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Am. J. Respir. Crit. Care Med., Volume 160, Number 3, September 1999, 873-878

Interleukin-18 Enhances Antigen-induced Eosinophil Recruitment into the Mouse Airways

KOTARO KUMANO, ATSUHITO NAKAO, HIROSHI NAKAJIMA, FUMIAKI HAYASHI, MASASHI KURIMOTO, HARUKI OKAMURA, YASUSHI SAITO, and ITSUO IWAMOTO

Departments of Medicine II and Physiology II, Chiba University School of Medicine, Chiba; Fujisaki Institute, Hayashibara Biochemical Laboratories, Inc., Okayama; and Department of Bacteriology, Hyogo College of Medicine, Nishinomiya, Japan

    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Interleukin-18 (IL-18) has recently been identified as an IFN-gamma -inducing factor. Previous studies have shown that CD4+ T cells, IL-5, and TNF-alpha mediate, but IFN-gamma and IL-12 (via IFN-gamma production) inhibit antigen-induced eosinophil recruitment into the airways of sensitized mice. Here, we showed that the administration of recombinant murine IL-18 enhanced antigen-induced eosinophil recruitment into the trachea and bronchoalveolar lavage fluids (BALF) of sensitized mice in a dose-dependent manner. The administration of IL-18 enhanced antigen-induced IFN-gamma and TNF-alpha production, but not IL-5 production, in the BALF and lungs of sensitized mice. Neutralizing antibody against TNF-alpha prevented antigen-induced eosinophil recruitment into the BALF of sensitized mice. Although IL-18 enhanced antigen-induced airway eosinophilia, IL-18 did not affect antigen-induced airway hyperresponsiveness in sensitized mice. These results indicate that IL-18, unlike IFN-gamma and IL-12, enhances antigen-induced eosinophil recruitment into the airways in part by increasing antigen-induced TNF-alpha production of sensitized animals. These findings suggest that IL-18 may contribute to the development and exacerbation of airway inflammation in asthma.

    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Asthma is characterized by airway inflammation with prominent eosinophil infiltrates (1). Recent studies have suggested that CD4+ T lymphocytes and interleukin-5 (IL-5) mediate the allergic eosinophil-rich airway inflammation in asthma (2- 5). We have previously shown that using a murine model of asthma, CD4+ T cells and IL-5 mediate antigen-induced eosinophil recruitment into the airways of sensitized mice (6), whereas interferon-gamma (IFN-gamma ) inhibits this eosinophil recruitment into the airways (7). Furthermore, we and others have recently reported that IL-12 also prevents antigen-induced eosinophil infiltration into the mouse airways by inducing IFN-gamma production (8, 9). Thus, the manipulation for inducing IFN-gamma production is a rational approach to the control of airway inflammation in asthma.

IL-18 has recently been identified as an IFN-gamma -inducing factor that exhibits a more potent IFN-gamma -inducing activity than IL-12 (10). IL-18 markedly induces IFN-gamma production in established Th1 cells as well as splenic T cells upon CD3 stimulation (11- 13). In addition, Yoshimoto and colleagues (14) recently showed that IL-18 together with IL-12 inhibited in vitro IgE production by induction of IFN-gamma production from activated B cells.

Therefore, to determine whether IL-18 downregulates antigen-induced eosinophil recruitment into the airways, we studied the effect of recombinant murine IL-18 on antigen- induced eosinophil infiltration in the airways of sensitized mice, and also the effect of IL-18 on IL-5 and IFN-gamma levels in the bronchoalveolar lavage fluids (BALF) of the mice. We also evaluated the effect of IL-18 on antigen-induced airway hyperresponsiveness in sensitized mice. Our results indicate that, contrary to our expectations, IL-18 enhances antigen-induced eosinophil recruitment into the airways of sensitized mice.

    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Mice and Immunization

Female BALB/c mice (8 wk of age) (Charles River Laboratories, Atsugi, Japan) were immunized intraperitoneally twice with 1 µg of ovalbumin (OVA) (Sigma Chemical Co., St. Louis, MO) in 4 mg of aluminum hydroxide at a 2-wk interval. Twelve to 14 d after the second immunization, the sensitized mice were challenged with aerosolized OVA as described below.

