Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur-Institut National de la Santé et de la Recherche Médicale U485, Institut Pasteur, 75015 Paris, France
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ABSTRACT |
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In mice, intratracheal challenges with antigen (ovalbumin) or recombinant murine interleukin-13 (IL-13) induce lung inflammation, bronchial hyperreactivity (BHR), and mucus accumulation as independent events (Singer M, Lefort J, and Vargaftig BB. Am J Respir Cell Mol Biol 26: 74-84, 2002), largely mediated by leukotrienes (LT). We previously showed that LTC4 was released 15 min after ovalbumin, and we show that it induces the expression of monocyte chemoattractant proteins 1 and 5 and KC in the lungs, as well as IL-13 mRNA. Instilled intratracheally, these chemokines induced BHR and mucus accumulation, which were inhibited by the 5-lipoxygenase inhibitor zileuton and by the cysteinyl-LT receptor antagonist MK-571, suggesting mediation by cysteinyl-LT. Because these chemokines also induced release of LT into the bronchoalveolar lavage fluid and IL-13 into the lungs, we hypothesize that LT- and chemokine-based loops for positive-feedback regulations cooperate to maintain and amplify BHR and lung mucus accumulation after allergic challenge and in situations where IL-13, LT, or chemokines are generated.
inflammation; asthma; MUC; leukotriene; cytokine/chemokine; bronchial hyperreactivity
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INTRODUCTION |
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DIFFERENT MEDIATORS,
including cytokines (17, 34, 38, 39, 42), chemokines (2, 10; unpublished observations), leukotrienes (LT) (20, 21, 25;
unpublished observations), and growth factors, can induce the asthma
phenotype in mice, with bronchopulmonary hyperresponsiveness (BHR),
inflammation, and mucus overproduction (16, 20, 21; unpublished
observations), but the underlying mechanisms remain unclear
(27). Murine models of lung allergy are widely used to
unravel these mechanisms, and much attention has been devoted to the
mediator role of interleukin-13 (IL-13), which, on administration into
the airways, duplicates the characteristic features of asthma (12, 17, 18, 20, 21, 34, 38, 42; unpublished observations). We demonstrated that
neither inflammation (34, 42) nor a T helper 1-T helper 2 imbalance (34) is required for BHR and mucus accumulation.
Because the effects of recombinant murine (rm) IL-13 are inhibited by
dexamethasone and, accordingly, may involve secondary mediators
(34), we investigated the role of LT as potential
mediators of the effects of ovalbumin and rmIL-13 on inflammation, BHR,
mucus accumulation, and lung remodeling (20, 21; unpublished
observations). Because some chemokines also exert intense
proinflammatory effects reminiscent of asthma, we extended our
investigations to chemokines that are expressed and involved in these
models (2, 11, 22; unpublished observations). Monocyte chemoattractant
protein (MCP)-1, MCP-5, and KC were selected because they were
expressed after ovalbumin, rmIL-13, or LT challenges and, once
instilled into the trachea, induced BHR and mucus accumulation more
than did eotaxin, regulated upon activation, normal T cell expressed,
and presumably secreted (RANTES), and macrophage inflammatory protein
(MIP)-1. Our results point out a major role for cysteinyl-LT (Cys-LT) in mediating the pulmonary effects of the relevant chemokines. Cys-LT, IL-13, and LT cooperate in inducing the asthma phenotype. In
addition, because of suggestions that activation of the epidermal growth factor receptor (EGFR) (3, 31, 33, 35, 40) may trigger the final common pathway leading to BHR and mucus production, its expression was also studied. Our results indicate that the different mediators, which have been considered individually to account
for the phenotype observed, interact positively, reinforcing their
respective release. Those positive-feedback loops may explain why drugs
that interfere specifically with single receptors or suppress
selectively the production of a given mediator show some, but limited,
therapeutic effectiveness and suggest that new therapeutic targets
should downregulate the common pathway.
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MATERIALS AND METHODS |
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Animals, immunization, and materials. Male BP2 mice (Centre d'Elevage R. Janvier), aged 6-7 wk, were immunized (or not) subcutaneously twice at 1-wk intervals with 0.4 ml of 0.9% NaCl containing 1 µg of ovalbumin (Immunobiologicals, Lisle, IL) and 1.6 mg of aluminum hydroxide (Merck, Darmstadt, Germany). One week after the second immunization, i.e., on day 14, mice were anesthetized with xylazine and ketamine (20 and 45 mg/kg, respectively; Sigma, St. Louis, MO), and groups of five animals were instilled intratracheally with 10 µg of ovalbumin, 4 µg of rmIL-13 [kindly provided by Dr. A. Minty, Sanofi Elf Biorecherches, Labége, France; diluted in 50 µl of endotoxin-free 0.9% NaCl (saline)], chemokines (1 µg/day for 3 days), or 1 µg of LTC4 (Cayman Chemical, Ann Arbor, MI). rmMCP-1, rmMCP-5, and rmKC were purchased from Immugenex (Los Angeles, CA).
