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. 1998 Jul;113(1):10–16. doi: 10.1046/j.1365-2249.1998.00619.x

Reduced IL-1 production in adolescents with mite antigen asthma in remission

T Noma *,‡, K Ichikawa †, I Yoshizawa ‡, K Aoki ‡, Y Kawano *,‡, M Baba †
PMCID: PMC1905019  PMID: 9697977

Abstract

To determine the immunological mechanisms associated with outgrowing mite antigen-induced bronchial asthma during adolescence, we studied the relationship between clinical status and Dermatophagoides farinae (Df) antigen-induced peripheral cell activation by measuring IL-1α and IL-lβ production in patients with bronchial asthma. After antigen-driven restimulation in vitro, there was increased IL-1α, IL-1β production by peripheral blood mononuclear cells (PBMC) from patients with active bronchial asthma, while cellular IL-1α, IL-1β production was reduced in patients with asthma in remission. IL-1α and IL-1β production by PBMC (possibly reflecting airway inflammation) after exposure to Df antigen might be down-regulated in patients outgrowing mite antigen-induced asthma, because lipopolysaccharide-induced IL-1α, IL-1β production (seen in both normal individuals and patients with active asthma) was also reduced when patients were in remission.

Keywords: childhood asthma, outgrowing, adolescence, Dermatophagoides farinae, lipopolysaccharide, IL-1α and IL-1β production

INTRODUCTION

Asthmatic children have been shown to undergo remission during or after adolescence (from 12 to 25 years old), with 20–70% of them becoming largely or totally asymptomatic [1–3]. However, the prevalence, hospitalization rate, and mortality due to asthma have increased dramatically during the last two decades [4,5]. The immunological mechanisms responsible for the clinical improvement of adolescent asthma sufferers have yet to be fully elucidated.

IL-1 is one of the principal proinflammatory cytokines and induces acute as well as chronic inflammatory responses. IL-1, IL-6 and/or tumour necrosis factor-alpha (TNF-α) are produced by monocytes/macrophages after antigen presentation or tissue damage [6]. These proinflammatory cytokines initiate a cascade of events that result in the entry, activation and prolonged survival of inflammatory cells in various tissues, as well as the differentiation of these cells from progenitors. Elevation of the level of haematopoietic progenitors for inflammatory cells in the peripheral blood of atopic patients, including those with bronchial asthma, appears to be related to the severity of their tissue reactivity [7].

In the present study, we examine the relationship between the clinical improvement of patients with bronchial asthma and the changes of IL-1α and IL-1β production by peripheral blood mononuclear cells (PBMC). We found a close correlation between the improvement in clinical status and changes of IL-1α, IL-1β production by Dermatophagoides farinae (Df) antigen- or lipopolysaccharide (LPS)-stimulated PBMC cultures. The existence of some immunosuppressive mechanism in the patients with remission was suggested, because LPS-induced IL-1 production by PBMC was reduced in adolescents outgrowing mite antigen-induced asthma when compared with that by PBMC from both normal individuals and patients with active bronchial asthma.

SUBJECTS AND METHODS

Subjects

PBMC were obtained from 19 Japanese patients with bronchial asthma (Table 1). Seven age-matched healthy individuals were also studied as the control group. The patients with active disease had recurrent asthma attacks and a positive immediate skin reaction (defined as an immediate wheal response ≥ 10 mm in mean diameter in a skin prick test) to house dust mite and Df antigen (mite 1; Torii & Co., Ltd, Tokyo, Japan). Serum lgE scores for mite antigen [8] varied from 3 to 5 as determined by radioallergosorbent test (RAST). The diagnostic criteria used for bronchial asthma were those of the American Thoracic Society. None of the patients had acute asthma at the time of examination and none was taking oral corticosteroids or anti-allergic agents such as ketotifen [9]. The subjects were identified prospectively and followed up until they could be divided into two groups. Group I comprised patients in remission, i.e. disease-free for 2 years without any medications, group II patients without remission, i.e. more than 10 mild to moderate attacks per year, despite use of medications such as theophylline (15–20 mg/kg per day), a β2-agonist, or some combination thereof. The severity of acute exacerbations of asthma and the overall disease severity were estimated according to the Guidelines for the Diagnosis and Management of Asthma (the National Asthma Education Program; Expert Panel Report) released by the National Institutes of Health (Bethesda, MD). A mild attack was defined as normal alertness, absent or mild dyspnoea (patient was able to speak in complete sentences), no or mild intercostal retraction, good skin colour, end-expiratory wheezing only, and 70–90% of the predicted or personal best PEFR or forced expiratory volume in 1 s (FEV1). The FEV1 of the two groups was within normal limits in the acute attack-free state or in the 4–6 weeks preceding examination, and there were no significant differences between the groups (95.3 ± 3.4% in active asthma (mean ± s.e.m.; n = 10) and 98.0 ± 5.4% in remission (n = 9). The severity of the disease in both groups was comparable before the study period, with both having mild or moderate asthma. A profile of the two groups is shown in Table 1. Informed consent was obtained either from the patient, or in the case of minors, the parents.

