The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mesquita-Santos, F. P.
Right arrow Articles by Bandeira-Melo, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mesquita-Santos, F. P.
Right arrow Articles by Bandeira-Melo, C.
The Journal of Immunology, 2006, 176: 1326-1330.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Prostaglandin D2 Enhances Leukotriene C4 Synthesis by Eosinophils during Allergic Inflammation: Synergistic In Vivo Role of Endogenous Eotaxin1

Fabio P. Mesquita-Santos*, Adriana Vieira-de-Abreu*, Andrea S. Calheiros*, Isabela H. Figueiredo*, Hugo C. Castro-Faria-Neto*, Peter F. Weller{dagger}, Patrícia T. Bozza*, Bruno L. Diaz{ddagger} and Christianne Bandeira-Melo2,*

* Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz, Rio de Janeiro, Brazil; {dagger} Department of Medicine, Harvard Medical School, Boston, MA 02215; and {ddagger} Divisão de Biologia Celular, Instituto Nacional do Cancer, Rio de Janeiro, Brazil


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
In addition to the well-recognized ability of prostaglandin D2 (PGD2) to regulate eosinophil trafficking, we asked whether PGD2 was also able to activate eosinophils and control their leukotriene C4 (LTC4)-synthesizing machinery. PGD2 administration to presensitized mice enhanced in vivo LTC4 production and formation of eosinophil lipid bodies–potential LTC4-synthesizing organelles. Immunolocalization of newly formed LTC4 demonstrated that eosinophil lipid bodies were the sites of LTC4 synthesis during PGD2-induced eosinophilic inflammation. Pretreatment with HQL-79, an inhibitor of PGD synthase, abolished LTC4 synthesis and eosinophil lipid body formation triggered by allergic challenge. Although PGD2 was able to directly activate eosinophils in vitro, in vivo PGD2-induced lipid body-driven LTC4 synthesis within eosinophils was dependent on the synergistic activity of endogenous eotaxin acting via CCR3. Our findings, that PGD2 activated eosinophils and enhanced LTC4 synthesis in vivo in addition to the established PGD2 roles in eosinophil recruitment, heighten the interest in PGD2 as a target for antiallergic therapies.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Leukotriene C4 (LTC4)3 and prostaglandin D2 (PGD2) are key lipid mediators of allergic airway inflammation that are released following allergen exposure in patients with asthma (1, 2, 3, 4). LTC4 and PGD2 exert a variety of asthma-relevant actions, including bronchoconstriction and infiltration of eosinophils (1, 4), one of the principal cell types recruited to and activated at sites of allergic inflammation.

Eosinophils represent a major source of cysteinyl leukotrienes (cysLTs; LTC4/D4/E4) (5, 6). The regulated synthesis of cysLTs is initiated by phospholipase A2-mediated release of arachidonic acid (AA) from phospholipids. Released AA binds to 5-lipoxygenase (5-LO)-activating protein (FLAP) enabling AA to be oxygenated by 5-LO to form LTA4. In eosinophils, a GST, LTC4 synthase, catalyzes the adduction of glutathione to LTA4 to form LTC4. Although the enzymatic pathways by which eosinophils synthesize LTC4 have been characterized, the pathophysiologic mechanisms that regulate these pathways during allergic conditions remain to be fully elucidated. Endogenous allergy-relevant stimuli, specialized intracellular compartments, and regulatory mechanisms are key features of allergen-induced LTC4 synthesis that remain to be characterized. Recently, we have demonstrated that allergic inflammation triggers in vivo formation of new lipid bodies, which compartmentalize LTC4 synthesis within infiltrating eosinophils. The enhanced formation of LTC4 at newly formed lipid bodies can be mediated by eotaxin/RANTES acting via CCR3 receptors (7), but the role of other eosinophilotactic mediators in the induction of eosinophil LTC4 synthesis during allergic inflammation has not been ascertained.

