Departments of 1 Physiology, 2 Comparative Medicine, and 3 Medicine, East Carolina University, Greenville, North Carolina 27858; and 4 Department of Internal Medicine, Section of Allergy and Immunology, University of Texas Medical Branch, Galveston, Texas 77555
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ABSTRACT |
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We investigated the effects of interleukin (IL)-10
administration on allergen-induced Th2 cytokine production,
eosinophilic inflammation, and airway reactivity. Mice were sensitized
by intraperitoneal injection of ragweed (RW) adsorbed to Alum and
challenged by intratracheal instillation of the allergen. Sensitization
and challenge with RW increased concentrations of IL-10 in
bronchoalveolar lavage (BAL) fluid from undetectable levels to 60 pg/ml
over 72 h. Intratracheal instillation of 25 ng of recombinant murine
IL-10 at the time of RW challenge further elevated BAL fluid IL-10
concentration to 440 pg/ml but decreased BAL fluid IL-4, IL-5, and
interferon- levels by 40-85% and eosinophil numbers by 70%
(P < 0.0001). Unexpectedly, the same IL-10
treatment increased airway reactivity to methacholine in spontaneously
breathing mice that had been sensitized and challenged with RW
(P < 0.001). IL-10 treatment in naive animals or
RW-sensitized mice challenged with PBS failed to increase airway
reactivity, demonstrating that IL-10 induces an increase in airway
reactivity only when it is administered in conjunction with allergic
sensitization and challenge. The results demonstrate that IL-10 reduces
Th2 cytokine levels and eosinophilic inflammation but augments airway hyperreactivity. Thus, despite its potent anti-inflammatory activity, IL-10 could contribute to the decline in pulmonary function observed in asthma.
interleukin-4; interleukin-5; interferon-; bronchial
hyperreactivity; interleukin-10
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INTRODUCTION |
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CUMULATIVE EVIDENCE SUGGESTS that Th2 cytokines play
important roles in inducing eosinophilic airway inflammation and
bronchial hyperresponsiveness (BHR) characteristic of asthma (1, 16, 44). Expression of Th2 cytokines is increased in allergic inflammation and asthma (44); animals with low levels of interleukin (IL)-4 and IL-5
exhibit reduced eosinophilia and BHR (8, 10, 15, 28, 29, 32), and in
the case of IL-5, overexpression enhances eosinophilia and BHR (25). In
contrast, the Th1 cytokine interferon (IFN)- inhibits Th2 responses
and attenuates allergen-induced eosinophilia, thereby inhibiting the
onset of allergic asthma (6, 26, 38).
IL-10 is another Th2 cytokine, but its pathophysiological role in asthma has not been clearly elucidated. Some evidence suggests that IL-10 production is reduced in patients with asthma compared with nonasthmatic control subjects (3), and murine studies provide evidence that IL-10 suppresses development of eosinophilic inflammation in the airways. Intranasal administration of recombinant IL-10 inhibits recruitment of eosinophils in allergic mice (47), and knockout of the IL-10 gene augments allergen-induced eosinophilic airway inflammation (12). However, the role of IL-10 in the development of BHR has not been defined.
We used a murine model of allergic asthma to investigate the effects of IL-10 on eosinophilic airway inflammation, the release of IL-4 and IL-5 into the airways, and development of airway hyperreactivity. In this model, treatment of ragweed (RW)-sensitized mice with a single dose of recombinant murine IL-10 (rmIL-10) at the time of RW challenge reduced IL-4 and IL-5 concentrations and eosinophil numbers in bronchoalveolar lavage (BAL) fluid but, unexpectedly, increased airway reactivity to methacholine. The results indicate that despite its potent anti-inflammatory activity, IL-10 may contribute to the decline in pulmonary function observed in asthma.
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METHODS |
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Allergic sensitization of animals.
