM). Results are mean ± 0.5 range from two experiments. B, Numbers of cells (expressed as a percentage of the numbers in cultures maintained without cys-LTs) arising from 4-wk (top panels) and 6-wk (bottom panels) cultures maintained with SCF, IL-6, and IL-10 along with the weekly additions of LTC4, LTD4, and LTE4 at the indicated concentrations. Data are mean ± SEM from three or four experiments. Toluidine blue staining (right panels) of cells from representative LTE4-treated cultures are shown. C, Annexin V staining of 6-wk-old cells maintained in SCF-, IL-6-, and IL-10-supplemented medium with or without the indicated cys-LT at 1 µM. Results in a second experiment were similar.

 

Figure 2
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  		FIGURE 2. Signaling events for cys-LT-mediated comitogenesis. A, Proliferation of hMCs cultured for 3 days with SCF (10 ng/ml) without or with LTD4 (1 µM). Some of the LTD4-treated cells were preincubated overnight with PTX (100 ng/ml) or for 30 min with the MEK inhibitor UO126 (5 ng/ml) before the addition of LTD4. Data are mean ± SD from triplicate samples in a single experiment representative of five (for PTX) and two (for UO126) performed. B, Phosphorylation of c-kit and ERK in hMCs stimulated for 5 min with SCF (100 ng/ml), medium alone, or LTD4 (500 nM). Some cells were treated with STI571 for 30 min before stimulation. Data are from a single experiment representative of three performed. Quantitative densitometry showing the effect of STI571 on c-kit (C) and ERK (D) phosphorylation. Data in C and D are expressed as density relative to the positive control (SCF) and are mean ± SEM from three experiments. *, p = 0.03 relative to cells not treated with STI571.

 
When LTC4, LTD4, or LTE4 were added at weekly intervals from the start of culture, each increased the numbers of hMCs even with the maximally effective dose of SCF (100 ng/ml) and the comitogenic cytokines IL-6 and IL-10. Cys-LTs did not alter the percentages of mature hMCs as determined by toluidine blue staining (Fig. 1B) and expression of c-Kit (data not shown). Although LTE4 (the weakest CysLT1 agonist) (17) induced the most significant increase in the number of MCs (p = 0.02 and 0.04 at 4 and 6 wk relative to untreated controls; n = 4), it was similar to LTD4 in stimulating thymidine incorporation (115 ± 19, 132 ± 6, and 202 ± 3% of the SCF control at 0.1, 0.5, and 1 µM, respectively; n = 2), and its effect was blocked by MK571. LTE4 could activate a second (uncharacterized) MK571-sensitive receptor, or it may induce a qualitatively different signal than LTD4 through CysLT1 to account for differences in cell numbers. Because none of the cys-LTs protected hMCs from apoptosis (Fig. 1C), the near doubling of hMCs arising over the 4–6 wk of culture likely reflects proliferation, largely through CysLT1 and the Gi/MEK/ERK signal sequence.

Whereas some G protein-coupled receptors stimulate Ras/MEK/ERK signaling directly through G proteins, others do so through transactivation of RTKs (reviewed in Ref. 27), promoting cell proliferation in circumstances where protein growth factor concentrations are low. Transactivation is implicated in fibrosis and malignancies. LTD4-induced c-Kit phosphorylation (Fig. 2B) and LTD4-dependent ERK phosphorylation were abrogated by STI571 (n = 3, Fig. 2C; as shown for one experiment, Fig. 2B). SCF, but not LTD4, strongly induced phosphorylation of c-Jun terminal kinase (n = 2, not shown), and p38 was weakly and constitutively phosphorylated under each of these conditions (not shown). Thus, CysLT1 requires transactivation of c-Kit to integrate the cys-LT-induced Gi/MEK/ERK cascade. These findings carry potential implications for mechanisms controlling proliferation of MCs and other c-Kit-dependent cell lineages as well as cys-LT-dependent proliferation of other cell types that express RTKs. The observation that LTD4 cannot completely substitute for SCF reflects the ability of the latter to induce additional signaling events (i.e., JNK activation) and cytoprotection.