PGD2 is a major mast cell derivative that appears to be critical for the pathogenesis of eosinophilic airway inflammation (3, 4) because of the following: 1) it is a potent chemoattractant for eosinophils both in vitro (8, 9) and in vivo (10); 2) overexpression of PGD2 synthase or inhalation of PGD2 enhanced eosinophilic airway inflammation in mice following allergen exposure (11, 12); and 3) disruption of the DP gene abolished eosinophil influx in a mouse model of asthma (13). Such PGD2 role in eosinophil trafficking is associated with PGD2’s ability to induce a variety of migration-related responses, including Ca2+ influx and actin polymerization (9, 14). Of note, in vitro data support an additional role for PGD2 as an eosinophil activator (14, 15). However, there is no evidence as yet indicating that PGD2-triggered signaling is important in vivo for activation/function of eosinophils, beyond its role in cell recruitment.

In this study, the interplay between two crucial lipid mediators of allergen-triggered eosinophilic inflammation, LTC4 and PGD2, was investigated. Specifically, we studied PGD2’s ability to activate LTC4-synthesizing machinery in eosinophils, by analyzing both LTC4 generation and the biogenesis of the cytoplasmic LTC4-synthesizing compartments (lipid bodies) of eosinophils in in vivo models of eosinophilic inflammation.


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

Swiss mice of 16–20 g from both sexes were used as approved by the institutional Animal Welfare Committee.

Allergic pleurisy in sensitized mice

Mice were sensitized with a s.c. injection (0.2 ml) of OVA (50 µg) and Al(OH)3 (5 mg) in 0.9% NaCl solution (saline) at days 1 and 7. Allergic challenge was performed at day 14 by means of an intrapleural (i.pl.) injection of OVA (12 µg/cavity; 0.1 ml) (7). Alternatively, sensitized or naive mice were challenged with saline or PGD2 (15–55 pmol/cavity; Cayman Chemicals). Mice were euthanized by CO2 inhalation 24 h after challenge. Pleural cavities were rinsed with 1 ml of PBS.

Lung allergic inflammation in sensitized mice

Mice were sensitized with i.p. injection of OVA (10 µg/mouse) and Al(OH)3 (10 mg/ml) in 0.2 ml of saline on days 1 and 10. From day 19 to day 24, mice were challenged for 20 min with OVA (5% in PBS) or PBS by aerosol (7). Mice were euthanized by CO2 24 h after the last aerosol. Bronchoalveolar lavage was collected by washing mice lungs with 1 ml of PBS.

Leukocyte and lipid body counts

Total leukocytes (diluted with Turk’s 2% acetic acid fluid) were counted using a Neubauer chamber. Differential counts were performed using cytopins stained by the May-Grunwald-Giemsa method. Lipid bodies were enumerated by microscopy in 50 consecutively scanned cells, in cytospin slides fixed in 3.7% formaldehyde and stained and contrasted with osmium (16).

Treatments

Using the pleurisy model, animals were pretreated with i.p. injections of PGD synthase inhibitor HQL-79 (1 mg/kg; Cayman Chemicals) (4) or anti-mCCR3 mAb (10 µg/cavity; clone 83103.111; R&D Systems) 30 min before allergic challenge. Animals pretreated with an irrelevant Ab showed no alteration of allergic response (data not shown). Using the asthma model, animals were pretreated (i.p.) four times with HQL-79 (1 mg/kg) 30 min before the four last aerosols.

In vitro stimulation of human blood eosinophils

Peripheral blood was obtained with informed consent from six normal donors, and eosinophils were isolated by negative selection using StemSep system (StemCell Technologies) (purity >99%; viability >95%) (17). Eosinophils (2 x 106 cells/ml in HBSS–/–) were incubated for 1 h (37°C) with PGD2 (5, 25, or 625 nM), recombinant human eotaxin (12 nM; R&D Systems), or a combination of eotaxin (0.1 nM) plus PGD2 (5 nM). For mechanistic studies, eosinophils were pretreated for 30 min with anti-hCCR3 mAb (10 µg/ml; clone 61828.111; R&D Systems). After samples were taken for lipid body analysis, eosinophils were resuspended in HBSS+/+ and stimulated with 0.1 µM A23187 (Sigma-Aldrich) for 15 min (37°C). Each experiment was repeated at least three times with eosinophils purified from distinct donors.

Quantification of eicosanoids and eotaxin

cysLTs, PGE2, and PGD2 levels were measured by EIA kits according to Cayman Chemicals’ protocols. Eotaxin levels were measured by the mEotaxin Duo Set (R&D Systems).

