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kováImmunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Canada
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, induced a similar pattern of CysLT1R
up-regulation. Monocytes pretreated with IL-13 or IL-4 for 24 h
showed enhanced CysLT1R protein expression, as assessed by
flow cytometry using a polyclonal anti-CysLT1R Ab. They
also showed enhanced responsiveness to LTD4, but not to
LTB4, in terms of Ca2+ mobilization, as well as
augmented chemotactic activity. Our findings suggest a possible
mechanism by which IL-13 and IL-4 can modulate CysLT1R
expression on monocytes and macrophages, and consequently their
responsiveness to LTD4, and thus contribute to the
pathogenesis of asthma and allergic diseases. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The inflammatory pathology associated with asthma is thought to be mediated by Th2 lymphocytes and their cytokine network. Numerous studies of bronchoalveolar lavage (BAL) and biopsies from asthmatic airways have shown an increase in CD4+ T lymphocytes producing Th2-like cytokines, IL-4, IL-5, and IL-13 (7, 8, 9). They have suggested the importance of these cytokines in AHR, which is one of the defining features of asthma and believed to result from chronic inflammation of the bronchial mucosa. Significantly elevated expression of IL-13 mRNA and protein has been observed in BAL cells of patients with atopic asthma after allergen challenge (10). More recently, blockade of IL-13 before aeroallergen challenge was shown to be sufficient to attenuate AHR (11). Unlike IL-4, the production of IL-13 can be sustained through the late asthmatic response, and the concentration of secreted IL-13 strongly correlates with the number of eosinophils in BAL and in bronchial submucosa (12). Together, these results suggest that IL-13 plays an important role in the pathogenesis of asthma.
IL-13 and IL-4 have several overlapping biological activities
(13, 14) that may be due to a shared receptor subunit,
IL-4R
(15), and signaling through a shared
STAT6-dependent pathway (16). In addition to potent
anti-inflammatory properties on macrophages and other cells
(17, 18, 19, 20), both cytokines also induce several
immunostimulatory functions, such as increase in VCAM-1 expression on
the surface of endothelial cells and induction of monocyte
chemoattractant protein-1 (MCP-1) production (21, 22).
Because both LTs and Th2 cytokines are major players in asthma and
because the level of expression of CysLT1R could
be expected to affect cellular responses to LTD4,
we initiated the present study to investigate the potential for IL-13
and IL-4 to modulate the expression and function of
CysLT1R.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Monocytes were obtained from peripheral blood of healthy medication-free volunteers, following informed consent in accordance with an Internal Review Board-approved protocol. Peripheral blood leukocytes were enriched by dextran sedimentation, layered over a Ficoll-Hypaque cushion, and centrifuged at 400 x g for 20 min. Mononuclear leukocytes were collected at the interface and washed twice with PBS and resuspended in RPMI 1640 (Life Technologies, Burlington, Ontario, Canada) supplemented with 10% heat-inactivated FBS (Sigma-Aldrich, Oakville, Ontario, Canada), 100 U/ml penicillin, and 100 µg/ml streptomycin in a humidified atmosphere with 5% carbon dioxide at 37°C. Monocytes were then purified by adherence (60 min, 37°C) on plastic petri dishes coated with defibrinized autologous serum and removed with EDTA (0.01 M) in RPMI 1640–10% FBS. Cells were resuspended in RPMI 1640–10% FBS at 1 x 106 cells/ml and allowed to rest overnight before stimulation with the appropriate stimuli. Adherent cells cultured on plastic petri dishes for up to 5 days were referred to as monocyte-derived macrophages.
Cytokines and reagents
Human rIL-4 and rIL-13 were obtained from PeproTech (Rocky Hill,
NC); human IFN- was obtained from R&D Systems (Minneapolis, MN); all
cytokine preparations contained <0.1 ng endotoxin per microgram (1
EU/µg); rabbit polyclonal anti-human
CysLT1R Ab was developed and characterized with
Cayman Chemical (Ann Arbor, MI); rabbit IgG isotype control was
obtained from Southern Biotechnology Associates (Birmingham, AL);
FITC-conjugated goat anti-rabbit IgG was obtained from Bio/Can
Scientific (Mississauga, Ontario, Canada); LTB4,
LTD4, and platelet-activating factor (PAF) were
obtained from Cayman Chemical; MK571 was obtained from Biomol (Plymouth
Meeting, PA).