Six- to eight-week-old female BALB/c mice were purchased from Harlan
Laboratories (Indianapolis, IN) and separated into groups defined by
the sensitization, challenge, and treatment protocols (Table
1). Mice were sensitized by intraperitoneal
injections of RW given on day 0 and day 4. Each
injection consisted of 200 µg of RW (lot 56-129, Greer Laboratories,
Lenoir, NC) in 25 µl of Alum (45 mg/ml aluminum hydroxide and 40 mg/ml magnesium hydroxide; Pierce, Rockford, IL) and 75 µl of Coca's
buffer (85 mM NaCl and 64 mM NaHCO3, pH 8.1). Endotoxin
content of the RW was <2.3 ng/mg.
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BAL cell counts and lung histology. To evaluate inflammation, animals were euthanized with ketamine (135 mg/kg body wt) and xylazine (15 mg/kg body wt), and the lungs were lavaged with two 0.75-ml aliquots of PBS. The cells were collected by centrifugation and resuspended in a constant volume, and total cell counts were determined. Differential cell counts were performed on cytocentrifuge preparations stained with Diff-Quik (Baxter Healthcare, Miami, FL). After BAL, the lungs were inflation fixed with 4% paraformaldehyde, embedded in paraffin, and sectioned to 15 µm. Lung sections were stained with hematoxylin and eosin. Perivascular and peribronchial inflammation were scored by a pathologist blinded to treatment groups, with a subjective scale of 1, 2, 3, and 4 corresponding to none, mild, moderate, and severe inflammation, respectively (2, 41). At least four sections from each animal were scored, and the scores from separate sections were averaged to obtain a score for each lung.
Cytokine measurement in BAL fluids.
Concentrations of IL-4, IL-5, and IFN- in BAL fluid were determined
with two-site immunoenzymetric assay kits (Endogen, Cambridge, MA)
according to the manufacturer's instructions. The capture and
detection antibodies for determination of IL-10 concentrations were
obtained from PharMingen (JES5-2A5 and SXC-1; San Diego, CA). The lower
limits of detection were 1 pg /ml for IL-4 and IL-5, 40 pg/ml for
IFN-
, and 5 pg/ml for IL-10.
Pulmonary function testing. Pulmonary function was assessed in anesthetized, spontaneously breathing animals with a Mumed PMS system (Mumed, London, UK). On day 14, animals were anesthetized with 95 mg/kg ketamine and 5 mg/kg xylazine delivered by intraperitoneal injection. A 20-gauge cannula was inserted into the trachea and connected to a Fleisch 00000 pneumotachograph to monitor airflow. PE-60 tubing was inserted into the esophagus to the level of the thorax to measure transpulmonary pressure. Airway resistance (Raw) was calculated as the quotient of the changes in flow and pressure between isovolumetric points on inspiration and expiration. Dynamic lung compliance (Cdyn) was calculated as the quotient of the change in volume and change in pressure at the end of inspiration and expiration. A 30-gauge cannula was inserted into the tail vein for administration of methacholine.
Animals were connected to the Mumed system, breathing was allowed to stabilize, and Raw and Cdyn were recorded. Saline was injected into the tail vein at a volume of 1 µl/g body wt followed by increasing doses of methacholine at 2-min intervals, a time that was sufficient for the animals' breathing to stabilize. Methacholine (Sigma) was dissolved in saline and injected in aliquots of 0.2-1 µl/g body wt. Values of Raw and Cdyn were recorded during stable breathing just before administration of the drug.Statistics. Values are reported as means ± SE for n animals. Differences between groups were identified by ANOVA and Fisher's test for least significant difference (P < 0.05). Differences between dose-response curves were verified by repeated-measures analysis.
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RESULTS |
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IL-10 levels in BAL fluid and serum after intratracheal
administration.