Intracellular immunodetection of newly formed LTC4

To localize LTC4 at its sites of formation, leukocytes were recovered from the pleural cavity with 500 µl of HBSS, and mixed with 500 µl of 1-ethyl-3-(3-dimethylamino-propyl) carbodiimide (1% in HBSS), before its immunofluorescent detection with rabbit anti-LTC4 Ab (1/5 dilution; Cayman Chemicals) or nonimmune rabbit IgG plus Cy2-labeled anti-rabbit IgG Ab (1/500) (7) (18). To specifically localize leukocyte lipid bodies, a guinea pig antiadipocyte-related protein (ADRP) Ab (1/300 final dilution) plus Cy3-labeled anti-guinea pig IgG Ab (1/1000 final dilution) were added. Fluorescent microscopy was imaged by Cool Snap digital camera and Image Pro Express program (Media Cybernetics).

Statistical analysis

Results were expressed as means ± SEM and analyzed by ANOVA followed by the Newman-Keuls-Student’s test (p ≤ 0.05).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
In this study, we studied whether PGD2, an eosinophilotactic mediator, is also able to trigger the activation of recruited eosinophils and control eosinophil LTC4-synthesizing machinery in vivo. To this end, we first developed a mouse model of PGD2-induced eosinophilia. Similar to other models (10, 12), administration of PGD2 in naive mice did not elicit eosinophil migration (Fig. 1A). In contrast, i.pl. injection of PGD2 (15, 35, or 55 pmol/cavity) into sensitized mice induced eosinophil accumulation with a bell-shaped dose-response curve (Fig. 1A). PGD2-induced pleural eosinophilia in sensitized mice was apparent within 6 h, reached maximum levels within 24 h, and was not associated with an influx of neutrophils or mononuclear cells (data not shown). It is noteworthy that PGD2’s ability to induce local eosinophilia had already been shown in other models of inflammation, which used different strategies to create a proper PGD2-sensitive environment (10, 12, 19). The mechanism involved in the PGD2 responsiveness acquired after sensitization has not been characterized but may involve differential expression of PGD2 receptors. In fact, in vitro functional studies revealed that whereas eosinophils from both naive and sensitized mice respond equally to PGD2 chemotactic stimulation, PGD2 was able to trigger in vitro chemotaxis of resident pleural mononuclear cells recovered from sensitized, but not from naive mice (data not shown).


Figure 1
View larger version (30K):
[in this window]
[in a new window]
  		FIGURE 1. PGD2 induces pleural eosinophil accumulation (A) plus eosinophil activation in vivo (B) and in vitro (C). In A and B, naive or sensitized mice received an i.pl. injection of PGD2 (15, 35, or 55 pmol/cavity). Analysis of eosinophil influx, lipid body formation and cysLTs production were performed 24 h after PGD2 administration. Results were expressed as the means ± SEM from at least eight animals. *, p ≤ 0.05 and **, p ≤ 0.01, compared with saline-injected sensitized animals. In C, human eosinophils were stimulated with PGD2 (5, 25, or 625 nM), eotaxin (0.1 or 12 nM), or costimulated with eotaxin (0.1 nM) and PGD2 (5 nM) in vitro. Analysis of lipid body formation was performed 1 h after PGD2 incubation. For in vitro cysLTs assays, PGD2-stimulated eosinophils were activated with A23187 (0.5 µM) for 15 min. Results are representative of three independent experiments.