Table 1.

Characteristics of subjects used in the study

graphic file with name cei0113-0010-t1.jpg

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* Per year over the previous 2 years.

† Mean value ± s.e.m.

IL-1α, IL-1β production

PBMC (1 × 106) samples separated from heparinized peripheral blood by Ficoll–Hypaque (Pharmacia, Uppsala, Sweden) density gradient centrifugation [10] were cultured in the absence or presence of 10 μg/ml Df antigen (Torii & Co.) or 10 μg/ml LPS (Sigma, St Louis, MO) [11,12]. Then the cells were suspended in a culture tube (Falcon Plastic 2054) in 1 ml of RPMI 1640 medium containing 40 μg/ml gentamycin and 2% heat-inactivated pooled human serum and cultured for 24 h at 37°C in a 10% CO2 atmosphere. The mites used as antigens were grown free from pathogens and the antigen was prepared in sterile conditions (Torii & Co.). Culture supernatants were harvested and stored at −80°C until assay for IL-1α, IL-1β by solid-phase ELISA. For kinetic studies of IL-1α, IL-1β production by PBMC, PBMC from the Df antigen-sensitive asthmatic children and age-matched normal individuals were stimulated in vitro with 10 μg/ml LPS or Df antigen, and then cultured for 3, 6, 12, 24 or 48 h.

In the present study, we analysed IL-1 production by PBMC, as the proportion of monocytes in PBMC of the patients with remission was similar to that in patients with active disease (11.8 ± 2.2% (n = 9) versus 12.1 ± 2.3% (n = 10), counting under a microscope). Cell viability of the cultured cells was > 98%.

IL-1α, IL-1β assay

A solid-phase ELISA was used, with slight modifications as reported elsewhere [12]. Briefly, each well of a 96-well microtitre plate (Linbro; Flow Labs, Inc., MacLean, VA) was coated with 100 μl of a monoclonal mouse anti-human IL-lα or IL-1β antibody (1 μg/ml; ANOC243 or ANOC301; Otsuka Biochemical Labs Inc., Tokyo, Japan) in 0.1 m NaHCO3 buffer (pH 9.6) and blocked overnight with 150 μl of 0.25% gelatin (Wako Pure Chemical Industries, Tokyo, Japan). Then 100 μl of undiluted culture supernatant were added per well. After 16 h of incubation at 4°C, the wells were emptied and washed three times, then 100 μl of rabbit anti-human IL-1α or IL-1β antibody (1μg/ml; OCT323K or no. 8; Otsuka Biochemical Labs) were added to each well, and the plate was incubated at room temperature for 2 h. After another three washes, 1:3000 diluted biotinylated goat anti-rabbit IgG antibody was added (Tago, Inc. Burlingame, CA), and the plate incubated for a further 2 h. The goat anti-rabbit IgG was preabsorbed on a human serum protein-conjugated cyanogen bromide (CnBr)-activated Sepharose 4B column before use. After three washes with PBS, streptavidin-conjugated horseradish peroxidase (HRP; Bethesda Research Laboratories Life Technologies, Inc., Gaithersburg, MD) was added to each well, and the plate was incubated at room temperature for 20 min. Then 100 μl of o-phenylenediamine (Bethesda Research Laboratories Life Technologies) solution were added to the wells after six washes with PBS–Tween and the absorbance at 492 nm was measured with an ELISA reader (BioTek Instruments, Inc., Burlington, VT). Recombinant IL-lα (Dainippon Pharmaceutical Co., Ltd, Tokyo, Japan) or recombinant IL-1β (Genzyme Corp., Boston, MA) was used as the standard. Results were expressed in ng/ml supernatant with reference to the IL-1 standard. The respective sensitivities of this sandwich ELISA assay for IL-1α and IL-1β were 12 and 49 pg/ml. Two percent human serum was used for cell cultures, because it allowed maximum IL-1 production by PBMC.