Like LTD4, IL-4 amplifies SCF-dependent MC proliferation through MEK/ERK (25). Because IL-4 also induces LTC4S expression, we suspected that IL-4-dependent comitogenesis might involve autocrine actions of endogenous cys-LTs. We tested this hypothesis with hMCs both derived from cord blood and from adult peripheral blood to ensure that the pathway was operative regardless of progenitor origin or culture methodology. IL-4 increased proliferation of the hMCs grown with both methods (Fig. 3A). Both PTX and MK571 decreased IL-4-induced comitogenesis in both hMC types (Fig. 3A). MK886, which inhibits cys-LT production by blocking both 5-lipoxygenase-activating protein and LTC4S, decreased IL-4-mediated proliferation of cord blood-derived hMCs in a dose-dependent manner (Fig. 3B) but not SCF-induced basal proliferation or LTD4-mediated proliferation (Fig. 3C). Exogenous LTD4 restored the response of hMCs to IL-4 in the presence of MK886. Thus, endogenous cys-LTs contribute 40–60% of the IL-4-mediated comitogenic signal in hMCs, likely reflecting the capacity of this cytokine to both up-regulate LTC4S and enhance CysLT1-mediated ERK signaling. Extracellular cys-LTs were below limits of detection in these experiments, suggesting likely synaptic functions of low-level endogenous cys-LTs at membrane or nuclear receptors (6).


Figure 3
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  		FIGURE 3. Requirement for cys-LTs, CysLT1, and Gi proteins in IL-4-induced comitogenesis of hMCs. A, Cord blood hMCs (left panel) and peripheral blood hMCs (right panel) were maintained in the presence of SCF (10 ng/ml) with or without IL-4 (10 ng/ml) for 3 days in the absence or presence of MK571 (1 µM) or PTX (100 ng/ml). Data are mean ± SEM of n = 6 and 4, respectively, for cord and peripheral blood hMCs. B, Dose-dependent effect of MK886 on IL-4-mediated comitogenesis of cord blood hMCs. Results in a second experiment were similar. C, Cord blood hMCs were treated with SCF with or without IL-4 in the presence or absence of MK886 (1 µM). LTD4 (1 µM) was added to the indicated samples. Data are the mean ± SEM from four separate experiments. *, p = 0.04 relative to IL-4-stimulated cells without MK886.

 
Restimulated lymphocytes from Ltc4s–/– mice with OVA-induced airway disease were deficient in the generation of Th2 cytokines (18). Their complete lack of RM could therefore reflect a loss of cys-LT-dependent autocrine/intracrine signaling combined with diminished Th2 cytokine production. We studied IL-4-dependent comitogenesis of mBMMCs from both enzyme- and receptor-null mice. IL-4 induced LTC4S protein expression in wild-type mBMMCs within 72 h (Fig. 4A). Although IL-4 was comitogenic for mBMMCs from both genotypes, the net response of the LTC4S–/– mBMMCs to IL-4 was only ~40% of the increment in the wild-type mBMMCs (n = 3; Fig. 4B). Moreover, Cyslt1r–/– but not Cyslt2r–/– mBMMCs showed markedly impaired comitogenic responses to IL-4 (Fig. 4C). MK571, MK886, zileuton (data not shown), and PTX attenuated the IL-4-driven comitogenic response only in the wild-type and Cyslt2r–/– mBMMCs. Thus the LTC4S/cys-LT/CysLT1/Gi sequence is a major autocrine/intracrine signal amplification pathway contributing to IL-4-driven comitogenesis, a central event in mucosal RM. The specialized functions of LTB4 (MCp recruitment) (26) and cys-LTs (comitogenesis) may synergize to facilitate RM in allergic disease. CysLT1 antagonists and 5-lipoxygenase inhibitors could interrupt these pathways as part of their therapeutic mechanism in asthma.


Figure 4
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  		FIGURE 4. Cys-LT signaling in IL-4-induced comitogenesis of mBMMCs. Cells derived from the indicated mouse strains were treated with SCF (5 ng/ml) with or without IL-4 (10 ng/ml). A, Immunoblot showing induced expression of LTC4S (top) and total ERK as a loading control. Results in a second experiment were identical. KO, knockout; WT, wild type; pos. control, positive control B, Proliferation of wild-type and Ltc4s–/– mBMMCs in the presence of SCF with or without IL-4 and the indicated inhibitors for 3 days. C, Comitogenic effect of IL-4 in Cyslt1r–/– and Cyslt2r–/– mBMMCs and wild-type C57BL/6 controls. Data in C and D are converted to percentage of control and are mean ± SEM from three experiments. *, differences from wild-type IL-4-treated cells.

 

   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


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

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

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

3 Abbreviations used in this paper: MC, mast cell; hMC, human MC; MCp, mast cell progenitor; mBMMC, mouse bone marrow-derived MC; LT, leukotriene; cys-LT, cysteinyl LT; CysLT1, type 1 receptor for cys-LTs; LTC4S, LTC4 synthase; PTX, pertussis toxin; RM, reactive mastocytosis; RTK, receptor tyrosine kinase; SCF, stem cell factor. Back

Received for publication May 3, 2006. Accepted for publication June 29, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