Northern blot analysis
Total cellular RNA was extracted by the guanidium thiocyanate
method (23), separated by electrophoresis on 1% agarose,
and transferred onto a Hybond-N+ (Amersham
Pharmacia Biotech, Baie d‘Urfé, Quebec, Canada) membrane for
Northern analysis. The cDNA corresponding to the whole coding sequence
of human CysLT1R (5) was amplified
by PCR from DNA of human monocytes, using the primers
5'-CGGGATCCGATGAAACAGGAAATC-3' as sense and
5'-CCGGAATTCAATGGGTTTAAACTATAC-3' as antisense. The amplified
CysLT1R fragment contained 1014 bp. Control
hybridizations were performed with the human GAPDH cDNA probe obtained
from the American Type Culture Collection (Manassas, VA). The probes
were labeled with a multiprime DNA labeling system (Amersham Pharmacia
Biotech) using [-32P]dCTP (sp. act., 3000
Ci/mmol; Amersham Pharmacia Biotech). Membranes were prehybridized for
4 h in a mixture containing 120 mM Tris (pH 7.4), 600 mM NaCl, 8
mM EDTA (pH 8), 0.1% sodium pyrophosphate, 0.2% SDS, and 100 µg/ml
heparin; hybridization was performed overnight at 60°C in the same
mixture in which the concentration of heparin was increased to 625
µg/ml and dextran sulfate at 10% was added. The membranes were then
washed once at room temperature for 20 min in 2x SSC (1x SSC: 0.15 M
NaCl, 0.15 M sodium citrate (pH 7)) and once with 0.1x SSC. The
membranes were exposed to Hyperfilm MP (Amersham Pharmacia Biotech)
with intensifying screens at -80°C.
Nuclear run-on transcription assay
Before nuclei isolation, monocytes were stimulated for 3 or
6 h with IL-13 (10 ng/ml). Following stimulation, cells were
washed with ice-cold PBS, and pelleted at 250 x g for
5 min. The cell pellet (5 x 107 cells) was
then resuspended in 1 ml lysis buffer (10 mM Tris-HCl (pH 7.4), 10 mM
KCl, 5 mM MgCl2, 0.5% Nonidet P-40 (v/v)),
incubated for 5 min on ice, and centrifuged at 500 x g
for 5 min at 4°C. The supernatant was discarded, and the nuclei were
resuspended in 200 µl freezing buffer (50 mM Tris-HCl, 40% glycerol
(v/v), 5 mM MgCl2 (pH 8), 0.1 mM DTT) and frozen
in liquid nitrogen. For the transcription assay, nuclei were thawed on
ice and pelleted at 500 x g for 30 s at 4°C,
and the supernatant was discarded. Nuclei were then mixed with 100 µl
reaction buffer containing 100 mM Tris-HCl (pH 7.9), 300 mM
(NH4)2SO4,
4 mM MgCl2, 200 mM NaCl, 0.4 mM EDTA, 1 mM DTT,
40% glycerol, 1 mM each of ATP, CTP, and GTP, 1 µl RNase inhibitor
(40 U/µl RNasin; Promega, Madison, WI), and 150 µCi
[-32P]UTP (3000 Ci/mmol; Amersham Pharmacia
Biotech) and incubated at 30°C for 30 min. The
32P-labeled RNA transcripts were then incubated
for a further 10 min at 30°C in the presence of 100 U DNase 1 (10
U/µl, RNase free; Promega) and 0.5 mM CaCl2.
This procedure was followed by addition of 1 vol of 2x proteinase K
buffer (20 mM Tris-HCl (pH 7.9), 20 mM EDTA, 1% SDS) and 5 µl
proteinase K (10 mg/ml) and incubation at 42°C for 30 min. The
32P-labeled RNA transcripts were then isolated
with saturated phenol solution and chloroform-isoamyl alcohol (49/1),
mixed well, incubated on ice for 15 min, and then centrifuged for 15
min at 500 x g at 4°C. The elongated RNA was then
purified on a Sephadex G-25 column. Before ethanol precipitation,
32P-labeled RNA transcripts were denatured adding
NaOH (final concentration of 0.2 M) for 15 min on ice. The solution was
neutralized by the addition of HEPES, pH 5.5 (final concentration of
0.28 M). Elongated 32P-labeled RNA transcripts
were then precipitated adding 1 vol of ethanol and 0.1 vol of 3 M
sodium acetate and centrifuged 15 min at 500 x g at
4°C. The pellet was resuspended in 500 µl hybridization solution
(0.75 M NaCl, 50 mM HEPES (pH 7), 2 mM EDTA (pH 8), 50% deionized
formamide, 0.5% SDS, 10x Denhardt’s, and 0.5 mg/ml salmon sperm
DNA). RNA was then denatured at 90°C for 5 min and hybridized at
42°C for 48 h to 5 µg denatured DNA immobilized on positively
charged nylon transfer membrane (Mandel, Saint-Laurent, Quebec, Canada)
in 3 ml hybridization solution. Membranes were then washed four times
at 42°C for 15 min in 0.1x SSC, 0.1% SDS and exposed to Hyperfilm
MP with intensifying screens at -80°C for 2 wk. For immobilization
of DNA to membranes, 5 µg cDNA was denatured with 0.3 M NaOH at room
temperature for 30 min, neutralized with ammonium acetate (final
concentration of 1.5 M), and spotted onto nylon membrane using a slot
blot apparatus.