Endogenous IL-10 was undetectable in BAL fluid from six naive mice
(Fig. 1). RW-sensitized animals exhibited a
baseline IL-10 concentration in BAL fluid of 20 ± 10 pg/ml before
allergen challenge (n = 6). RW challenge of sensitized mice
induced a gradual increase in endogenous IL-10 concentration in BAL
fluid, resulting in a maximum concentration of 60 ± 25 pg/ml being
measured 72 h after the challenge. Instillation of 25 ng of rmIL-10
into the trachea at the time of RW challenge elevated total IL-10
concentration in BAL fluid to 440 ± 61 pg/ml at 12 h. By 72 h after
administration, total IL-10 concentration in BAL fluid had returned to
the level measured on day 11 in unchallenged animals.
Instillation of 300 ng of rmIL-10, the highest dose used in this study,
resulted in a total IL-10 concentration in BAL fluid of 4,600 ± 950 pg/ml 12 h after administration (n = 6). As with the 25-ng
dose, the concentration returned to baseline level by 72 h after
administration (28 ± 14 pg/ml; n = 6).
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IL-10 dose-dependent effects on airway inflammation.
Intratracheal administration of rmIL-10 at doses of 2.5 and 25 ng/animal reduced the number of eosinophils recovered in BAL fluid 72 h
after allergen challenge by 65 and 70%, respectively (P < 0.001; Fig. 2B). Doses as low as
2.5 ng/animal also reduced the number of macrophages, lymphocytes, and
neutrophils recovered in BAL fluid 72 h after allergen challenge (Fig.
2). In contrast, the 300-ng dose did not reduce the number of
eosinophils, macrophages, and lymphocytes in BAL fluid. The number of
neutrophils recovered in BAL fluid was increased with the 300-ng dose.
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Dose-dependent effects on cytokine secretion in vivo.
The 2.5-, 25-, and 300-ng doses of rmIL-10 decreased IL-4 concentration
relative to the vehicle control by 81, 75, and 69%, respectively (Fig.
3A). IL-5 concentration in BAL
fluid was not altered by the 2.5-ng dose of IL-10 but was decreased
61% by the 25-ng dose and 41% by the 300-ng dose (Fig. 3B).
In contrast to the Th2 cytokines, IFN- concentration was increased
70% by the 2.5-ng dose of rmIL-10 (Fig. 3C) and decreased 80%
by the 25- and 300-ng doses. These results demonstrate that low doses
of IL-10 are effective in reducing Th2 cytokine levels in the airways after allergen challenge.
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Paradoxical effect on airway reactivity to methacholine.
Airway resistance was measured in RW-sensitized animals that had been
challenged with PBS or 8 µg of RW to determine the degree of
hyperreactivity induced by allergen challenge in this model (Fig.
4). Baseline resistance was not different
in the PBS- and RW-challenged groups [229 ± 54 cmH2O · l1 · s
(n = 13) and 209 ± 45 cmH2O · l
1 · s
(n = 14), respectively]. RW induced a twofold increase in airway responsiveness to methacholine compared with the PBS control (P = 0.01; Fig. 4). Variability of resistance data and
potential for undesirable effects on the cardiovascular system and loss of study subjects increased with increasing doses of intravenous methacholine. Subsequent evaluation of airway reactivity in
IL-10-treated animals was therefore restricted to doses of methacholine < 300 µg/kg.
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DISCUSSION |
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The findings of this study provide evidence that allergic sensitization and challenge increases IL-10 levels in the lungs and that augmenting endogenous levels with a single dose of rmIL-10 reduces allergen-induced eosinophilic inflammation and Th2 cytokine production. In contrast to these anti-inflammatory activities, administration of IL-10 increases airway hyperreactivity, resulting in an apparent dissociation between Th2-driven inflammation and decreased pulmonary function.