 
Human eosinophils upon stimulation preferentially synthesize LTC4 as their 5-LO product. LTC4 and its derivatives, LTD4 and LTE4, play a critical role in the pathogenesis of allergic conditions (1, 2). In vitro studies have identified a variety of allergy-relevant stimuli capable of inducing LTC4 synthesis by human eosinophils (20). In vivo, eosinophils appear to play a central role in LTC4 secretion during allergic inflammatory reactions (6, 7); however, the endogenous stimuli and regulatory mechanisms that trigger LTC4 production in vivo by recruited/activated eosinophils have not been fully characterized. PGD2 administration induced in vivo secretion of LTC4 (Fig. 1B), but not PGE2 (data not shown), in the pleural fluid of sensitized mice, indicating that PGD2 activates preferentially, the 5-LO- and not COX-dependent pathway of eicosanoid synthesis in vivo. Confirming a previous observation (14), PGD2 was also able to prime human eosinophils in vitro for an enhanced, A23187-activated LTC4 synthesis in a concentration-dependent manner (Fig. 1C). Similar to the in vivo responses, in vitro stimulation with PGD2 failed to enhance PGE2 synthesis (data not shown), indicating that PGD2-elicited intracellular signaling in eosinophils is preferentially coupled to activation of leukotriene- but not prostanoid-synthesizing mechanisms. Of note, human eosinophils are capable of enhanced PGE2 synthesis upon proper stimulation, such as platelet-activating factor (16).

Eosinophils attracted to the site of PGD2-induced inflammatory reactions exhibited signs of cell activation. In vivo eosinophil activation-mediated by PGD2 was confirmed by analyzing the biogenesis of new cytoplasmic lipid bodies within infiltrating eosinophils (Fig. 1B). Lipid bodies are not conventional membrane-bound organelles, which represent specialized intracellular domains whose induced biogenesis is centrally related to activating mechanisms within the cells. Lipid body numbers are characteristically increased in eosinophils following in vitro activation, as well as in in vivo inflammatory disorders, and can be used as a marker of eosinophil activation (20). Administration of PGD2 in sensitized mice promoted formation of new lipid bodies within the eosinophils recruited to the inflammatory site in a dose-dependent (bell-shaped curve; Fig. 1B) and cell type-selective manner, because PGD2 failed to induce lipid body formation within resident mononuclear cells (data not shown). Moreover, as observed for LTC4 production, in vitro stimulation of human eosinophils with PGD2 also induced a rapid, dose-dependent biogenesis of cytoplasmic lipid bodies (Fig. 1C). In vivo dose-response curves shown for exogenous PGD2-induced eosinophil influx, lipid body formation, and LTC4 synthesis in sensitized mice are quite narrow (Fig. 1, A and B), but tends to be extended by synergistic interactions with local produced mediators during allergic inflammatory reactions (vide infra). Moreover, the mechanisms of PGD2 bell-shaped curve may depend on counterregulatory effects of the PGD2 dual receptor system (currently under investigation).

Based on prior findings with other stimuli (20), such increases in lipid body numbers may represent part of the mechanism of PGD2’s ability to directly prime eosinophils for an enhanced LTC4 production. Concurrent up-regulation of LTC4S expression does not seem to represent a complementary mechanism contributing to the PGD2-driven LTC4 synthesis, because this can be a very rapid event (detected within 1 h). In an elegant study, Mandal et al. (21) have established that successful LTC4 production is not merely determined by AA availability and kinetic properties of the relevant enzymes, but requires spatial interactions between specific biosynthetic proteins, FLAP and LTC4-synthase. In addition to proper assembly of enzymatic complexes, it is now well recognized that LTC4 biosynthesis also depend on the intracellular localization of these complexes. Within activated eosinophils, two distinct intracellular domains may compartmentalize such molecular organization for LTC4 synthesis: the nuclear membrane (22, 23) and/or lipid bodies (7, 16, 18). Such putative role for eosinophil lipid bodies as specific sites for LTC4 formation was validated by the direct intracellular immunofluorescent localization of newly formed LTC4 within eosinophil lipid bodies by a new methodology that cross-linked LTC4 at its sites of synthesis (17, 18). By using the same technique, we verified that the cell population responsible for LTC4 production during PGD2-induced inflammatory reaction corresponds to the infiltrating eosinophils (Fig. 2, top panels). Because PGD2 is able to induce in vitro chemotaxis of mononuclear cells from sensitized mice (data not shown), the failure by resident mononuclear cells in synthesizing LTC4 (Fig. 2, top panels) indicates that the signaling pathways engaged by PGD2 in mononuclear cells are distinct from those involved in PGD2-regulated LTC4 synthesis. The eosinophil intracellular LTC4-synthesizing compartment was in a clear punctate cytoplasmic pattern, proximate to, but separate from the nucleus, and fully consistent in size and form with eosinophil lipid bodies (Fig. 2, middle panels). Lipid body localization of newly formed LTC4 within eosinophils was ascertained by the colocalization with ADRP (Fig. 2, middle panels). So, PGD2 is able to trigger in vivo an inflammatory reaction characterized by eosinophil influx and activation that culminates with lipid body-driven LTC4 synthesis. The obvious subsequent question was as follows: does PGD2 contribute to eosinophil activation and LTC4 production caused by allergic challenge?