Flow cytometry
For flow cytometry studies, cells were washed with PBS and fixed with 2% paraformaldehyde for 15 min at room temperature, followed by permeabilization with 0.1% saponin for an additional 15 min at room temperature. Cells were resuspended with PBS-2% BSA and labeled for 30 min at 4°C with anti-CysLT1R Ab or with isotype control Ab. Cells were then washed with cold PBS and incubated for 30 min at 4°C with FITC-conjugated goat anti-rabbit IgG. Finally, cells were washed again and resuspended in PBS before single-color immunofluorescence analysis of 5000 cells was performed on a FACScan flow cytometer (BD Biosciences, San Jose, CA).
Intracellular calcium mobilization
For Ca2+ mobilization assays, 5 x 106 cells were loaded in HBSS (Life Technologies) containing 350 mg/L NaHCO3 and 10 mM HEPES (pH 7) with the calcium indicator fura 2-AM (Molecular Probes, Eugene, OR) for 30 min at room temperature. Loaded cells were washed twice, suspended in fresh loading buffer, and added to a constantly stirred cuvette, maintained at 37°C in a SLM/Aminco spectrofluorometer (SLM Instruments, Urbana, IL). The concentration of extracellular Ca2+ was brought to 1.5 mM by addition of a solution of CaCl2 into the cuvette 10 min before recordings. Maximal cell fluorescence (Fmax) was obtained by adding Triton X-100 to a final concentration of 0.5%. Minimal fluorescence (Fmin) was determined by subsequent addition of the chelator EGTA in Tris-HCl buffer (100 mM (pH 9)) at 125 mM. Stimuli consisted of LTD4, LTB4, and PAF.
Chemotaxis assay
Monocytic chemotactic activity was performed with Boyden chambers using a modified Boyden chamber chemotaxis assay. A volume of 200 µl cells (6 x 105) in RPMI 1640, supplemented with 2.5 mg/ml BSA, was added to the upper chamber. The lower chamber contained graded concentrations of LTD4 or its vehicle. For chemokinesis studies, both chambers contained LTD4 or its vehicle. The two chambers were separated by a 5-µm-pore-size polycarbonate filter (Osmonics, Westborough, MA). After incubation for 2 h at 37°C in 5% CO2, the chambers were disassembled and the upper side of the filter was scraped free of cells. Cells on the lower side were removed with 5 mM EDTA, centrifuged, and resuspended in PBS. An aliquot of 100 µl was then counted in the FACScan.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A, human monocytes
constitutively expressed low levels of CysLT1R
mRNA, and IL-13 induced a time-dependent augmentation of transcript
levels. Accumulation was augmented 3- to 5-fold over baseline, and the
effect was detectable as soon as 4 h of stimulation, was maximal
at 8 h, and was still detectable at 24 h. IL-13 induced a
concentration-dependent augmentation in steady state levels of
CysLT1R mRNA, which plateaued at 10 ng/ml (Fig. 1B). In parallel experiments, we also examined the effect of
the cytokine IL-4 on CysLT1R mRNA expression.
Fig. 1C illustrates CysLT1R mRNA
levels in monocytes and monocyte-derived macrophages following 6 h
of incubation in the absence or presence of IL-13 (10 ng/ml) or IL-4
(10 ng/ml). Both cytokines induced similar levels of
CysLT1R mRNA expression in both cell populations.
Fig. 1D illustrates the kinetics of up-regulation of
CysLT1R mRNA expression by IL-4, with a maximal
effect at 4 h of incubation. Fig. 1E shows the effect
to be concentration dependent, with up-regulation detectable at 0.1
ng/ml IL-4. Moreover, the Th1-type cytokine IFN- was not capable of
up-regulating CysLT1R.