The increase in IL-10 levels in BAL fluid after sensitization and challenge with RW in our study is consistent with the findings in patients with asthma, as reported by Borish et al. (3) and Robinson et al. (35). These investigators found that IL-10 expression in sensitized human skin, lungs, and peripheral blood cells increases 6-48 h after allergen challenge, perhaps as a normal negative-feedback response to allergic inflammation. Differences in IL-10 expression between asthmatic and normal individuals were also reported. A greater number of IL-10-expressing cells has been reported in the lungs of asthmatic subjects (35), but measurements of protein in the BAL fluid have revealed a lower amount of IL-10 in asthmatic subjects compared with normal subjects (3). The discrepancy between the number of IL-10-expressing cells and protein levels may reflect reduced cellular expression of IL-10 in asthma. This idea is buttressed by the observation that cellular expression of IL-10 is low in allergic and nonallergic asthmatic children compared with normal controls (20). These observations and the findings of the current study indicate that allergen challenge induces recruitment of IL-10-expressing cells to the airways and increases IL-10 release, but in asthma, the recruited cells have a reduced capacity to produce IL-10. Given that the severity and time course of inflammation are increased in asthmatic subjects compared with nonasthmatic individuals, it is conceivable that cumulative exposure of the airways to IL-10 is actually greater in this group. A kinetic study is required to evaluate this possibility.
In the present study, a single 25-ng dose of IL-10 administered at the time of RW challenge significantly decreased eosinophil numbers 72 h later. Prior studies have shown that recruitment of eosinophils to the lungs is inhibited by IL-10. Zuany-Amorin et al. (47) demonstrated that a 100-ng dose of IL-10 reduced eosinophil infiltration into the airway wall and BAL compartment 24 h after intranasal ovalbumin challenge. Likewise, Grunig et al. (12) demonstrated that eosinophilic airway inflammation was augmented in the absence of endogenous IL-10. These studies indicate that induction of endogenous IL-10 by allergen challenge regulates allergen-induced eosinophilic lung inflammation.
Even though 25 ng of IL-10 inhibited BAL eosinophil recruitment, the lungs of the same animals failed to demonstrate corresponding changes in tissue inflammation. One explanation for this difference is that histological evaluation is less sensitive than BAL fluid analyses in detecting relatively small differences in inflammation. Alternatively, it could reflect the timing of the tissue collection relative to the IL-10 treatment. Zuany-Amorin et al. (47) examined lung histology 6 and 24 h after treatment with IL-10 and reported significant reduction in tissue inflammation. In that same study, BAL cell counts were determined 24 and 96 h after treatment. IL-10 treatment reduced the number of eosinophils in BAL fluid at the 24-h time point, but no difference was observed 96 h after treatment (Fig. 3B in Ref. 47). These observations suggest that a single dose of IL-10 delays but does not prevent the onset of eosinophilic inflammation. This delay could explain the differences in inflammation exhibited by BAL and lung tissue samples collected 72 h after IL-10 treatment in the present study.
IL-10 treatment at the time of RW challenge modulated the levels of
IL-4, IL-5, and IFN- in the BAL fluids. These cytokines are known to
regulate eosinophilic inflammation. IL-5 plays an important role in
eosinophil differentiation and recruitment to the airways and in naive
guinea pigs has been shown to induce airway hyperreactivity through
activation of neurokinin-2 receptors (21). However, in the present
study, the 2.5-ng dose of IL-10 decreased eosinophil numbers in BAL
fluid but did not change IL-5 concentration. Ochiai et al. (31) have
reported that IFN-
inhibits differentiation of eosinophils. The
2.5-ng dose of IL-10 increased IFN-
concentration in BAL fluid. Thus
high levels of IFN-
could have counteracted the proeosinophilic
activity of IL-5. Another explanation for divergence in the IL-5 levels
and eosinophilia is that IL-4 production was reduced by the 2.5-ng dose
of IL-10. IL-4 induces differentiation of Th2 cells and promotes
eosinophil recruitment. Two studies of knockout mice have demonstrated
that IL-4 attenuates allergen-induced airway eosinophilia (5, 15). The
main effect of IL-4 appears to be exerted during the sensitization process, since neutralizing IL-4 during allergen challenge does not
inhibit eosinophilia (5, 15). It should be noted, however, that another
study failed to demonstrate a role for IL-4 in lung eosinophilia (22).