Figure 2
View larger version (42K):
[in this window]
[in a new window]
  		FIGURE 2. Cytoplasmic lipid bodies of recruited eosinophils compartmentalize LTC4 synthesis during PGD2-induced inflammatory reaction. In top panels, anti-LTC4 was merged with identical field of anti-ADRP fluorescent images of pleural leukocytes recovered from sensitized mice 24 h after PGD2 administration. Middle panels show LTC4-immunoreactive lipid bodies (as identified by anti-ADRP) of a PGD2-recruited eosinophil. In bottom panels, a nonimmune rabbit serum replaced anti-LTC4 Ab. Arrow-heads, macrophages with ADRP-positive lipid bodies; arrows, eosinophils; bars, 5 µm.

 
In addition to well-known induction of LTC4 production, we have recently reported that allergic challenge also triggers the biogenesis of lipid bodies within recruited eosinophils, which function as compartments for LTC4 synthesis (7). To investigate the role of PGD2 in eosinophil lipid body-driven LTC4 synthesis triggered by allergic challenge, two models of allergic inflammation in sensitized mice (asthma and pleurisy models) and pretreatments with HQL-79–a selective inhibitor of PGD synthase–were used. As expected, PGD2 levels detected in pleural fluid of allergic challenged sensitized mice were reduced markedly by HQL-79 pretreatment (from 46.3 ± 5.0 to 6.2 ± 2.6 ng/cavity of PGD2 in nontreated vs HQL-79-treated group, respectively; p ≤ 0.05; n = 8). Interestingly, HQL-79 treatment inhibited allergen-induced LTC4 secretion without interfering with PGE2 pleural levels, and decreased significantly the numbers of cytoplasmic lipid bodies found within eosinophils attracted to the sites of allergic reaction in both models studied (Fig. 3, A and B). Thus, similar to administer PGD2, endogenous PGD2 secreted during allergic reaction has an important role in in vivo activation of eosinophils and stimulates LTC4 synthesis that takes place at newly formed lipid bodies.


Figure 3
View larger version (39K):
[in this window]
[in a new window]
  		FIGURE 3. PGD2 mediates lipid body formation and LTC4 synthesis induced by allergic challenge in sensitized mice. Pretreatment with HQL-79 (1 mg/kg) (A and B) or anti-CCR3 (10 µg/cavity) was performed 30 min before OVA or PGD2 (35 pmol/cavity) challenges (as indicated) in pleurisy (A and C) or asthma (B) models. Analyses of lipid body formation, cysLTs, and PGE2 production were performed 24 h after allergic challenge. Results were expressed as the means ± SEM from at least eight animals. *, p ≤ 0.05, compared with control group. #, p ≤ 0.05, compared with allergen-challenged mice.

 
The mechanisms involved in PGD2-elicited eosinophil lipid body-driven LTC4 synthesis in vivo may have direct and indirect components. Of special relevance to allergic inflammation, mediators like platelet-activating factor (16, 24), IL-5 (25), and CC chemokines (18) acting directly on their receptors on eosinophil surface initiate intracellular signaling in eosinophils that culminate with de novo formation of lipid bodies and priming for LTC4 synthesis. In this study, we identified PGD2 as a novel mediator capable of eliciting the biogenesis of lipid bodies in eosinophils, and consequently priming eosinophils for enhanced LTC4 production (Fig. 1C), indicating that part of the mechanism of PGD2-induced in vivo lipid body-driven LTC4 production may be due to a direct stimulatory effect of PGD2 (which is present in allergic site) on recruited eosinophils. We have recently shown that CCR3 activation by eotaxin and RANTES generated after allergic challenge partially mediates allergen-induced formation of eosinophil lipid bodies (7). Even though PGD2 can have direct effects on eosinophils (Fig. 1C), in vivo we observed a cross talk between PGD2- and eotaxin/CCR3-driven stimulatory pathways.