  1. Boyce, J. A.. 2003. Mast cells: beyond IgE. J. Allergy Clin. Immunol. 111: 24-32. [Medline]
  2. Kitamura, Y., S. Go, K. Hatanaka. 1978. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 52: 447-452. [Abstract/Free Full Text]
  3. Kitamura, Y., S. Go. 1979. Decreased production of mast cells in Sl/Sld anemic mice. Blood 53: 492-497. [Free Full Text]
  4. Urban, J. F., Jr, L. Schopf, S. C. Morris, T. Orekhova, K. B. Madden, C. J. Betts, H. R. Gamble, C. Byrd, D. Donaldson, K. Else, F. D. Finkelman. 2000. Stat6 signaling promotes protective immunity against Trichinella spiralis through a mast cell- and T cell-dependent mechanism. J. Immunol. 164: 2046-2052. [Abstract/Free Full Text]
  5. Heavey, D. J., P. B. Ernst, R. L. Stevens, A. D. Befus, J. Bienenstock, K. F. Austen. 1988. Generation of leukotriene C4, leukotriene B4, and prostaglandin D2 by immunologically activated rat intestinal mucosa mast cells. J. Immunol. 140: 1953-1957. [Abstract/Free Full Text]
  6. Bandeira-Melo, C., L. J. Woods, M. Phoofolo, P. F. Weller. 2002. Intracrine cysteinyl leukotriene receptor-mediated signaling of eosinophil vesicular transport-mediated interleukin-4 secretion. J. Exp. Med. 196: 841-850. [Abstract/Free Full Text]
  7. Alizadeh, H., K. D. Murrell. 1984. The intestinal mast cell response to Trichinella spiralis infection in mast cell-deficient W/Wv mice. J. Parasitol. 70: 767-773. [Medline]
  8. Ruitenberg, E. J., A. Elgersma. 1976. Absence of intestinal mast cell response in congenitally athymic mice during Trichinella spiralis infection. Nature 264: 258-260. [Medline]
  9. Madden, K. B., J. F. Urban, Jr, H. J. Ziltener, J. W. Schrader, F. D. Finkelman, I. M. Katona. 1991. Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis. J. Immunol. 147: 1387-1391. [Abstract]
  10. Rennick, D., B. Hunte, G. Holland, L. Thompson-Snipes. 1995. Cofactors are essential for stem cell factor-dependent growth and maturation of mast cell progenitors: comparative effects of interleukin-3 (IL-3), IL-4, IL-10, and fibroblasts. Blood 85: 57-65. [Abstract/Free Full Text]
  11. Matsuzawa, S., K. Sakashita, T. Kinoshita, S. Ito, T. Yamashita, K. Koike. 2003. IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J. Immunol. 170: 3461-3467. [Abstract/Free Full Text]
  12. Bischoff, S. C., G. Sellge, A. Lorentz, W. Sebald, R. Raab, M. P. Manns. 1999. IL-4 enhances proliferation and mediator release in mature human mast cells. Proc. Natl. Acad. Sci. USA 96: 8080-8085. [Abstract/Free Full Text]
  13. Kulka, M., D. D. Metcalfe. 2005. High-resolution tracking of cell division demonstrates differential effects of Th1 and Th2 cytokines on SCF-dependent human mast cell production in vitro: correlation with apoptosis and Kit expression. Blood 105: 592-599. [Abstract/Free Full Text]
  14. Hsieh, F. H., B. K. Lam, J. F. Penrose, K. F. Austen, J. A. Boyce. 2001. T helper cell type 2 cytokines coordinately regulate IgE- dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C4 synthase expression by interleukin 4. J. Exp. Med. 193: 123-133. [Abstract/Free Full Text]
  15. Mellor, E. A., A. Maekawa, K. F. Austen, J. A. Boyce. 2001. Cysteinyl leukotriene receptor 1 is also a pyrimidinergic receptor and is expressed by human mast cells. Proc. Natl. Acad. Sci. USA 98: 7964-7969. [Abstract/Free Full Text]
  16. Lin, D. A., J. A. Boyce. 2005. Interleukin 4 regulates the expression of mitogen-activated protein kinase kinase-1 necessary for cytokine generation by human mast cells. J. Immunol. 175: 5430-5438. [Abstract/Free Full Text]
  17. Lynch, K. R., G. P. O’Neill, Q. Liu, D. S. Im, N. Sawyer, K. M. Metters, N. Coulombe, M. Abramovitz, D. J. Figueroa, Z. Zeng, et al 1999. Characterization of the human cysteinyl leukotriene cysLT1 receptor. Nature 399: 789-793. [Medline]
  18. Kim, D. C., F.I. Hsu, N. A. Barrett, D. S. Friend, R. Grenningloh, I. C. Ho, A. Al-Garawi, J. M. Lora, B. K. Lam, K. F. Austen, Y. Kanaoka. 2006. Cysteinyl leukotrienes regulate Th2 cell-dependent pulmonary inflammation. J. Immunol. 176: 4440-4448. [Abstract/Free Full Text]
  19. Ochi, H., W. M. Hirani, Q. Yuan, D. Friend, K. F. Austen, J. A. Boyce. 1999. T helper type 2 cytokine-mediated comitogenic responses and CCR3 expression during differentiation of human mast cells in vitro. J. Exp. Med. 190: 267-280. [Abstract/Free Full Text]
  20. Kanaoka, Y., A. Maekawa, J. F. Penrose, K. F. Austen, B. K. Lam. 2001. Attenuated zymosan-induced peritoneal vascular permeability and IgE-dependent passive cutaneous anaphylaxis in mice lacking leukotriene C4 synthase. J. Biol. Chem. 276: 22608-22613. [Abstract/Free Full Text]
  21. Beller, T. C., A. Maekawa, D. S. Friend, K. F. Austen, Y. Kanaoka. 2004. Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J. Biol. Chem. 279: 46129-46134. [Abstract/Free Full Text]
  22. Mackawa, A., K. F. Auster, Y. Kanaoka. 2002. Targeted gene disruption reveals the role of cysteinyl leukotriene 1 receptor in the enhanced vascular permeability of mice undergoing acute inflammatory responses. J. Biol. Chem. 277: 20820-20824. [Abstract/Free Full Text]
  23. Figueroa, D. J., L. Borish, D. Baramki, G. Philip, C. P. Austin, J. F. Evans. 2003. Expression of cysteinyl leukotriene synthetic and signalling proteins in inflammatory cells in active seasonal allergic rhinitis. Clin. Exp. Allergy 33: 1380-1388. [Medline]
  24. Zhu, J., Y. S. Qiu, D. J. Figueroa, V. Bandi, H. Galczenski, K. Hamada, K. K. Guntupalli, J. F. Evans, P. K. Jeffery. 2005. Localization and upregulation of cysteinyl leukotriene-1 receptor in asthmatic bronchial mucosa. Am. J. Respir. Cell Mol. Biol. 33: 531-540. [Abstract/Free Full Text]
  25. Lorentz, A., M. Wilke, G. Sellge, H. Worthmann, J. Klempnauer, M. P. Manns, S. C. Bischoff. 2005. IL-4-induced priming of human intestinal mast cells for enhanced survival and Th2 cytokine generation is reversible and associated with increased activity of ERK1/2 and c-Fos. J. Immunol. 174: 6751-6756. [Abstract/Free Full Text]
  26. Weller, C. L., S. J. Collington, J. K. Brown, H. R. Miller, A. Al-Kashi, P. Clark, P. J. Jose, A. Hartnell, T. J. Williams. 2005. Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors. J. Exp. Med. 201: 1961-1971. [Abstract/Free Full Text]
  27. Waters, C., S. Pyne, N. J. Pyne. 2004. The role of G-protein coupled receptors and associated proteins in receptor tyrosine kinase signal transduction. Semin. Cell Dev. Biol. 15: 309-323. [Medline]