Pulmonary function testing revealed increased airway reactivity in mice treated with 25 ng of IL-10. In a study of wild-type and IL-10 knockout mice, Grunig et al. (12) failed to detect an effect of endogenous IL-10 on airway reactivity. In that study, animals were sensitized and challenged with doses of Aspergillus fumigatus antigen that resulted in a high rate of early mortality and marked airway hyperresponsiveness to ACh. The dose of intravenous ACh that induced a 200% change in Raw was 300 µg/kg body wt in allergic animals vs. 2,240 µg/kg body wt in control animals (Table 1 in Ref. 12). In contrast, the low dose of RW used in the present study yielded moderate pulmonary inflammation and airway hyperreactivity with no premature death. The moderate degree of reactivity induced by the low-dose RW challenge in the present model may have allowed detection of an increase in airway reactivity that was masked in the previous study.
The finding that IL-10 treatment decreased BAL eosinophilia but increased airway reactivity to methacholine was surprising, since evidence from human and guinea pig studies indicates that eosinophils play a major role in development of BHR (9, 11, 42). However, the role of eosinophils in induction of hyperreactivity in mice is controversial (34). Foster et al. (10) demonstrated a correlation between eosinophilia and development of hyperreactivity in mouse airways. Other studies, however, have failed to find extracellular deposition of major basic protein or other evidence of eosinophil activation in mouse lungs (25, 40). In addition, inhibition of eosinophil infiltration into the airways is not always linked to decreased hyperreactivity to methacholine (13, 19) and, as observed in the present study, can be associated with increased airway reactivity. Finally, a recent study performed in patients with asthma also demonstrated a dissociation between eosinophil numbers and airway reactivity (7). Thus pathophysiological responses to eosinophilic inflammation appear to be complex, and consideration of alternative explanations for airway reactivity is warranted.
There is evidence that cytokines and chemokines like IFN- and
monocyte chemoattractant protein-1 (MCP-1) play a role in
development of airway reactivity. In guinea pigs, IFN-
enhances
-adrenergic-mediated relaxation of airway smooth muscle (4), and
under this scenario, reduction in IFN-
levels by IL-10 treatment
could augment airway reactivity. However, there is also evidence that
IFN-
induces airway hyperreactivity in a mouse model (14), perhaps
through the release of excitatory cytokines and chemokines from smooth muscle cells (17, 18, 23, 24). Whether changes in IFN-
levels can be
the explanation for the IL-10-induced airway reactivity observed in
this study is unclear. IL-10-induced airway reactivity may be linked to
release of histamine. IL-10 increases murine mast cell and basophil
proliferation, differentiation, and degranulation (30). IL-10
stimulates MCP-1 production (37, 39), and MCP-1 is a potent stimulator
of histamine release. Depletion of MCP-1 has been shown to reduce
airway reactivity without attenuating eosinophilia (27). It is
therefore plausible that airway reactivity induced by the 25-ng dose of
IL-10 resulted from an increase in MCP-1-stimulated histamine release
from mast cells and basophils.
In summary, this study demonstrates that IL-10 accumulation in the airways is increased in response to allergic sensitization and challenge. Supplementing endogenous levels with low doses of recombinant IL-10 decreases accumulation of proinflammatory Th2 cytokines, IL-4 and IL-5, in the airways and reduces allergen-induced eosinophilic airway inflammation. In contrast to these anti-inflammatory activities, administration of IL-10 increases airway hyperreactivity. This effect could contribute to the decline in pulmonary function observed in asthma.
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ACKNOWLEDGEMENTS |
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Cynthia Kukoly and Christine Welch assisted in animal and laboratory management.
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FOOTNOTES |
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This project was supported in part by American Lung Association Grant RG-081-N.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: M. R. Van Scott, Dept. of Physiology, East Carolina University, 6N98 Brody Bldg., Greenville, NC 27858 (E-mail: mrvanscott{at}brody.med.ecu.edu).
Received 1 June 1999; accepted in final form 17 November 1999.
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