In evidence of the PGD2/eotaxin functional interactions, treatment with HQL-79 (1 mg/kg) abolished allergen-induced eotaxin production detected 24 h after challenge (from 17.6 ± 2.8 to 3.7 ± 0.5 ng/cavity of eotaxin in nontreated vs HQL-79-treated group, respectively; p ≤ 0.05; n = 8). Increased levels of eotaxin were found in the pleural fluid of sensitized mice given injections with PGD2 (35 pmol/cavity) (data not shown), identifying endogenous PGD2 as a stimulus for the production of eotaxin during allergic reaction. Therefore, one can speculate that part of PGD2’s effects on lipid body-driven LTC4 production in vivo may be due to eotaxin activity. In fact, treatment with a neutralizing Ab against eotaxin receptor CCR3 inhibited PGD2-induced lipid body formation and LTC4 generation in vivo (Fig. 3C). Which cell secretes eotaxin in response to PGD2 stimulation is now under investigation, but does not seem to be the eosinophils themselves. Interestingly, in vitro CCR3 neutralization failed to affect PGD2-induced lipid body formation and priming for enhanced LTC4 production by human eosinophils (data not shown), indicating that eotaxin autocrine activity played no role in PGD2 in vitro stimulatory effect. Of note, autocrine activation of eosinophils through CCR3 by eotaxin is a phenomenon that can mediate lipid body-driven LTC4 production in vitro (17). Anti-CCR3 also failed to inhibit in vitro PGD2-induced lipid body formation by mouse eosinophils (data not shown), indicating that species differences are not the reason for such phenomenon and strengthens the hypothesis that human or mouse eosinophils do not secrete eotaxin under in vitro PGD2 stimulation and therefore this chemokine cannot autocrinaly regulate an in vitro effect. Altogether, lipid body-driven LTC4 production triggered by PGD2 in vivo seems to be mediated by eotaxin, acting in a paracrine fashion on eosinophils, because PGD2 seems not to be able to trigger eotaxin secretion by eosinophils. Finally, suboptimal concentrations of eotaxin (0.1 nM) and PGD2 (5 nM) cooperated to induce lipid body formation and prime human eosinophils for enhanced LTC4 synthesis in vitro (Fig. 1C). In vivo, similar cooperation between eotaxin and PGD2 (15 or 150 pmol/cavity) is also able to trigger lipid body formation within eosinophils (data not shown). Thus, physiological local levels of eotaxin and PGD2 in vivo may synergize to effectively activate recruited eosinophils. Altogether, the mechanism of PGD2-induced eosinophil activation that leads to lipid body-driven LTC4 synthesis in vivo may involve complementary activities, including direct stimulation of recruited eosinophils and indirect effects dependent on a paracrine/synergic activity of endogenous eotaxin acting on CCR3.

PGD2 is a major candidate to mediator of allergic inflammatory disorders, such as asthma. Because PGD2 modulates key aspects of this prevalent pathology, including the recruitment of eosinophils to inflamed tissue, and as described in this study eosinophil activation, production of chemokines, and synthesis of cysLTs, PGD2 emerges as a key target for antiallergic treatments. In future years, PGD2 receptor antagonists or inhibitors of synthesis may provide further therapeutic options in the management of allergic airway diseases.


   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 Fogarty International Center-National Institutes of Health (NIH) Grant TW05890; NIH Grants AI20241 and AI22571; Howard Hughes Medical Institute (to P.T.B.), PRONEX-MCT; PROFIX (to B.L.D. and C.B.-M.); National Counsel of Technological and Scientific Development; and Fundaçao de Amparo a Pesquisa do Estado do Rio de Janeiro, Brazil. Back

2 Address correspondence and reprint requests to Dr. Christianne Bandeira-Melo, Laboratorio de Imunofarmacologia, Instituto Oswaldo Cruz, Avenue Brazil 4365, 21045-900, Rio de Janeiro, Brazil. E-mail address: cbmelo{at}ioc.fiocruz.br Back

3 Abbreviations used in this paper: LTC4, leukotriene C4; PGD2, prostaglandin D2; cysLTs, cysteinyl leukotrienes; AA, arachidonic acid; 5-LO, 5-lipoxygenase; i.pl., intrapleural; ADRP, adipocyte-related protein. Back

Received for publication August 12, 2005. Accepted for publication November 18, 2005.