Groups of five mice were challenged and treated separately with different drugs. The specific 5-lipoxygenase (5-LO) inhibitor zileuton (Zyflo, Abbott, Chicago, IL) (6, 29, 34, 38; unpublished observations) was given orally 1 h before and 6 h after challenge, and then three times a day at 50 mg/kg for up to 72 h (for BHR and mucus accumulation). The receptor antagonist for Cys-LT, MK-571 (24) (Cayman Chemical), was instilled intratracheally at 660 or 2,200 µg (15 or 50 mg/kg, respectively) (38; unpublished observations), and LY-171883 (14) was instilled at 375 or 1,250 µg (15 or 50 mg/kg, respectively) (38; unpublished observations).Evaluation of BHR.
Basal resistance of the airways and BHR were assessed in unrestrained
conscious animals by barometric plethysmography (Buxco Electronics,
Troy, NY). Bronchial reactivity was evaluated using noncumulative
methacholine challenges (18, 19, 34, 38). Briefly, mice
were placed in a Buxco chamber, and respiratory parameters were
measured after aerosol inhalation of 60 mM methacholine for 90 s.
Resistance was calculated according to the manufacturer's recommendations as follows: enhanced pause = [(expiratory
time/relaxation time) 1] × (peak expiratory flow/peak
inspiratory flow).
Bronchoalveolar lavage fluid. Mice were anesthetized with urethane (45 mg/30 g body wt, ip), and the trachea was cannulated. For collection of bronchoalveolar lavage fluid (BALF), samples were washed three times with 1 ml of saline containing 0.005 M EDTA and 0.005 M phenylmethylsulfonyl fluoride (both from Sigma). The total number of nucleated cells was determined automatically with a Coulter counter, and cytospins were prepared and colored with Diff Quick (Baxter Dade, Duedingen, Switzerland) for differential cell count.
Determination of Cys-LT and LTB4 in BALF by ELISA. Fresh cell-free BALF or nitrogen-frozen cell-free BALF kept for <72 h were used. In some samples, a known quantity of the specific LT (LTC4 or LTB4 used as internal standard) was added before freezing to verify the integrity of the samples over time. The quantification (pg/ml) was achieved by enzyme immunoassay according to the manufacturer's instructions (enzyme immunoassay kit for Cys-LT or LTB4; Cayman Chemicals) compared with a standard curve for LTB4 or Cys-LT.
Quantitative RT-PCR. Lungs were isolated and washed with saline via the pulmonary artery. Dispersion was performed with an Ultraturrax (model T25, Janke and Kunkel, IKA-Labortechnik) for 30 s in RTL buffer (RNeasy Mini-kit, Qiagen, Hilden, Germany) for RNA extraction.
Intron-differential RT-PCR was performed for lungs using specific primers: 5' TGCTACTCATTCACCAGCAAG and 3' GCATTAGCTTCAGATTTACGG (nt 191-468) for MCP-1, 5' TAAGCAGAAGATTCACGTCCGGAA and 3' AGGATGAAGGTTTGAGACGTCTTA for MCP-5, 5' CAGCCACCCGCTC- GCTTCTC and 3' TCAAGGCAAGCCTCGCGACCAT (nt 91-315) for KC, 5' CCAGTCCCGGCCGGGGGTA and 3' CCTCCTCATAGGGGCTACGCTT (nt 1610-1815) for MUC1, 5' CGACACCAGGGCTTTCGCTTAAT and 3' CACTTCCACCCTCCCGGCAAAC (nt 510-967) for MUC2, 5' TCTGTAAGGAAGCCACGCTAAC and 3' AAAGGGCAGGTCTTCGGTATA (nt 1643-2058) for MUC5AC, 5' CTGGAAACCG- AAATTTGTGCTACG and 3' GGCGTAGTGTACGCTTTCGAAC for EGFR, and 5' ACTCCTATGTGGGTGACGAGG and 3' GGGAGAGCATAGCCCTCGTAGAT forHistology. The lungs were flushed to remove blood; then they were inflated with optimum cutting temperature medium (Sakura Finetck, Torrance, CA) that was diluted 1:2 in saline. For paraffin inclusion, the lungs were immersed in 10% formaldehyde in PBS overnight at 4°C and processed to paraffin wax. Sections (5 µm) were stained with periodic acid-Schiff (PAS) or hematoxylin for mucins. To assess the frequency of staining, the ratio of stained cells to total cells was evaluated by counting the epithelial cells under the microscope with a grid as described elsewhere (34), and results are given as percentages.