Antigen-induced Eosinophil Infiltration in Mouse Airways

The eosinophil infiltration into the airways was induced by the inhalation of antigen in sensitized mice, and the number of eosinophils infiltrating into the submucosal tissue of trachea was evaluated as described previously (6). Briefly, the sensitized mice inhaled aerosolized OVA (50 mg/ml) dissolved in 0.9% saline by a DeVilbiss 646 nebulizer (DeVilbiss Corp., Somerset, PA) for 20 min. As a control, 0.9% saline alone was administered by the nebulizer. At 9, 24, and 48 h after the inhalation, the tracheas were excised, fixed in 10% formalin, and stained with Luna solution and hematoxylin-eosin solution. The number of eosinophils in the submucosal tissue of trachea was counted in Luna-stained sections and expressed as the number of eosinophils per the length of the basement membrane of trachea, which was measured with a digital curvimeter.

The eosinophil infiltration into the bronchoalveolar lavage fluids (BALF) was also evaluated at 9, 24, and 48 h after OVA or saline inhalation as described previously (8). BALF were centrifuged at 400 × g for 5 min at 4° C, and cell differentials were determined by counting 500 cells stained with Wright-Giemsa solution.

Effect of Recombinant Murine IL-18

To determine whether IL-18 regulates antigen-induced eosinophil recruitment into the airways, we examined the effect of murine rIL-18 on antigen-induced eosinophil infiltration in the trachea and BALF of sensitized mice. OVA-sensitized mice were injected intraperitoneally with murine rIL-18 (10 to 20 µg) (Hayashibara Biochemical Laboratories, Okayama, Japan) (10) at 24 and 4 h before the inhaled OVA challenge. As a control, OVA-sensitized mice were injected intraperitoneally with phosphate-buffered saline (PBS). The eosinophil infiltration into the trachea and BALF was then evaluated at 9, 24, and 48 h after OVA or saline inhalation. In some experiments, as a positive control, we also examined the effect of murine rIL-12 (2 µg) (Genetics Institute, Cambridge, MA), which is also known to induce IFN-gamma production from T cells and natural killer cells (15), on the antigen- induced eosinophil recruitment into the airways of sensitized mice. In addition, to determine whether endogenous tumor necrosis factor-alpha (TNF-alpha ) is involved in IL-18-induced enhancement of airway inflammation, OVA-sensitized mice were injected intraperitoneally twice with a polyclonal rabbit antimouse TNF-alpha antibody (50 µg/mouse) (Genzyme, Cambridge, MA) (16) or control rabbit serum together with or without murine rIL-18 (20 µg) at 24 and 4 h before the inhaled OVA challenge. In these experiments, the eosinophil infiltration into the BALF was then evaluated at 48 h after OVA or saline inhalation.

To determine whether the in vivo administration of rIL-18 affects cytokine production in the airways, we examined IL-5 and IFN-gamma levels in the BALF of rIL-18-treated mice (20 µg/mouse) at 24 h after OVA or saline inhalation as described below. We also evaluated TNF-alpha levels in lung tissues of rIL-18-treated mice at 1, 8, 24, and 48 h after OVA or saline inhalation as described below.

IL-5 and IFN-gamma Levels in BALF and TNF-alpha Levels in Lung Tissues

Bronchoalveolar lavage was performed with 1.2 ml of PBS at 24 h after saline or OVA inhalation in rIL-18-treated or control (PBS-treated) mice. The BALF were centrifuged at 400 × g for 10 min at 4° C, and the amount of IL-5 and IFN-gamma in the supernatant was measured by the enzyme immunoassays using murine IL-5 and IFN-gamma ELISA kits (Endogen Inc., Boston, MA). The assays were performed in duplicate according to the manufacturers' recommendations.

Whole lung homogenates of rIL-18-treated or control mice were prepared as described by Lukacs and colleagues (17), and the amount of TNF-alpha in the supernatant of lung homogenates was determined by using a murine TNF-alpha ELISA kit (Toyobo, Osaka, Japan).