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S. Paruchuri, H. Tashimo, C. Feng, A. Maekawa, W. Xing, Y. Jiang, Y. Kanaoka, P. Conley, and J. A. Boyce
Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor
J. Exp. Med., October 26, 2009; 206(11): 2543 - 2555.
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N. A. Barrett, A. Maekawa, O. M. Rahman, K. F. Austen, and Y. Kanaoka
Dectin-2 Recognition of House Dust Mite Triggers Cysteinyl Leukotriene Generation by Dendritic Cells
J. Immunol., January 15, 2009; 182(2): 1119 - 1128.
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Y. Jiang, L. Borrelli, B. J. Bacskai, Y. Kanaoka, and J. A. Boyce
P2Y6 Receptors Require an Intact Cysteinyl Leukotriene Synthetic and Signaling System to Induce Survival and Activation of Mast Cells
J. Immunol., January 15, 2009; 182(2): 1129 - 1137.
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D. D. Metcalfe
Mast cells and mastocytosis
Blood, August 15, 2008; 112(4): 946 - 956.
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S. Paruchuri, Y. Jiang, C. Feng, S. A. Francis, J. Plutzky, and J. A. Boyce
Leukotriene E4 Activates Peroxisome Proliferator-activated Receptor {gamma} and Induces Prostaglandin D2 Generation by Human Mast Cells
J. Biol. Chem., June 13, 2008; 283(24): 16477 - 16487.
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Y. Jiang, L. A. Borrelli, Y. Kanaoka, B. J. Bacskai, and J. A. Boyce
CysLT2 receptors interact with CysLT1 receptors and down-modulate cysteinyl leukotriene dependent mitogenic responses of mast cells
Blood, November 1, 2007; 110(9): 3263 - 3270.
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