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Clin Exp Immunol. Aug 2001; 125(2): 177–183.
PMCID: PMC1906135

Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-γ, IL-4, IL-10 and IL-13) in patients with allergic asthma

Abstract

Allergen-reactive T helper type-2 (Th2) cells and proinflammatory cytokines have been suggested to play an important role in the induction and maintenance of the inflammatory cascade in allergic asthma. We compared the plasma concentrations of novel proinflammatory cytokines IL-17 and IL-18, other proinflammatory cytokines IL-6 and IL-12, Th2 cytokines IL-10 and IL-13, and intracellular interferon-γ (IFN-γ) and IL-4 in Th cells of 41 allergic asthmatics and 30 sex- and age-matched health control subjects. Plasma cytokines were measured by enzyme-linked immunosorbent assay. Intracellular cytokines were quantified by flow cytometry. Plasma IL-18, IL-12, IL-10, IL-13 concentrations were significantly higher in allergic asthmatic patients than normal control subjects (IL-18: median 228·35 versus 138·72 pg/ml, P < 0·001; IL-12: 0·00 versus 0·00 pg/ml, P = 0·001; IL-10: 2·51 versus 0·05 pg/ml, P < 0·034; IL-13: 119·38 versus 17·89 pg/ml, P < 0·001). Allergic asthmatic patients showed higher plasma IL-17 and IL-6 concentrations than normal controls (22·40 versus 11·86 pg/ml and 3·42 versus 0·61 pg/ml, respectively), although the differences were not statistically significant (P = 0·077 and 0·053, respectively). The percentage of IFN-γ-producing Th cells was significantly higher in normal control subjects than asthmatic patients (23·46 versus 5·72%, P < 0·001) but the percentage of IL-4 producing Th cells did not differ (0·72 versus 0·79%, P > 0·05). Consequently, the Th1/Th2 cell ratio was significantly higher in normal subjects than asthmatic patients (29·6 versus 8·38%, P < 0·001). We propose that allergic asthma is characterized by an elevation of both proinflammatory and Th2 cytokines. The significantly lower ratio of Th1/Th2 cells confirms a predominance of Th2 cells response in allergic asthma.

Keywords: allergic asthma, intracellular cytokines, proinflammatory cytokines, Th cytokines

Introduction

Allergic asthma is a complex and heterogeneous disease that is characterized by intermittent reversible obstruction and chronic inflammation of the airways, bronchial hyperreactivity and an infiltration of lymphocytes and eosinophils into the airway submucosa [1]. It has been shown that the integration of Th cells, mast cells and basophils plays an important role of bronchial asthma [2]. Allergen-induced IgE synthesis can trigger eosinophils, basophils and mast cells to release cytokines for the differentiation of Th cells into Th2 cells to secrete IL-4, IL-5, IL-10 and IL-13. Moreover, basophils, mast cells and eosinophils act as effectors of allergic inflammation through the release of proinflammatory, vasoactive and fibrogenic factors (histamine, peptide leukotrienes, platelet activating factor, tryptase, chymase, etc.) that are responsible for symptoms of bronchial asthma [2]. Th2 cytokines, including IL-4 and IL-5, are crucially involved in the local infiltration and activation of eosinophils [1,3], while other Th2 cytokine IL-10 and IL-13 are important in inducing airway hyperreactivity and allergic inflammation [4].

Th2 cytokine IL-10 is an anti-inflammatory cytokine that suppresses the secretion of proinflammatory cytokines [5], allergen-induced airway inflammation and non-specific airway responsiveness [6]. IL-13 shares a receptor component, signalling pathways and many biological activities with IL-4. In fact, IL-13 is also an anti-inflammatory cytokine that plays a unique role in the optimal induction and maintenance of IgE production and IgE-mediated allergic responses when IL-4 production is low or absent [7,8]. Moreover, IL-13 or IL-4 shows synergistic effect with tumour necrosis factor (TNF-α) or IL-5 on eosinophil activation [9].

IL-18, formerly called interferon (IFN)-γ-inducing factor, is a novel proinflammatory cytokine related to the IL-1 family that is produced by Kupffer cells, activated macrophages, keratinocytes, intestinal epithelial cells, osteoblasts and adrenal cortex cells [10]. It plays an important role in the Th1 response to toxic shock and shares functional similarities with IL-12 [10]. The primary functions of IL-18 include the induction of IFN-γ in T cells and natural killer cells (NK) [10], up-regulation of Th1 cytokines including IL-2, granulocyte-macrophage colony stimulating factor (GM-CSF) and IFN-γ [10], stimulation of the proliferation of activated T cells [10], and enhancement of Fas ligand (FasL) expression in NK and cytotoxic T lymphocytes (CTL) [11]. Murine model of allergic asthma has indicated that IL-18 can increase allergic sensitization, serum IgE, Th2 cytokines and airway eosinophilia [12,13]. Moreover, clinical studies have also shown that mRNA levels IL-18, IL-10, IL-13 and regulated upon activation normal T-cell expressed and secreted (RANTES) increase in nasal mucosa after nasal allergen provocation in patients with allergic rhinitis [4].

IL-17 is another novel proinflammatory Th1 cytokine produced by activated T helper cells [14]. It is capable of inducing the production of pro-inflammatory cytokine IL-6 and GM-CSF, prostaglandin E2, leukaemia inhibitory factor and intercellular adhesion molecule-1, proliferation of T cells as well as growth and differentiation of CD34+ human progenitors into neutrophils [15,16]. IL-17 also appears to play an upstream role in T cell-triggered inflammation and haematopoiesis by stimulating stromal cells to secrete other cytokines and growth factors.

To further investigate the role of proinflammatory and Th cytokines in the pathogenesis of allergic asthma, we measured the plasma concentrations of two novel proinflammatory cytokines IL-17 and IL-18, other proinflammatory cytokines IL-6 and IL-12, and two Th2 cytokines IL-10 and IL-13 in patients with allergic asthma and normal control subjects. Since IFN-γ and IL-4 are representative of Th1 and Th2 cytokines, respectively, the percentage of intracellular Th1 IFN-γ-and Th2 IL-4-producing cells was also assessed using flow cytometry to further elucidate the predominance of Th cytokine response.

Materials and methods

Asthmatic patients, control subjects and blood samples

Forty-one Chinese patients (29 females and 12 males, aged 36 ± 11 years, range 19–69) with asthma were recruited at the asthma clinics of the Prince of Wales Hospital and Alice Ho Miu Ling Nethersole Hospital, Hong Kong. Diagnosis of asthma was based on the guidelines proposed by the American Thoracic Society [17]. At the time of participation in the study, all asthmatic patients underwent spirometric assessment (Vitalograph, Model S, UK) to determine their lung function according to the American Thoracic Society standards [18]. Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and ratio of FEV1/FVC were measured before and 15 min after inhalation of salbutamol (Glaxo Wellcome, UK). The results were compared with the local age- and sex-matched predicted values [19]. The severity of asthma in these patients was classified into four groups according to the GINA guideline [20,21]. All our studied asthmatic patients were on short-acting bronchodilator. They were also on treatment with regular inhaled steroids: 29 (70·7%) with Becloforte (Glaxo Wellcome, USA) 476·92 ± 139·53 μg daily and 12 (29·3%) on Pulmicort (AstraZeneca, USA) 363·64 ± 77·14 μg daily. All subjects had no oral steroid intake or change of asthma medications 4 weeks prior to recruitment of study. They were also not on theophylline, long-acting beta-2 agonist or antileukotriene therapy. Thirty sex- and age-matched healthy non-allergic Chinese volunteers (23 females and seven males, aged 34 ± 8 years, range 21–49) were recruited as controls. The occurrence of allergic diseases in these subjects was excluded using a detailed questionnaire. All subjects were non-smokers and free from upper respiratory tract infection for 4 weeks preceding the study. Twenty ml of heparinized venous peripheral blood was collected from each patient and control subject. An aliquot of whole blood from each subject was processed immediately for flow analysis of intracellular cytokines. Plasma samples were preserved at −70°C for assays. The above protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong and informed consent was obtained from all participants.

Plasma allergen-specific IgE and ECP

The atopic status of patients and control subjects was ascertained by positive plasma-specific IgE assays to house dust mites (Der p1), cat, dog, mixed cockroaches and mixed moulds by fluorescence enzyme immunoassay (FEIA) (AutoCAP analyser, Pharmacia Diagnostics AB, Uppsala, Sweden) [22]. Sensitization to local pollens was not tested due to its low prevalence in our community [23]. The grading of specific IgE into radioallergosorbent test (RAST) classes 1–6 was made according to the manufacturer's instruction, with specific IgE concentration ≥0·35 kIU/l being positive. Subjects were defined as atopic if they had at least one positive result on testing for allergen-specific IgE. Eosinophilic cationic protein (ECP) was similarly measured (AutoCAP analyser).

Plasma cytokines

Plasma IL-17, IL-6, IL-18, IL-12, IL-10 and IL-13 concentrations were measured by enzyme-linked immunosorbent assay (ELISA) using reagent kits of R&D Systems Inc, MN, USA.

Detection of intracellular cytokines in peripheral T helper cells

Flow cytometric determination of IFN-γ and IL-4 in the cytoplasm of peripheral CD4+ T cells was performed by a previously described method [24] using the FastImmune Cytokine System (Becton Dickinson Co., CA, USA). Briefly, aliquots (500 µl) of heparinized whole blood of each normal control and asthmatic patient were stimulated with a combination of 25 ng/ml of phorbal myristate acetate (PMA) and 1 µg/ml ionomycin in the presence of 10 µg/ml of brefeldin A (Sigma Chemical Co., MO, USA) and cultured for 4 h at 37°C with 5% CO2. Brefeldin A was used to increase the sensitivity of cytokine detection, through its inhibitory effect on protein secretion by interference with the function of Golgi apparatus. Activated lymphocytes were confirmed with the 96% expression of activation marker CD 69 using PE-conjugated CD69 specific monoclonal antibody (Becton Dickinson). Activated cultures were aliquoted and stained with 20 µl of peridinin chlorophyll protein (PerCP)-conjugated CD4-specific monoclonal antibody (Becton Dickinson) for 15 min at room temperature, and treated with 2 ml fluorescence-activated cell sorted (FACS) lysing solution (Becton Dickinson). After incubation for 10 min, samples were centrifuged, added with FACS permeabilizing solution and incubated for 10 min at room temperature in the dark. The cells in sample tubes were washed and incubated with fluorescein isothiocyanate (FITC)-conjugated IFN-γ-specific MoAb and phycoerythrin (PE)-conjugated IL-4-specific MoAb (Becton Dickinson) for 30 min at room temperature in the dark. FITC-conjugated mouse IgG2a and PE-conjugated mouse IgG1 were used as controls. After washing, cells were resuspended in 1% paraformaldehyde and analysed by flow cytometry. The typical forward and side scatter gate for lymphocytes together with a CD4+ gate (logical gate) were set to exclude contaminating monocytes from the analysis. Data were obtained on a three-colour Becton Dickinson FACSCaliburTM flow cytometer and the percentages of IFN-γ- and IL-4-producing cells (% IFN-γ and % IL-4) were analysed using CellQuest software (Becton Dickinson).

Statistical analysis

Since plasma cytokine concentrations were not in a Gaussian distribution, the Mann–Whitney rank sum test was used to assess the differences in the concentration of cytokines in asthmatic patients and control subjects. The Spearman's rank correlation test was used to ascertain the correlation among plasma cytokine concentrations. All analyses were performed using the Statistical Package for the Social Sciences (SPSS) statistical software for Windows, Version 9·0 (SPSS Inc., IL, USA). A probability of P < 0·05 was considered as significantly different. Unless otherwise specified, results are expressed as median (interquartile range).

Results

Asthma severity, atopic status and plasma ECP

The mean ±s.d. FEV1 of the 41 subjects recruited for this study was 2·16 ± 0·68 l/min (78·29 ± 17·09% predicted normal), while the FEV1/FVC ratio was 76·80 ± 11·22%. The severity of asthma in this group of patients according to GINA guideline was as follows: intermittent asthma 9 (23%), mild persistent asthma 11 (27%), moderate persistent asthma 17 (40%) and severe persistent asthma 4 (10%).

As shown in Table 1, atopy as defined by the presence of ≥one specific IgE to inhalants was found in all 41 (100%) of patients and 12 (40%) of control subjects. The major environmental allergen was house dust mite with 100% sensitization in patients versus 40% in controls resulting in plasma concentrations of specific IgE to Der p1 being significantly elevated in patients, 45·55 (16·75–71·70) versus 0·17 kU/l (0·07–0·59), P < 0·001]. As expected, plasma ECP concentration was also significantly higher in asthmatic patients [4·13 µg/l (2·17–8·62 µg/l) versus 1·82 µg/l (1·37–2·11 µg/l), P < 0·001].

Table 1
Sensitization of asthmatic patients (n = 41) and control subjects (n = 30) to common inhalant allergens as assessed by plasma specific IgE assays

Plasma concentrations of proinflammatory and Th2 cytokines

Plasma concentrations of proinflammatory cytokines IL-18 and IL-12, and Th2 cytokines IL-10 and IL-13 were significantly higher in allergic asthma patients than normal control subjects [IL-18: 228·35 (180·36–306·77) versus 138·72 pg/ml (77·10–222·56), P < 0·001; IL-12: 0·00 (0·00–0·00) versus 0·00 pg/ml (0·00–11·51), P = 0·001; IL-10: 2·51 (0·00–6·92) versus 0·05 pg/ml (0·00–4·26), P < 0·05; IL-13: 119·38 (58·29–153·87) versus 17·89 pg/ml (0·00–73·07), P < 0·001] (Fig. 1). Allergic asthmatic patients showed higher plasma IL-17 and IL-6 concentrations than normal controls [IL-17: 22·40 (8·33–27·39) versus 11·86 pg/ml (0·00–24·47); IL-6: 3·42 (0·00–10·51) versus 0·61 pg/ml (0·00–4·42)], although the differences were not statistically significant (P = 0·077 and 0·053, respectively). There was no significant positive correlation between plasma concentrations of IL-6 against IL-17 and IL-12 against IL-18 (IL-6 versus IL-17: asthmatic patients, r = − 0·047, P = 0·773; control subjects, r = − 0·351, P = 0·057; IL-12 vs. IL-18: asthmatic patients, r = 0·098, P = 0·539; control subjects, r = − 0·372, P = 0·043).

Fig. 1
Box & whiskers plots of plasma cytokine concentrations of normal controls (n = 30) and allergic asthmatic patients (n = 41): (a) IL-17; (b) IL-6; (c) IL-18; (d) IL-12; (e) IL-10; and (f) IL-13. The differences between normal controls and patients ...

Detection of intracellular cytokines in peripheral T helper cells

Figure 2 shows the representative dot-plots (PE-conjugated anti-IL-4 versus FITC-conjugated anti-IFN-γ) from flow analysis of intracellular cytokines in Th cells from (a) normal control subjects and (b) allergic asthmatics. The percentage of IFN-γ-producing CD4+ Th1 cells was found to be significantly higher in normal control subjects than allergic asthmatic patients [23·46% (14·59–27·47) versus 5·72% (3·48–12·57), P < 0·001], but there was no statistical difference in the percentage of IL-4-producing CD4+ Th2 cells between controls and patients [0·72% (0·52–1·17) versus 0·79% (0·33–1·36), P > 0·05]. Therefore, the Th1/Th2 ratios of normal controls were significantly higher than those of allergic asthmatic patients [26·96% (19·15–46·99) versus 8·38% (5·71–11·78), P < 0·001] (Fig. 3).

Fig. 2
Representative dot-plots (PE anti-IL-4 versus FITC anti-IFN-γ) for the analysis of intracellular Th cytokines using FastImmune Cytokine System by flow cytometry: (a) control subject and (b) allergic asthmatic patient. The number in the quadrants ...
Fig. 3
Box & whiskers plot of (a) percentage of IFN-γ producing cells; (b) percentage of IL-4 producing cells; and (c) the ratio of Th1/Th2 cytokine (IFN-γ and IL-4) determined by FastImmune Cytokine System for normal controls (n = 30) ...

Discussion

The pathophysiological basis underlying reversible airway obstruction in bronchial asthma is inflammation [25]. Many studies have suggested that the severity of asthma is related to the degree of inflammation [26,27]. Animal models and clinical studies in humans have indicated an important role for Th2 cells producing IL-4, IL-5 and IL-13 in the pathogenesis of allergic asthma [1], with the induction of a Th1 response that seems to aggravate an inflammatory process [2].

Specific IgE serves as a mediator of the allergic response and ECP a marker of allergic inflammation in asthma [28,29]. Our results confirmed that all our asthmatic patients were atopic with an inflammatory response manifesting ≥1 sensitization to common inhalant allergens and significantly elevated plasma ECP concentration.

We found that plasma concentration of the novel Th1 response cytokine, IL-18, was significantly elevated in allergic asthmatic patients compared to normal controls. Since IL-12 has been shown to induce the production of IL-18 in primates [30], the elevation of IL-12 might therefore induce the release of IL-18 so that both plasma IL-12 and IL-18 concentrations were simultaneously elevated in asthmatic patients in this study. IL-18 can enhance the FasL expression in NK and CTL causing Fas-mediated apoptosis in epithelial cells and tissue damage during inflammatory response [31,32]. In combination with other proinflammatory cytokines including IL-1 and TNF-α, as well as toxic granular proteins release from activated eosinophils including ECP and major basic protein, IL-18 must be an important cytokine for initiating and perpetuating the catabolic and inflammatory responses in allergic asthma [31,32]. IL-18 can also act as a coinducer of the Th2 cytokine IL-4, IL-10, IL-13 and histamine from T cells and basophils, respectively [3335], and contribute to CD4+ T cell-dependent and IL-4-independent IgE production [34]. It may therefore cause the significant increase in plasma levels of IL-10 and IL-13 in our present studies.

Another novel proinflammatory cytokine IL-17 was found previously to increase in skin affected by allergic contact dermatitis and psoriasis, which regulates keratinocyte expression of adhesion molecules and chemokines [36]. Taken together, the elevated production of IL-18 and IL-17 and other proinflammatory cytokines IL-12 and IL-6 should exert a combined effect for the inflammatory reactions in patients with allergic asthma.

Our finding of increased plasma IL-10 in asthmatic patients concurs with previous report that there is an increased IL-10 mRNA expression in allergy and atopic asthma [37]. However, contrasting results have been reported in other studies showing stimulated macrophage IL-10 production to be deficient in asthma [38]. Therefore, it is possible that IL-10 production from T cells is unregulated in asthma, with further autoregulatory IL-10 being produced after allergen challenge, but that induced macrophage IL-10 production is reduced [39]. Since IL-10 promoter polymorphisms have been reported [40], it is possible that IL-10 effector functions are reduced in atopic asthmatic subjects. In conjunction with the recent study of increased IL-13 mRNA expression in bronchoalveolar lavage cells [41] and our present result of increased plasma IL-13 in asthmatic patients, Th2 cytokine IL-10 and IL-13 must play a central role in allergic asthma.

The ratio of Th1 and Th2 cytokine-producing cells can reflect cytokine hoemeostasis and indicate Th1 or Th2 predominance during the exacerbation of disease. CD4+ T cells isolated from bronchoalveolar lavage fluid of allergic asthmatics express increased levels of both acute and chronic activation markers and elevated levels of mRNA for Th2 cytokine IL-4 and IL-5 [42]. Our present result of intracellular cytokine analysis in CD4+ cells indicated that Th1/Th2 ratio of normal controls is significantly higher than allergic asthmatic patients, thereby showing a predominance of Th2 in allergic asthma. Although there is no significant change in percentage of IL-4 producing Th2 cells between normal control subjects and allergic asthmatic patients, decrease in IFN-γ-producing Th1 cells in asthmatic patients can elevate the level of IL-13 and IL-4 receptor to develop a humoral Th2 response [36,42]. Lymphocytes from both control subjects and asthmatic patients showed the same 96% activation after the treatment of PMA and ionomycin. Therefore, the decrease in IFN-γ production in asthmatic patients is not due to the differences in PMA and ionomycin responsiveness between the two groups.

In conclusion, the present study has demonstrated that both proinflammatory and Th2 cytokines play critical roles in the inflammatory characters of allergic asthma. The significantly lower ratio of Th1/Th2-producing cells confirms a predominance of Th2 cells response in allergic asthma. Besides the imbalance of Th cytokine expression, dysregulation of apoptosis of T cells and eosinophils [43,44] and abnormal expression of Fas [45] and adhesion molecules [46] have been shown to be important for the pathogenesis of allergic asthma. Therefore, further investigation on cellular mechanisms of the pathogenesis of allergic inflammation is required.

Acknowledgments

This study was supported by a Chinese University of Hong Kong direct grant for research and a donation from Zindart (De Zhen) Foundation Ltd, Hong Kong.

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