Measurement of Airway Responsiveness

Airway responsiveness to acetylcholine challenge was measured as previously described (9). Briefly, at 24 h after OVA or saline inhalation, mice were anesthetized with pentobarbital (50 mg/kg) (Abott Laboratories, North Chicago, IL), intubated with a 20-gauge tracheal cannula, and ventilated at a rate of 120 breaths/min with a constant tidal volume of air (0.2 ml). Airway pressure was measured with a pressure transducer via a port of the tracheal cannula. Muscle paralysis were provided by intravenous administration of pancuronium bromide (0.1 mg/kg) (Tocris Cookson, Ballwin, MO). After establishment of a stable airway pressure recording, acetylcholine (500 mg/kg) (Wako Co., Osaka, Japan) was injected intravenously, and the changes in airway pressure were recorded. Airway responsiveness was defined by the time-integrated change in peak airway pressure (airway pressure-time index [APTI]; cm of H2O × seconds).

Data Analysis

Data are summarized as mean ± SD. The statistical analysis of the results was performed by the analysis of variance using Fisher's least significant difference test for multiple comparisons; p values < 0.05 were considered significant.

    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

IL-18 Enhances Antigen-induced Eosinophil Recruitment into the Mouse Airways

The eosinophil infiltration into the trachea and BALF of OVA-sensitized mice was significantly increased at 48 h after OVA inhalation as compared with those after saline inhalation (n = 5 mice in each group, p < 0.001) (Figure 1A and 1B). The administration of murine rIL-18 significantly increased OVA-induced eosinophil recruitment into the trachea (control: 22.0 ± 5.8 versus rIL-18 10 µg 63.3 ± 16.2, rIL-18 20 µg 91.8 ± 15.9 eosinophils/mm, mean ± SD, n = 5, p < 0.005) (Figure 1A) and into the BALF (control: 1.5 ± 0.4 × 105 versus rIL-18 10 µg 4.0 ± 1.0 × 105, rIL-18 20 µg 6.3 ± 0.9 × 105 eosinophils/ml, n = 5, p < 0.005) (Figure 1B) of sensitized mice at 48 h in a dose-dependent fashion. However, the administration of rIL-18 did not significantly affect the number of eosinophils infiltrating in the trachea and BALF of sensitized mice after saline inhalation (Figure 1A and 1B), indicating that the enhancement of the eosinophil infiltration in the airways by IL-18 is antigen-driven.


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  		Figure 1.   Effect of murine rIL-18 on antigen-induced eosinophil infiltration into the mouse airways. OVA-sensitized mice were injected intraperitoneally with murine rIL-18 (10 to 20 µg), murine rIL-12 (2 µg) or PBS at 24 and 4 h before the inhaled OVA or saline challenge. The eosinophil infiltration in the trachea (A) and BALF (B) and leukocyte infiltration in BALF (C ) were then examined at 48 h after OVA (closed columns) or saline (open columns) inhalation. Data are means ± SD for five mice in each group. *p < 0.005, **p < 0.001, significantly different from the mean value of the corresponding control response (PBS).

In contrast to IL-18, the administration of murine rIL-12 (2 µg) inhibited OVA-induced eosinophil recruitment into the trachea and BALF of sensitized mice at 48 h by 82 and 88%, respectively (n = 5, p < 0.001) (Figure 1A and 1B), confirming previous findings (8, 9).