Statistical analysis

The respective sensitivities of the ELISA assay for IL-1α and IL-1β were 12 and 49 pg/ml, and undetectable levels were taken to be these values. The values were converted to log scales and the data were then analysed by employing the Dunnett t-test for evaluation of decreased IL-1 production in the remission group compared with the active group and control group. Intra-group comparisons of IL-1 production were performed using the paired two-tailed Student's t-test.

RESULTS

IL-lα, IL-1β production

A small amount of spontaneous secretion of both IL-1α and IL-1β was detectable in the supernatants of unstimulated PBMC. The actual supernatant concentrations of IL-1α secreted spontaneously, expressed as the mean value, were 0.018 ng/ml for the non-asthmatic individuals (n = 7), 0.015 ng/ml for the asthmatics in remission (n = 9), and 0.047 ng/ml for the active asthma group (n = 10). For IL-1β, the values were 0.073 ng/ml for the non-asthmatic individuals, 0.068 ng/ml for the asthmatics in remission, and 0.174 ng/ml for the active asthma group. The differences of IL-1α and IL-1β among the groups were statistically not significant, except that of IL-1α between the active group and the asthmatics in remission (P < 0.05). Upon stimulation with Df antigen, PBMC from both patients and normal controls secreted IL-1α and IL-1β in a dose-dependent manner. The optimal concentration of Df antigen seemed to be 10 μg/ml (Fig. 1), and this was therefore used to stimulate IL-1α, IL-1β production in subsequent experiments.

Fig. 1.

Fig. 1

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Production of IL-1α, IL-1β after stimulation with Dermatophagoides farinae (Df) antigen. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with serial dilutions of Df antigen and then cultured for 24 h. Data are shown as the mean ± s.e.m. of three independent experiments in three patients with active bronchial asthma, and the mean of triplicate experiments for one normal subject. *P < 0.001 compared with unstimulated cultures.

A 10-μg/ml dose of LPS also induced high amounts of IL-1α, IL-1β production in both normal individuals and patients with active bronchial asthma. The response was initiated within 3 h of LPS stimulation and gradually increased up to 12 h (Fig. 2). Df antigen-induced IL-1α, IL-1β production occurred within 6 h of antigen stimulation, and was thus delayed in comparison with the LPS-stimulated response, and increased gradually up to 12 h (Fig. 2). The kinetics of spontaneous production of IL-1 were similar to those of Df stimulation (Fig. 2). Each of four independent experiments showed the same trends regarding the kinetics of IL-1 production. However, the extent of production varied considerably and spontaneous or Df-induced IL-1 production occurred at low or trace levels, especially in normal subjects. Therefore, data are shown for the experiment with the highest IL-1 production among the four performed (Fig. 2). The amount of IL-1β secreted by both the LPS- and Df antigen-stimulated PBMC was ≈ 10-fold greater than the amount of IL-1α, but the kinetics were similar for the production of both types of IL-1. In succeeding experiments, culture of PBMC for 24 h was used to assess IL-1α, IL-1β production.

Fig. 2.

Fig. 2

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Kinetics of IL-1 production by peripheral blood mononuclear cells (PBMC). PBMC were stimulated in vitro with 10 μg/ml lipopolysaccharide (LPS) or Dermatophagoides farinae (Df) antigen and then cultured for 3, 6, 12, 24 or 48 h. The IL-1α and IL-1β activities in culture supernatants were determined by ELISA. The mean of triplicate values obtained in an experiment representative of four is shown, since each of the four experiments revealed the same trends in the kinetics of IL-1 production, but the level of production varied markedly between experiments.

IL-1 production by Df antigen-stimulated PBMC

Df antigen-induced IL-1 activity in the PBMC cultures from patients with active asthma (n = 10) had a mean value of 0.201 ng/ml for IL-1α and 0.658 ng/ml for IL-1β (Fig. 3). Mean activity was significantly decreased in the PBMC cultures from patients in remission (n = 9) to 0.047 ng/ml for IL-1α and 0.228 ng/ml for IL-1β, levels comparable to those in the cultures from non-asthmatic subjects (mean value: IL-1α, 0.062 ng/ml; IL-1β, 0.318 ng/ml, n = 7) (Fig. 3). However, the difference between patients with active asthma and normal subjects was not significant. Thus, Df antigen-induced IL-1α, IL-1β production by the PBMC of patients with active bronchial asthma was markedly increased by antigen-driven restimulation in vitro, unlike that by the cells of patients in remission, and IL-1α, IL-1β production decreased with the improvement of asthma symptoms.