Statistical analysis. Values are means ± SD (n = 5). Significance levels were calculated using one-way ANOVA followed by Scheffé's test, using the SPSS 6.1 software, with a threshold of P < 0.05 for statistical significance (n = 5).
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RESULTS |
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We recently demonstrated that LT mediate BHR and mucus overproduction in the mouse airways after provocations with ovalbumin or rmIL-13 (unpublished observations). To investigate the interactions between chemokines and LT for inducing those changes, we first studied mRNA expression for MCP-1, MCP-5, and KC, which are chemokines involved in allergy. Because Cys-LT are the first LT released, as early as 10 min after challenge (38), we also evaluated chemokine synthesis and IL-13 expression after the intratracheal instillation of LTC4. In addition, because these chemokines were expressed after challenge with ovalbumin, rmIL-13, or LTC4, they were instilled directly into the airways, and the release of LT, as well as their effects on BHR and mucus production, was studied. Then, to understand the mediator role of LT after chemokine challenge, the 5-LO inhibitor zileuton and the Cys-LT receptor antagonist MK-571 were used against BHR, MUC genes, and mucus induction. Finally, because EGFR may be involved in the signaling pathway for BHR and mucus, its expression was studied.
Ovalbumin or rmIL-13 challenges induce chemokine mRNA expression.
After ovalbumin instillation, a time-dependent progressive induction of
mRNAs for MCP-1 (Fig. 1A) was
observed. Expression of MCP-5 was high after 15 min (Fig.
1B), remained elevated for 3-6 h, and then decreased.
Expression of KC mRNA was high after 15 min, decreased, and increased
again progressively from 3 to 48 h (Fig. 1C).
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LTC4 challenge induces expression of mRNA for MCP-1,
MCP-5, KC, and IL-13.
Intratracheal instillation of LTC4 also induced the
expression of mRNA for chemokines, with an early peak at 15 min for
MCP-1 and MCP-5 and a late peak at 72 h (Fig. 2, A and
B), or a more progressive
increase of KC (Fig. 2C). LTC4 induced IL-13
mRNA at all time points (Fig. 2D).
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Chemokines induce LT release into the BALF.
Release of Cys-LT into the BALF after challenge with MCP-1,
MCP-5, or KC peaked at 1 h and then decreased progressively until a plateau was reached after 48 h (Fig.
3B). LTB4 release
was more constant and elevated at all time points (Fig.
3A) after the challenges.
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LT mediate chemokine-induced BHR.
At 72 h after intratracheal challenge with 1 µg of MCP-1, MCP-5,
or KC, an intense BHR to methacholine was induced. Zileuton drastically
abolished BHR by MCP-1 or KC and reduced it after MCP-5 (Fig.
5A). MK-571 also abolished
BHR, indicating that Cys-LT are largely involved in BHR induced by the
chemokines, but to a lesser extent in the case of MCP-5 (Fig.
5B).
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Chemokines induce expression of MUC gene mRNAs.
Expression of the MUC1 gene was stable after the different challenges,
confirming that it is constitutive (Fig.
6A). MUC2 mRNAs were induced
from 24 to 72 h after rmIL-13, and the chemokines MCP-1, MCP-5,
and KC were poorly induced after ovalbumin (Fig. 6B at
24 h). MUC5AC mRNAs were intensely induced in all cases (Fig.
6C at 24 h).
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EGFR expression is increased after ovalbumin, rmIL-13, or LTC4 challenges. EGFR, which is implicated in MUC gene induction (33, 35), was time dependently increased after challenge with ovalbumin (Fig. 6D) or rmIL-13 (Fig. 6E), with an early peak at 15 min and a later peak at 6-72 h. LTC4 induced a marked expression of EGFR from 6 to 72 h (Fig. 6F).
LT mediate chemokine-induced mucous cell metaplasia in the airway
epithelium.
At 72 h after intratracheal instillation of 1 µg of MCP-1,
MCP-5, or KC, a strong mucous cell metaplasia of airway epithelial cells was observed. Elevated ratios of PAS-positive cells to total cells of the epithelium were obtained after challenges: 62 ± 4% with MCP-1, 51 ± 3% with MCP-5, and 66 ± 4% with KC
compared with saline (0-1%; P < 0.05, n = 5). Other chemokines (MIP-1, eotaxin, and
RANTES) induced only traces of mucus (not shown).