Because IL-18 enhanced OVA-induced eosinophil recruitment into the mouse airways, we studied whether the action of IL-18 was specific to eosinophils. Thus, we examined the effect of IL-18 on the number of macrophages, neutrophils, and lymphocytes in the BALF of sensitized mice after OVA inhalation. The total cell number in the BALF of sensitized mice was significantly increased at 48 h after OVA inhalation, which was enhanced by rIL-18 (control: 7.3 ± 2.3 × 105 versus rIL-18 10 µg 12.5 ± 3.5 × 105, rIL-18 20 µg 18.0 ± 4.8 × 105/ ml, n = 5, p < 0.005). The administration of rIL-18 enhanced OVA-induced infiltration of neutrophils and lymphocytes, but not of macrophages, in the BALF of sensitized mice (Figure 1C), indicating that IL-18 enhanced antigen-induced airway inflammatory cell infiltration in general. Furthermore, the administration of rIL-18 did not significantly affect blood leukocyte and eosinophil counts at 48 h after OVA inhalation compared with those of control mice (control: 4,200 ± 481 versus rIL-18 20 µg 3,700 ± 314 leukocytes/µl; control: 32.8 ± 6.2 versus rIL-18 20 µg 30.1 ± 5.7 eosinophils/µl, n = 6), suggesting that the enhancement of the leukocyte and eosinophil infiltration in the airways by IL-18 was not due to systemic leukocytosis or eosinophilia.

IL-18 Increases Antigen-induced IFN-gamma but Not IL-5 Production in the Airways

Because we have previously shown that IL-5 and IFN-gamma regulate antigen-induced eosinophil recruitment into the mouse airways positively and negatively, respectively (6, 7), we examined the effect of the administration of rIL-18 on antigen- induced IL-5 and IFN-gamma production in the airways of sensitized mice. IL-5 and IFN-gamma levels in the BALF of control mice were significantly increased at 24 h after OVA inhalation as compared with those after saline inhalation (Figure 2A and 2B). The administration of rIL-18 (20 µg) did not significantly affect OVA-induced IL-5 production in BALF of sensitized mice (control: 233.0 ± 49.1 pg/ml versus rIL-18 253.0 ± 55.4 pg/ml, n = 4) (Figure 2A), whereas the administration of rIL-18 increased OVA-induced IFN-gamma production in BALF of sensitized mice (control: 86.6 ± 11.5 pg/ml versus rIL-18 166.7 ± 23.1 pg/ml, n = 4, p < 0.005) (Figure 2B). These results suggest that the enhancement of antigen-induced eosinophil recruitment into the mouse airways by IL-18 was not due to increased IL-5 production or decreased IFN-gamma production.


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  		Figure 2.   Effect of murine rIL-18 on antigen-induced IL-5 and IFN-gamma production in the BALF of sensitized mice. OVA-sensitized mice were treated with rIL-18 (20 µg/mouse) or PBS as described in Figure 1. At 24 h after OVA (closed columns) or saline (open columns) inhalation, IL-5 (A) and IFN-gamma (B) levels in the BALF were determined by ELISA. Data are means ± SD for four mice in each group. *p < 0.005, significantly different from the mean value of the corresponding control response (PBS).

IL-18 Increases Antigen-induced TNF-alpha Production in the Lung Tissues and Endogenous TNF-alpha Mediates Antigen-induced Eosinophil Recruitment into the Airways

Because it has most recently been shown that IL-18 induces TNF-alpha production from CD4+ T cells in vitro (17) and endogenous TNF-alpha production has been shown to mediate antigen-induced eosinophil recruitment into the mouse airways (18), we examined whether IL-18 upregulates antigen-induced TNF-alpha production in the lungs of sensitized mice. As shown in Figure 3A, TNF-alpha production in the lungs of sensitized mice reached a peak at 8 h after OVA inhalation, and decreased gradually thereafter as previously reported (18). The administration of rIL-18 significantly enhanced OVA-induced TNF-alpha production in the lungs of sensitized mice at 1 h to 48 h (n = 4 mice at each time point, p < 0.005) (Figure 3A).


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  		Figure 3.   Effect of murine rIL-18 on antigen-induced TNF-alpha production in the lungs of sensitized mice (A) and effect of anti-TNF-alpha antibody on antigen-induced airway eosinophilia (B). A. OVA-sensitized mice were treated with rIL-18 (20 µg/mouse) (squares) or PBS (circles) as described in Figure 1. TNF-alpha levels in the lung tissues were determined by ELISA at 1, 8, 24, and 48 h after OVA (closed symbols) or saline (open symbols) inhalation. Data are means ± SD for four mice in each group. *p < 0.005, significantly different from the mean value of the corresponding control response (PBS). B. OVA-sensitized mice were injected intraperitoneally twice with a rabbit antimouse TNF-alpha antibody (50 µg/mouse) or control rabbit serum together with rIL-18 (20 µg) or PBS at 24 and 4 h before the inhaled OVA challenge. The eosinophil infiltration in the BALF was then examined at 48 h after OVA inhalation. Data are means ± SD for five mice in each group. *p < 0.005, **p < 0.001, significantly different from the mean value of the corresponding control response (normal rabbit serum).