Fig. 3.

Fig. 3

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Spontaneous, Dermatophagoides farinae (Df) antigen-induced, and lipopolysaccharide (LPS)-induced production of IL-1 by peripheral blood mononuclear cells (PBMC) from normal subjects, patients in remission, and patients with active asthma. Unstimulated, Df antigen-stimulated, or LPS-stimulated cells were cultured for 24 h, and the IL-1α and IL-1β activity of the supernatant was measured by ELISA. Df antigen-induced IL-1 production was significantly increased compared with spontaneous production (IL-1α, P < 0.01; IL-1β, P < 0.02). LPS-induced IL-1 production was significantly increased compared with both spontaneous (IL-lα, P < 0.000 02; IL-1β, P < 0.0002) and Df antigen-induced production (IL-lα, P < 0.000 006; IL-1β, P < 0.000 002). Dot plots with the mean values are shown. *P < 0.05.

Collectively, results from patients in remission showed down-regulation of IL-1 production following exposure to Df antigen.

IL-1 production by LPS-stimulated PBMC

We cultured PBMC from normal individuals, patients with active asthma, and patients in remission with 10 μg/ml LPS for 24 h, then measured the IL-1α, IL-1β activity (Fig. 3). The activity in cultures from patients with active asthma was markedly increased relative to both no stimulation and Df antigen stimulation (mean values: IL-1α, 1.409 ng/ml; IL-lβ, 9.005 ng/ml; n = 10), and was comparable to that in normal PBMC cultures (IL-1α, 1.345 ng/ml; IL-1β, 9.268 ng/ml; n = 7) (Fig. 3). However, the activity in PBMC cultures from patients in remission (IL-1α, 0.467 ng/ml; IL-1β, 3.567 ng/ml; n = 9) was significantly lower than that in cultures from patients with active asthma or normal individuals (Fig. 3). Thus, the IL-1 secretory response to LPS stimulation was decreased when asthma was in remission.

DISCUSSION

Df antigen or LPS was added to PBMC from asthma patients and the cells were cultured for 24 h to evaluate IL-1 production. Df-induced IL-1α, IL-1β production by PBMC from patients with active bronchial asthma showed a significant increase compared with unstimulated production, although it was lower than LPS-induced production. IL-1 has two subtypes, which are IL-lα (PI 5) and IL-1β (PI 7), and both act via the same IL-1 receptor. We found that secretion of both IL-1α and IL-1β by PBMC commenced within 3 h of LPS stimulation and within 6 h of Df antigen stimulation, results similar to those reported previously [13]. The amount of IL-1β released by PBMC was ≈ 10-fold greater than that of IL-1α, as also reported elsewhere [14].

Spontaneous IL-1α, IL-1β production was also observed in PBMC cultures from patients with active asthma, but was reduced in cultures from patients in remission to a level comparable to that in normal control cultures. It was reported previously that PBMC from patients with active asthma were activated in vivo [15,16], but the difference was not statistically significant in our study. On exposure to Df antigen a dose-dependent increase of in vitro IL-1α, IL-1β production occurred. Df antigen-induced IL-1α, IL-1β production by the PBMC of patients with active bronchial asthma, unlike that by the cells of non-asthmatic subjects, was increased after antigen-driven restimulation in vitro, but the difference was not significant. These results are supported by the report that when stimulated with D. pteronyssinus antigen, monocytes from patients with allergic asthma have the same ability to produce IL-1 as monocytes from healthy controls [17]. In contrast, in our patients with remission of asthma symptoms, Df-induced IL-1α, IL-1β production surprisingly showed a significant decrease. These results indicate that the PBMC of patients in remission showed down-regulation of IL-1 production in response to Df antigen.