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DISCUSSION |
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We previously showed that LT are released in the BALF of mice after intratracheal instillation of ovalbumin or rmIL-13 and that they mediate some of the resulting effects (38; unpublished observations). Here we show that LT also largely mediate the stimulating effects of the chemokines MCP-1, MCP-5, and KC on BHR and mucus accumulation. LT induce these chemokines, as well as IL-13, in a positive-feedback regulation, which perpetuates and amplifies the phenomenon in vivo.
Accordingly, the initial release of Cys-LT 10 min after ovalbumin or rmIL-13 (38; unpublished observations) may constitute a first step for further cytokine and chemokine induction, as in the case of IL-13 generation after instillation of LTC4 (Fig. 2, A-D).
Chemokines cooperate with LT and IL-13 to induce BHR and mucus. The potential role of chemokines for mediating inflammation is largely documented (2, 10, 22, 38, 40; unpublished observations). Our concept is that C-C chemokines, such as MCP-1 and MCP-5 (5, 11, 23, 28), and C-X-C chemokines, such as KC (4), which are expressed after ovalbumin, rmIL-13, or LTC4 challenges in mice (Fig. 1), induce at least part of their effects, such as BHR and mucus production, via the Cys-LT, because their inhibition or antagonism abolished these effects.
LT are associated with or induce cytokines and chemokines in other models, for instance, in mast cells (30). They potentiate chemoattraction by eotaxin (25). In a mouse model of septic peritonitis, cross talk between MCP-1 and LT has been highlighted: MCP-1 stimulated the production of LTB4 from peritoneal macrophages. LTB4 attracts and activates protective neutrophils and macrophages to the site of challenge, thus extending survival (28). Neutralization of MCP-1 resulted in a significant decrease in LTB4 production. In this model, MCP-1 cooperates with LT to exert defensive effects, probably when an appropriate ratio of MCP-1 to LTB4 is maintained, or induces deleterious effects by enhancing inflammation via the accumulation of cells and mediators, as may occur in the allergic lung model. MCP-1 is expressed in the lungs at high levels after ovalbumin challenge, and its neutralization drastically diminishes BHR and inflammation (5, 16). Using MK-571, we have shown that MCP-1 induced Cys-LT release in the BALF and that Cys-LT mediate MCP-1-induced BHR. Subsequently, Cys-LT induced BHR (38). Thus, in situations where MCP-1 is generated, BHR may increase via LT. IL-13 also induced MCP-1, and the latter induced IL-13 mRNA (Fig. 2), showing a loop of positive regulation when IL-13 is generated. After ovalbumin challenge, we have shown the early release of Cys-LT (38), which induced IL-13 and MCP-1, which release Cys-LT. These reiterative relationships are summarized in Fig. 8.
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Coordinated action of the different mediators perpetuates and amplifies the asthma-like phenotype in mice. Biological loops, leading to increased basal levels of the relevant mediators, seem to emerge from this analysis (16, 22, 28, 34, 38). Their coordinated effects should lead to signal transduction for BHR via LT (2, 16, 22, 25, 28, 38) and mucus accumulation, in addition to inflammation. Even single molecules (MCP-1, MCP-5, KC, and IL-13 in vivo) were able to induce an effect. Indeed, high levels of the relevant mediators, expressed at the same time, are observed in mouse models (16, 21, 28) as well as in asthmatic patients (22).
Other biological loops have been suggested in which chemokines induce their further production via G protein-coupled receptors as an autocrine regulatory mechanism that enhances the effects of chemokines (40). Regulatory molecules such as interferon-Which pathway links LT, IL-13, and chemokines?
Different receptors are involved in the effects of the mediators we
studied (CCR2-CCR4 for MCP-1, MCP-5-CXCR1/2 for KC, and IL-4R for
IL-13). The common feature is that C-C chemokines (MCP-1 and MCP-5),
the GRO
-KC, and chemoattractants including LT (LTB4) bind to and transactivate the G protein-coupled receptors, such as EGFR
(33, 40), which mediate activation of nuclear factor-
B and, thus, induce MUC gene expression.
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ACKNOWLEDGEMENTS |
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We thank Dr. M. Huerre, P. Ave, and N. Wusher (Unité d'Histopathologie, Institut Pasteur) for technical advice and Dr. L. Touqui for helpful discussions.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. Singer, Unité de Pharmacologie Cellulaire, Unité Associée Institut Pasteur-INSERM U485, Institut Pasteur, 25, rue du Dr Roux, 75015 Paris, France (E-mail: msinger{at}pasteur.fr).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published September 6, 2002;10.1152/ajplung.00226.2002
Received 15 July 2002; accepted in final form 24 July 2002.
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