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

  1. Busse, W., M. Kraft. 2005. Cysteinyl leukotrienes in allergic inflammation: strategic target for therapy. Chest 127: 1312-1326. [Abstract/Free Full Text]
  2. Kanaoka, Y., J. A. Boyce. 2004. Cysteinyl leukotrienes and their receptors: cellular distribution and function in immune and inflammatory responses. J. Immunol. 173: 1503-1510. [Abstract/Free Full Text]
  3. Mitsumori, S.. 2004. Recent progress in work on PGD2 antagonists for drugs targeting allergic diseases. Curr. Pharm. Des. 10: 3533-3538. [Medline]
  4. Kanaoka, Y., Y. Urade. 2003. Hematopoietic prostaglandin D synthase. Prostaglandins Leukot. Essent. Fatty Acids 69: 163-167. [Medline]
  5. Weller, P. F., C. W. Lee, D. W. Foster, E. J. Corey, K. F. Austen, R. A. Lewis. 1983. Generation and metabolism of 5-lipoxygenase pathway leukotrienes by human eosinophils: predominant production of leukotriene C4. Proc. Natl. Acad. Sci. USA 80: 7626-7630. [Abstract/Free Full Text]
  6. Cowburn, A. S., K. Sladek, J. Soja, L. Adamek, E. Nizankowska, A. Szczeklik, B. K. Lam, J. F. Penrose, F. K. Austen, S. T. Holgate, A. P. Sampson. 1998. Overexpression of leukotriene C4 synthase in bronchial biopsies from patients with aspirin-intolerant asthma. J. Clin. Invest. 101: 834-846. [Medline]
  7. Vieira-de-Abreu, A., E. F. Assis, G. S. Gomes, H. C. Castro-Faria-Neto, P. F. Weller, C. Bandeira-Melo, P. T. Bozza. 2005. Allergic challenge-elicited lipid bodies compartmentalize in vivo LTC4 synthesis within eosinophils. Am. J. Respir. Cell Mol. Biol. 33: 254-261. [Abstract/Free Full Text]
  8. Hirai, H., K. Tanaka, O. Yoshie, K. Ogawa, K. Kenmotsu, Y. Takamori, M. Ichimasa, K. Sugamura, M. Nakamura, S. Takano, K. Nagata. 2001. Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2. J. Exp. Med. 193: 255-261. [Abstract/Free Full Text]
  9. Monneret, G., S. Gravel, M. Diamond, J. Rokach, W. S. Powell. 2001. Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor. Blood 98: 1942-1948. [Abstract/Free Full Text]
  10. Almishri, W., C. Cossette, J. Rokach, J. G. Martin, Q. Hamid, W. S. Powell. 2005. Effects of prostaglandin D2, 15-deoxy-{Delta}12,14-prostaglandin J2, and selective DP1 and DP2 receptor agonists on pulmonary infiltration of eosinophils in Brown Norway rats. J. Pharmacol. Exp. Ther. 313: 64-69. [Abstract/Free Full Text]
  11. Fujitani, Y., Y. Kanaoka, K. Aritake, N. Uodome, K. Okazaki-Hatake, Y. Urade. 2002. Pronounced eosinophilic lung inflammation and Th2 cytokine release in human lipocalin-type prostaglandin D synthase transgenic mice. J. Immunol. 168: 443-449. [Abstract/Free Full Text]
  12. Honda, K., M. Arima, G. Cheng, S. Taki, H. Hirata, F. Eda, F. Fukushima, B. Yamaguchi, M. Hatano, T. Tokuhisa, T. Fukuda. 2003. Prostaglandin D2 reinforces Th2 type inflammatory responses of airways to low-dose antigen through bronchial expression of macrophage-derived chemokine. J. Exp. Med. 198: 533-543. [Abstract/Free Full Text]
  13. Matsuoka, T., M. Hirata, H. Tanaka, Y. Takahashi, T. Murata, K. Kabashima, Y. Sugimoto, T. Kobayashi, F. Ushikubi, Y. Aze, et al 2000. Prostaglandin D2 as a mediator of allergic asthma. Science 287: 2013-2017. [Abstract/Free Full Text]