To determine whether the increased production of TNF-alpha by IL-18 was responsible for the enhancement of antigen- induced eosinophil infiltration into the airways, we examined the effect of neutralizing antibody against TNF-alpha (16) on antigen-induced eosinophil recruitment into the mouse airways. As shown in Figure 3B, anti-TNF-alpha antibody prevented OVA-induced eosinophil infiltration into the BALF of sensitized mice by 43% (n = 5, p < 0.005), indicating that endogenous TNF-alpha partially mediated antigen-induced eosinophil recruitment into the mouse airways. IL-18-induced enhancement of OVA-induced eosinophil infiltration in the airways was also suppressed by anti-TNF-alpha antibody by 58% (n = 5, p < 0.001) (Figure 3B). We also found that anti-TNF-alpha antibody prevented OVA-induced neutrophil and lymphocyte infiltration into the BALF of sensitized mice (data not shown). Taken together, these results suggested that IL-18 enhanced antigen-induced eosinophil recruitment into the airways of sensitized mice, possibly in part, by increasing antigen-induced TNF-alpha production in the lungs.

IL-18 Does Not Affect Antigen-induced Airway Hyperresponsiveness in Sensitized Mice

Airway hyperresponsiveness (AHR) is a central feature of asthma (1). Thus, we examined the effect of IL-18 on antigen-induced AHR in sensitized mice. Inhaled OVA challenge of sensitized mice resulted in significant increases in airway responsiveness to acetylcholine (n = 5, each, p < 0.001) (Figure 4) as previously reported (9). The administration of IL-18 (20 µg/mouse) did not significantly affect OVA-induced AHR in sensitized mice (n = 5) (Figure 4). These results indicated that IL-18 did not affect antigen-induced AHR in sensitized mice.


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  		Figure 4.   Effect of murine rIL-18 on airway responsiveness to acetylcholine of sensitized mice. OVA-sensitized mice were treated with rIL-18 (20 µg/mouse) or PBS as described in Figure 1. At 24 h after OVA (closed columns) or saline (open columns) inhalation, airway responsiveness was assessed by the time-integrated change in peak airway pressure (airway pressure time index [APTI]; centimeters of H2O × seconds) after intravenous acetylcholine challenge. Data are means ± SD for five mice in each group.

    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

In this study, we have shown that IL-18 enhances antigen- induced eosinophil recruitment into the airways. We found that the administration of murine rIL-18 enhanced antigen- induced eosinophil recruitment into the trachea and BALF of sensitized mice in a dose-dependent manner (Figure 1). We also found that the administration of rIL-18 did not affect antigen-induced IL-5 production but enhanced antigen-induced IFN-gamma and TNF-alpha production in the BALF and lungs of sensitized mice (Figures 2 and 3A). Furthermore, we found that anti-TNF-alpha antibody partially prevented antigen-induced eosinophil recruitment into the BALF of sensitized mice (Figure 3B). Taken together with previous studies of the regulatory role of IL-5, IFN-gamma , and TNF-alpha in antigen-induced eosinophil recruitment into the mouse airways (6, 7, 18), these results indicate that IL-18 enhances antigen-induced eosinophil recruitment into the airways in part by increasing antigen-induced TNF-alpha production of sensitized animals. These findings suggest that IL-18 may contribute to the development and exacerbation of airway inflammation in asthma.