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A,
CysLT1R mRNA
t1/2 was 
2.5 h in unstimulated
human monocytes. IL-13 treatment did not induce a significant change in
CysLT1R mRNA
t1/2, suggesting that the increased
accumulation of CysLT1R mRNA by IL-13 was not
caused by stabilization of the transcripts. To assess whether IL-13
induced CysLT1R mRNA accumulation through a
transcriptional mechanism, we performed experiments in which monocytes
were pretreated with actinomycin D for 15 min to block new RNA
synthesis and were then treated with either medium or IL-13. As shown
in Fig. 2B, this pretreatment completely abolished the
IL-13-induced accumulation of CysLT1R mRNA,
suggesting a transcriptional mechanism in the regulation of
CysLT1R expression by IL-13. Transcriptional
activation of the CysLT1R gene was confirmed by a
nuclear run-on experiment (Fig. 2C) that showed that nuclear
transcription of the CysLT1R gene was indeed
increased (4-fold at 3 h) by IL-13 treatment.
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A, both
IL-13 and IL-4 induced a markedly augmented expression of
CysLT1R protein in monocytes. The effect was
maximal following a 24-h stimulation with the cytokines. The effects of
the two cytokines were both concentration and time dependent, being
maximal at 10 ng/ml after 24 h (Fig. 3, B and
C). Similarly to monocytes, IL-13 and IL-4 also up-regulated
the expression of CysLT1R in monocyte-derived
macrophages (Fig. 3A).
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A, monocytes cultured for
24 h with 10 ng/ml IL-13 or IL-4 showed increased calcium flux in
response to LTD4 (
intracellular
Ca2+ concentration
([Ca2+]i) =
129.5 ± 34.9 nM for control cells vs 251.8 ± 63.7 nM for
IL-13-treated cells (p < 0.02), and 244
± 66.8 nM for IL-4-treated cells (p < 0.05),
n = 4), but not to LTB4
([Ca2+]i = 111.8
± 25.5 nM for control cells vs 132.8 ± 38.2 nM for IL-13-treated
cells (p > 0.1), and 149.4 ± 28.4 nM for
IL-4-treated cells (p > 0.1),
n = 5), nor to PAF (data not shown). The response to
LTD4, but not to LTB4, was
totally blocked by the selective CysLT1R
antagonist MK571. As shown in Fig. 4B, responsiveness to
LTD4 in monocyte-derived macrophages was
augmented even more than in monocytes, following a 24-h incubation with
the cytokines IL-13 or IL-4 (10 ng/ml).
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A shows that a significantly
augmented response to LTD4 was observed when
monocytes had been exposed for 24 h to IL-13. Enhanced migration
to LTD4 was concentration dependent, with
activity already present at 1 nM and reaching a plateau between 10 and
100 nM LTD4. Similar results were obtained with
IL-4-treated cells. Chemokinesis was not affected, however, by
pretreatment of cells with either IL-4 or IL-13 (Fig. 5B).
Moreover, monocyte chemotactic responses to the chemokine MCP-1 were
not affected by such pretreatment (Fig. 5B). These
observations suggest that the augmentation of
CysLT1R expression following stimulation with
IL-13 or IL-4 is accompanied by an enhanced functional activity of the
receptor.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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did not modify
CysLT1R expression. The pathology associated with asthma is thought to be mediated by Th2 cells and involves potentially important roles for the cytokines IL-4, IL-13, and IL-5, because both mRNA and protein levels of these cytokines are elevated in allergic patients as compared with normal individuals (7, 8, 9, 10, 24). A particular association between IL-13 and asthma has also been suggested by several studies. IL-13 was produced by BAL cells of atopic asthma patients after allergen challenge (7), and increased IL-13 mRNA was detected in the bronchial mucosa of asthmatic patients (10). More recently, several studies have demonstrated the central role IL-13 appears to play, at least in experimental asthma, in terms of induction of AHR and mucus hypersecretion (11, 25, 26). Its preferential role in asthma may be due, in part, to its longer half-life in vivo and its higher levels in asthmatic lung, compared with IL-4, and, in part, to its predominant effect on some features of asthma, such as goblet cell activation (11, 25).
Of the different mediators that are known to be involved in asthma, LTs are considered to be among the most important because they participate in both the bronchoconstriction and the inflammatory components of the disease. In general, cyclooxygenase metabolites of arachidonate are associated with nonallergic inflammation, whereas 5-lipoxygenase metabolites such as LTB4, LTC4, and LTD4 are predominantly involved in allergic inflammation. In this context, it is quite interesting that the allergy-associated cytokines IL-13 and IL-4 tend to suppress cyclooxygenase-2 activity (17, 27), whereas they enhance LTA4 hydrolase activity, resulting in the increased production of LTB4 (28). In other reports, IL-13 was shown to enhance 15-hydroxyeicosatetraenoic acid release in monocytes (19, 29), to increase cytosolic phospholipase A2 expression, and to modulate zymosan-stimulated arachidonic acid mobilization (30).