To analyse further the characteristics of the decreased IL-1α, IL-1β production by PBMC from patients with asthma in remission, we evaluated IL-1α, IL-1β activity in the culture supernatants after 24 h of stimulation with LPS, a toxic cell wall component of Gram-negative bacteria that induces a local acute inflammatory reaction [18,19]. Stimulation with LPS induced IL-1α, IL-1β production in cultures from the patients with active asthma. Surprisingly, the IL-1α, IL-1β production by LPS-stimulated PBMC from asthma patients in remission was significantly lower than that by PBMC from active asthma patients, while production by cells from normal individuals was comparable to that by cells from the active asthma patients. Thus, both Df- and LPS-induced IL-1α, IL-1β production were reduced in the patients with asthma in remission. This suggested that in vitro anergy or active inhibition of mediator-driven processes such as IL-1 synthesis was likely to relate to the clinical unresponsiveness of our patients in remission to inflammatory stimuli such as Df antigen or LPS.

Thus, IL-1 production by PBMC exposed to Df antigen, which may reflect the airway inflammation [15,16,20–26], was reduced in our patients with remission of asthma as they grew older. We did not evaluate IL-1 production by PBMC from patients with non-allergic bronchial asthma (i.e. patients not sensitized to mite antigen); but early in life a large population of children acquires mite antigen-induced asthma which terminates during adolescence. Mechanisms suppressing Df-induced responses are suggested to be active in the patients outgrowing bronchial asthma. Df antigen may induce a suppressive mechanism for the response to LPS as well as its own response in patients with remission of asthma.

To avoid non-specific stimuli against the cells, including endotoxin, the mites were grown free from pathogens and the Df antigen used was prepared in sterile conditions (Torii & Co.), resulting in the preparation of antigens contaminated with no or trace levels of endotoxin that can not induce IL-1 production. Otherwise, the IL-1 production by normal PBMC stimulated with Df antigen had increased comparable to the level on stimulation with LPS.

In the present study, we analysed IL-1 production by PBMC from atopic children. Since the proportion of monocytes in PBMC of the patients with remission was similar to that in patients with active disease, monocytes from the active group might have more Df-specific IgE bound to their surface and thus show an exaggerated response to Df antigen [28]. Otherwise, IL-1 production by the monocytes of active asthma patients (including T cells) might be enhanced by cytokines such as transforming growth factor-beta (TGF-β) [29], and granulocyte-macrophage colony-stimulating factor (GM-CSF) [30] that are released by T cells which also are activated by mite culture. In view of LPS stimulation, LPS probably affected patient monocytes directly or via cytokine production by B cells to augment IL-1 production. The mechanisms of induced tolerance in the patients with remission remain to be elucidated.

In certain conditions, interferon-gamma (IFN-γ) may play a self-limiting role in the immune response. Indeed, in a cutaneous (DTH) reaction, antibodies against IFN-γ were shown to enhance the development of the reaction and to inhibit class II antigen expression on keratinocytes [31]. A reduction in local levels of IFN-γ may abrogate a suppressive action of the induced class II antigens on keratinocytes. In contrast, systemic administration of IFN-γ inhibits LPS-induced inflammation [32]. An excess of class II molecules can induce the development of suppressive macrophages and inhibit T cell proliferation. Thus increased IFN-γ production in patients in remission [27] is likely to suppress the inflammatory immune responses, resulting in suppression of IL-1 production. The latter possibility seems more likely because Df-induced activation of T cells (Df-induced IL-2 responses, Df-induced IL-2 and IL-4 production) has been found in patients with active asthma, and the response was weaker for patients in remission [27]. To develop our hypothesis, the production of other proinflammatory cytokines such as IL-6 and TNF-α as mentioned should be evaluated in the subsequent study, which seems an ideal opportunity.

Finally it would be interesting to know that immune responses to an irrelevant antigen such as ovalbumin are influenced in the context of reduced proinflammatory cytokines such as IL-1 and IL-4, and increased IFN-γ to a major IgE-inducing allergen such as Df. Ovalbumin (10 μg/ml) was capable of increasing IL-1α, IL-1β production by patient cells (a median of 0.148 ng/ml for IL-1α and 0.298 ng/ml for IL-1β) compared with unstimulation, but the differences of ovalbumin-induced IL-1α, IL-1β production were statistically not significant among the groups (data not shown). The results suggest that irrelevant antigen such as ovalbumin might not be a strong IL-1 inducer and is unlikely to be related to production of other cytokines such as IL-4 and IFN-γ, because irrelevant antigen (ovalbumin) is not capable of influencing production of these cytokines in Df-, but not ovalbumin-sensitive patients [27]. However, the more precise mechanisms of Df-induced tolerance have yet to be determined.

Acknowledgments

We thank Mrs Masako Kobayashi for her secretarial assistance. This research was supported in part by a grant from the Ministry of Education, Culture and Science, Japan.

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