IL-18 has recently been identified as an IFN-gamma -inducing factor (10), which induces IFN-gamma production from Th1 cells by antigen stimulation (11), but has no effect on Th2 cells (11). Therefore, our findings of increased antigen-induced IFN-gamma but not IL-5 production in the mouse airways by IL-18 are consistent with these in vitro effects of IL-18 on T cells (11). However, because IFN-gamma and IL-12 (via IFN-gamma production) have been shown to inhibit antigen-induced eosinophil recruitment into the airways of sensitized mice (7), our findings of the enhanced antigen-induced eosinophil infiltration in the airways by IL-18 cannot be explained by the increased antigen-induced IFN-gamma production in the airways by IL-18.

Our findings of increased antigen-induced TNF-alpha production in the lungs by IL-18 can account in part for the IL-18- induced enhancement of antigen-induced eosinophil infiltration in the airways because anti-TNF-alpha antibody partially inhibited the enhancement of the antigen-induced eosinophil infiltration (Figure 3B). Our findings of the increased antigen-induced TNF-alpha production in the lungs by IL-18 are in agreement with a recent study showing that IL-18 induces TNF-alpha production from CD4+ T cells in vitro (17). Furthermore, it has been shown that IL-18 induces IL-1beta and IL-8 production in monocytes in vitro through the stimulation of TNF-alpha produced from CD4+ T cells (17). Therefore, it is still possible that IL-18 may induce other cytokine/chemokine production than TNF-alpha , thereby enhancing antigen-induced airway inflammation.

Yoshimoto and colleagues (14) showed that IL-18 together with IL-12 inhibited in vitro IgE production by induction of IFN-gamma production from activated B cells. However, they observed that IL-18 alone did not significantly inhibit IgE production in vitro and in vivo in mice. Furthermore, their study also showed that the combination of IL-18 and IL-12 rather enhanced in vivo IgE production in IFN-gamma -knockout mice. Therefore, our findings of the enhancement of antigen-induced airway inflammation by IL-18 do not seem to be contradictory to their findings.

Sur and colleagues (19) showed that IL-12 administered during the sensitization period suppressed IgE production in mice, whereas IL-12 administered during the challenge period did not inhibit IgE production, which is probably due to the preferential development of Th1 cells by IL-12 administered during the sensitization period (20), but not during the challenge period. Similarly, IFN-gamma administered during the sensitization period suppressed IgE production in mice (21), whereas IFN-gamma administered during the challenge period did not inhibit IgE production but significantly inhibited antigen-induced eosinophil infiltration in the mouse airways (7 and our unpublished data). We then employed this latter experimental protocol of IL-18 administration during the challenge period in order to study the effect of IL-18 on the established Th2 cell-mediated allergic inflammation. Therefore, because IL-18 acts as a costimulant for IFN-gamma production (10) and IFN-gamma enhances Th1 cell development (22, 23), IL-18, if it is given during the sensitization period, might inhibit antigen- induced eosinophil infiltration in mice.

IL-18 enhanced antigen-induced airway inflammation, but it did not affect antigen-induced AHR in sensitized mice (Figure 4). Recent evidence has suggested that AHR is associated with Th2-type T cells and their cytokines including IL-4 and IL-13 (24). Our findings that IL-18 did not affect antigen-induced AHR might be consistent with the inability of IL-18 to develop Th2-type T cells (10).

In summary, we have shown that IL-18, unlike IFN-gamma and IL-12, enhances antigen-induced eosinophil recruitment into the mouse airways. These results suggest that IL-18 may contribute to the development and exacerbation of airway inflammation in asthma.

    Footnotes

Correspondence and requests for reprints should be addressed to Itsuo Iwamoto, M.D., Department of Medicine II, Chiba University School of Medicine, 1-8-1 Inohana, Chiba City, Chiba 260-8670, Japan. E-mail: iwamoto{at}intmed02.m.chiba-u.ac.jp

(Received in original form May 11, 1998 and in revised form April 1, 1999).

Drs. Kumano and Nakao contributed equally to this work.

Acknowledgments: The writers thank Dr. K. Kurasawa for valuable discussion and Drs. M. Mamura and K. Tsukahara for technical assistance.

Supported in part by a grant from the Ministry of Science, Education, and Culture in Japan.

    References
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INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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