Excessive production of leukocytes and their subsequent invasion of the airways and other target organs are characteristic features of asthma and allergic diseases. Thus, priming of leukocytes with cytokines such as IL-13 and IL-4, combined with an increase in CysLT production in the airways of asthmatics, may contribute to the influx and activation of leukocytes. In another receptor system, IL-13 and IL-4 were shown to augment the expression of the chemokine receptors CXCR1 and CXCR2 in human monocytes (31). Hence, our findings, in addition to the latter observations, suggest that, in Th2-dominated responses, IL-13 and IL-4 could participate in the recruitment and activation of mononuclear phagocytes. We have also recently shown that CysLT1R expression can be up-regulated by the Th2 cytokine IL-5 in eosinophil-differentiated HL-60 cells (32).
IL-13 exhibits pleiotropic biological functions on multiple cell types, and it shares one chain of its receptor with IL-4. Whereas Janus kinase (JAK)3 is one of the kinases that transduces signals from the IL-4R (33), the signaling pathway of IL-13 seems to be quite variable depending on the cell type. Tyrosine kinases were recently suggested to play a role in the signaling pathway following binding of IL-13, which was shown to induce JAK3 phosphorylation in primary human NK and T cells (34). In human colon carcinoma cell lines, IL-13 induced phosphorylation and activation of JAK2 (35), whereas phosphorylation of tyrosine kinase and JAK2 was induced in human monocytes (29). However, both IL-13 and IL-4 induce the phophorylation and nuclear translocation of the transcription factor STAT6 (16). The eventual involvement of these signaling molecules in the observed up-regulation of CysLT1R by IL-13 or IL-4 remains to be elucidated. The promoter region of the CysLT1R gene is undefined at present, but our findings would predict that it contains STAT6-binding elements.
Monocytes and macrophages are believed to play a pivotal role at sites of inflammation, as they have the potential to activate other cell types through the production of stimulatory cytokines. Our findings provide evidence that the cytokines IL-13 and IL-4 can enhance the expression and function of CysLT1R, a receptor for a potent proinflammatory lipid mediator. In the context of a Th2 response, IL-13 and IL-4 may thus play a crucial role in the accumulation and activation of mononuclear cells within the inflammatory lesion.
In conclusion, our observations that Th2 cytokines can up-regulate CysLT1R expression suggest a mechanism by which IL-13 and IL-4 can modulate leukocyte function and particularly their responsiveness to LTD4, and thus possibly contribute to the pathogenesis of asthma and allergic diseases.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marek Rola-Pleszczynski, Immunology Division, Department of Pediatrics, Faculty of Medicine, Université de Sherbrooke, 3001, North 12th Avenue, Sherbrooke, J1H 5N4 Quebec, Canada. E-mail address: mrolaple{at}courrier.usherb.ca
3 Abbreviations used in this paper: LT, leukotriene; Cys, cysteinyl; AHR, airway hyperresponsiveness; CysLT1R, LTD4 receptor; BAL, bronchoalveolar lavage; [Ca2+]i, intracellular Ca2+ concentration; JAK, Janus kinase; MCP, monocyte chemoattractant protein; PAF, platelet-activating factor.
Received for publication March 6, 2001. Accepted for publication June 22, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects. Am. J. Respir. Cell Mol. Biol. 12:477.[Abstract]
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and Stat6 phosphorylation. Immunology 91:450.[Medline]
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J. A. Elias, C. G. Lee, T. Zheng, Y. Shim, and Z. Zhu Interleukin-13 and Leukotrienes: An Intersection of Pathogenetic Schema Am. J. Respir. Cell Mol. Biol., April 1, 2003; 28(4): 401 - 404. [Full Text] [PDF]
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R. T. Strait, S. C. Morris, K. Smiley, J. F. Urban Jr., and F. D. Finkelman IL-4 Exacerbates Anaphylaxis J. Immunol., April 1, 2003; 170(7): 3835 - 3842. [Abstract] [Full Text] [PDF]
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 C. Brink, S.-E. Dahlen, J. Drazen, J. F. Evans, D. W. P. Hay, S. Nicosia, C. N. Serhan, T. Shimizu, and T. Yokomizo International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors Pharmacol. Rev., March 1, 2003; 55(1): 195 - 227. [Abstract] [Full Text] [PDF]
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W. M. Abraham Of Mice and Men Am. J. Respir. Cell Mol. Biol., January 1, 2003; 28(1): 1 - 4. [Full Text] [PDF]
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 A. Maekawa, K. F. Austen, and Y. Kanaoka 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., May 31, 2002; 277(23): 20820 - 20824. [Abstract] [Full Text] [PDF]
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