  14. Raible, D. G., E. S. Schulman, J. DiMuzio, R. Cardillo, T. J. Post. 1992. Mast cell mediators prostaglandin-D2 and histamine activate human eosinophils. J. Immunol. 148: 3536-3542. [Abstract]
  15. Gervais, F. G., R. P. Cruz, A. Chateauneuf, S. Gale, N. Sawyer, F. Nantel, K. M. Metters, G. P. O’Neill. 2001. Selective modulation of chemokinesis, degranulation, and apoptosis in eosinophils through the PGD2 receptors CRTH2 and DP. J. Allergy Clin. Immunol. 108: 982-988. [Medline]
  16. Bozza, P. T., W. Yu, J. F. Penrose, E. S. Morgan, A. M. Dvorak, P. F. Weller. 1997. Eosinophil lipid bodies: specific, inducible intracellular sites for enhanced eicosanoid formation. J. Exp. Med. 186: 909-920. [Abstract/Free Full Text]
  17. Bandeira-Melo, C., K. Sugiyama, L. J. Woods, M. Phoofolo, D. M. Center, W. W. Cruikshank, P. F. Weller. 2002. IL-16 promotes leukotriene C4 and IL-4 release from human eosinophils via CD4- and autocrine CCR3-chemokine-mediated signaling. J. Immunol. 168: 4756-4763. [Abstract/Free Full Text]
  18. Bandeira-Melo, C., M. Phoofolo, P. F. Weller. 2001. Extranuclear lipid bodies, elicited by CCR3-mediated signaling pathways, are the sites of chemokine-enhanced leukotriene C4 production in eosinophils and basophils. J. Biol. Chem. 276: 22779-22787. [Abstract/Free Full Text]
  19. Spik, I., C. Brenuchon, V. Angeli, D. Staumont, S. Fleury, M. Capron, F. Trottein, D. Dombrowicz. 2005. Activation of the prostaglandin D2 receptor DP2/CRTH2 increases allergic inflammation in mouse. J. Immunol. 174: 3703-3708. [Abstract/Free Full Text]
  20. Bandeira-Melo, C., P. F. Weller. 2003. Eosinophils and cysteinyl leukotrienes. Prostaglandins Leukotriences Essent. Fatty Acids 69: 135-143.
  21. Mandal, A. K., J. Skoch, B. J. Bacskai, B. T. Hyman, P. Christmas, D. Miller, T. T. Yamin, S. Xu, D. Wisniewski, J. F. Evans, R. J. Soberman. 2004. The membrane organization of leukotriene synthesis. Proc. Natl. Acad. Sci. USA 101: 6587-6592. [Abstract/Free Full Text]
  22. Brock, T. G., J. A. Anderson, F. P. Fries, M. Peters-Golden, P. H. Sporn. 1999. Decreased leukotriene C4 synthesis accompanies adherence-dependent nuclear import of 5-lipoxygenase in human blood eosinophils. J. Immunol. 162: 1669-1676. [Abstract/Free Full Text]
  23. Soberman, R. J., P. Christmas. 2003. The organization and consequences of eicosanoid signaling. J. Clin. Invest. 111: 1107-1113. [Medline]
  24. Bozza, P. T., W. Yu, J. Cassara, P. F. Weller. 1998. Pathways for eosinophil lipid body induction: differing signal transduction in cells from normal and hypereosinophilic subjects. J. Leukocyte Biol. 64: 563-569. [Abstract]
  25. Bartemes, K. R., S. McKinney, G. J. Gleich, H. Kita. 1999. Endogenous platelet-activating factor is critically involved in effector functions of eosinophils stimulated with IL-5 or IgG. J. Immunol. 162: 2982-2989. [Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mesquita-Santos, F. P.
Right arrow Articles by Bandeira-Melo, C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mesquita-Santos, F. P.
Right arrow Articles by Bandeira-Melo, C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS