Th17 cytokines induce pro-fibrotic cytokines release from human eosinophils
© Al-Muhsen et al.; licensee BioMed Central Ltd. 2013
Received: 14 November 2012
Accepted: 7 March 2013
Published: 13 March 2013
Subepithelial fibrosis is one of the most critical structural changes affecting bronchial airway function during asthma. Eosinophils have been shown to contribute to the production of pro-fibrotic cytokines, TGF-β and IL-11, however, the mechanism regulating this process is not fully understood.
In this report, we investigated whether cytokines associated with inflammation during asthma may induce eosinophils to produce pro-fibrotic cytokines.
Eosinophils were isolated from peripheral blood of 10 asthmatics and 10 normal control subjects. Eosinophils were stimulated with Th1, Th2 and Th17 cytokines and the production of TGF-β and IL-11 was determined using real time PCR and ELISA assays.
The basal expression levels of eosinophil derived TGF-β and IL-11 cytokines were comparable between asthmatic and healthy individuals. Stimulating eosinophils with Th1 and Th2 cytokines did not induce expression of pro-fibrotic cytokines. However, stimulating eosinophils with Th17 cytokines resulted in the enhancement of TGF-β and IL-11 expression in asthmatic but not healthy individuals. This effect of IL-17 on eosinophils was dependent on p38 MAPK activation as inhibiting the phosphorylation of p38 MAPK, but not other kinases, inhibited IL-17 induced pro-fibrotic cytokine release.
Th17 cytokines might contribute to airway fibrosis during asthma by enhancing production of eosinophil derived pro-fibrotic cytokines. Preventing the release of pro-fibrotic cytokines by blocking the effect of Th17 cytokines on eosinophils may prove to be beneficial in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases.
Asthma is a chronic inflammatory disorder of the lung that is usually associated with airway tissue remodelling. This term refers to the structural changes affecting lung tissue which normally include epithelial detachment, increased airway smooth muscle (ASM) mass, subepithelial fibrosis, mucous gland and goblet cell hyperplasia, vascular changes, and edema [1–4]. Subepithelial fibrosis is one of the most critical structural changes associated with airway remodeling. In normal subjects, a loose array of collagen fibrils resides beneath the basal membrane. In asthmatics, however, this layer is replaced by a dense network of extra-cellular matrix (ECM) proteins including collagens . ECM protein deposition is known to be regulated by a number of cytokines and growth factors including TGF-β . Several reports have shown that the majority of TGF-β1 mRNA positive cells in bronchial biopsies of severe asthmatics were eosinophils [7–9]. Eosinophils were also shown to produce IL-11 mRNA and protein . These reports suggested that eosinophils could play an important role in regulating tissue fibrosis. IL-5 deficient mice experiments  and human studies  supported this hypothesis. In addition to lowering eosinophil levels, using anti-IL-5 antibodies was shown to be associated with reduced expression of ECM proteins particularly tenascin, lumican, and procollagen III .
Since its recent discovery, IL-17 has been described to be involved in various aspects of asthma pathogenesis. Elevated IL-17A levels were shown to correlate with increased airway hyper-responsiveness (AHR) in asthmatics . In fact, IL-17 was shown to modulate airway structural cells leading to tissue remodeling. Over-expression of IL-17 F resulted in goblet cell hyperplasia and mucin gene expression . In addition, using an in vitro cell migration assay, Change et al. have recently shown that Th17-associated cytokines IL-17A, IL-17 F, and IL-22 promote migration of human ASMCs. These effects were shown to be mediated by selective activation of receptors on ASMCs, with IL-17A and IL-17 F acting through p38 MAPK activation while IL-22 acting through a distinct nuclear factor kB (NF-kB)–dependent signaling pathway . These studies indicated for a role of IL-17 in airway remodeling and hence in regulating asthma pathogenesis.
Eosinophils have receptors for a number of mediators that are associated with asthma including Th1, Th2, and Th17 cytokines [16–18]. The expression of IL-17 cytokines was also associated with subepithelial fibrosis [19–21]. In fact, Th17 cytokines were shown to trigger the expression of pro-fibrotic cytokines in bronchial fibroblasts . We, hence, hypothesized that IL-17 cytokines may induce eosinophils to produce pro-fibrotic cytokines. In this paper, we stimulated eosinophils, isolated from normal and asthmatic subjects, with Th17 cytokines as well as a group of Th1 and Th2 cytokines known to be associated with asthma. Eosinophil production of TGF-β and IL-11 pro-fibrotic cytokines was then investigated.
Materials and methods
Demography and spirometry data of the recruited subjects
33.3 ± 2.6
38.2 ± 3.4
Atopy (% of total)
Duration of disease (years)
16.5 ± 9.8
Peripheral Blood Eosinophls
0.78 ± 0.04×109/l
0.31 ± 0.02×109/l
FEV1 (mean ± SD)
57.73 ± 2.56
107.5 ± 5.63
FVC (mean ± SD)
104.6 ± 6.87
FEV/FVC (mean ± SD)
66.34 ± 5.39
83 ± 4.62
- Inhaled corticosteroids: Symbicort II (Budesonide/Formoterol) (160/4.5 ug) (1–2 inhalations twice daily).
- Anti-leukotriene: Singulair (montelukast sodium) (10 mg/d).
- Ventolin (albuterol) (as needed).
Isolation and culture of eosinophils
Peripheral venous blood were drawn from patients with severe asthma (120-180 ml) (60 ml every 3 months) and from normal control subjects (180-240 ml) (60 ml every 3 months). Eosinophils were isolated by negative selection using MACS Isolation Kit (Miltenyi Biotec, Auburn, CA, USA) as previously described . Neutrophils, monocytes and T cells were labeled with anti-CD16, anti-CD14 and anti-CD3 Abs respectively bound to immunemagnetic beads and separated with MACS LD Separation column. Eosinophil purity was consistently >98% as evaluated by Hema3 (Fisher) staining and the viability of freshly isolated eosinophils was >99% as evaluated by Trypan blue dye exclusion. Isolated eosinophils were then cultured in RPMI + 10% FCS in the presence of 30 pg/ml IL-5 cytokine required for eosinophil survival in vitro [25, 26]. Eosinophil viability ranged between 85 and 92% following stimulation and culture.
Eosinophils (2×106 cells/ml cultured in 24 well plate) were stimulated with Th1 (IL-2, IFN-γ) (50 ng/ml), Th2 (IL-4, IL-5, IL-9, IL-13) (50 ng/ml), and Th17 (IL-17A, IL-17 F, IL-23) (10, 25, 50, or 100 ng/ml) cytokines (R&D Systems, Minneapolis, Minn., USA) for 24 hrs and supernatants were collected. In some experiments, eosinophils were treated with p38 mitogen-activated protein kinase (MAPK) inhibitors (SB 203580; 5 μM, Invivogen San Diego, CA, USA) or PI3K inhibitor (PI103; 5 μM, Cayman Chemical, Ann Arbor, Mich., USA) 2 hours prior to stimulation with IL-17. Levels of secreted TGF-β and IL-11 in supernatants were determined using ELISA assay (R&D Systems, Minneapolis, Minn., USA) according to the manufacturer instructions.
RNA extraction and real-time RT-PCR
Eosinophils were stimulated with cytokines (Th1 (50 ng/ml), Th2 (50 ng/ml) or Th17 (50 ng/ml)) for 4 hours prior to cell harvest. In some experiments, eosinophils were treated with p38 MAPK inhibitors (SB 203580; 5 μM), or PI3K inhibitor (PI103; 5 μM) 2 hours prior to stimulation with IL-17. Cells were then harvested, total RNA extracted (levels of RNA extracted from 2×106 eosinophils were 18.4 ± 4.7 μg for asthmatic eosinophils and 16.3 ± 3.9 μg for healthy controls) (RNeasy Mini kit, Qiagen, CA, USA) and modulations of the level of expression of TGF-β and IL-11 mRNA were determined using quantitative RT-PCR (Applied Biosystems, 7900 Fast RT-PCR system). Specific primers for TGF-β and IL-11 were as follows: TGF-β: Forward: 5-CTGGACACCCTAACCGTGAT-3, Reverse: 5-CTAGGCCGTGCTGCTGCT-3; IL-11: Forward: 5-GTGGCCAGATACAGCTGTCGC-3, Reverse: 5- GGTAGGACAGTAGGTCCGCTC-3. Relative expressions of TGF-β and IL-11 genes normalized with GAPDH were determined by the delta-delta Ct method .
Assessment of p38 MAPK phosphorylation by western analysis
2×106 eosinophil cells were starved using medium with 0.1% FBS for 18 hours. Cells were stimulated with 50 ng/mL IL-17A and IL-17 F for 0, 10, and 20 minutes and total proteins were extracted using lysis buffer (1% Triton X-100 containing protease and phosphatase inhibitor cocktails (Roche, Mannheim, Germany). Protein lysates (10 μg) were then resolved on 10% acrylamide SDS-PAGE gel and blots were probed with antibodies to phosphorylated p38 MAPK (Millipore) and total p38 MAPK (Millipore). Membranes were analyzed with an Odyssey IR scanner using Odyssey imaging software 3.0 (LI-COR Biosciences, Inc).
Data are presented as mean ± SD. Expression of pro-fibrotic cytokines was evaluated using ANOVA followed by Bonferroni-Dunn post hoc test. Non-parametric Mann–Whitney U test (Systat, version 7.0, SPSS, Chicago, IL) was used to evaluate significance in differential phosphorylation of MAPK. Values of p < 0.05 were considered statistically significant.
Th1 and Th2 cytokines do not induce expression of eosinophil derived pro-fibrotic cytokines
Th17 cytokines enhance the expression of eosinophil derived pro-fibrotic cytokines in asthmatic individuals
IL-17 cytokine enhance eosinophil derived TGF-β and IL-11 production through P38 MAP kinase activation
Eosinophils constitute a major source of TGF-β in asthmatic lung tissue [7–9]. Reduction of lung eosinophilia by anti–IL-5 therapy in humans  or genetic knock down in mice  significantly reduced airway fibrosis and pulmonary TGF-β1 levels. Here, we show, for the first time, that Th17 cytokines enhance eosinophil derived TGF-β and IL-11 production. This effect of Th17 cytokines was prominent on eosinophils isolated from asthmatics but not healthy subjects. Our results clearly demonstrate that eosinophils constitute an additional site of action for Th17 cytokines in asthma supporting a role for IL-17 in regulating fibrosis and airway remodeling.
Although Th2 (IL-4, IL-5, and IL-13) cytokines has earlier been reported to regulate the expression of TGF-β1 by eosinophils [37, 38], other studies had shown no effect of these cytokines on TGF-β expression . Our results support the latest reports as we did not see any increase in TGF-β or IL-11 mRNA or protein expression following stimulation with Th2 cytokines. Similarly, Th1 cytokines had no effect on eosinophil derived TGF-β expression. In fact, IFN-γ was previously shown to inhibit TGF-β production in human airway epithelial cells which is in consistence with our findings .
The enhancement of eosinophil derived pro-fibrotic cytokine release upon IL-17 cytokines stimulation was only significant in eosinophils isolated from asthmatic individuals. Although there was a slight upregulation of TGF-β and IL-11 expression in eosinophils isolated from healthy individuals upon IL-17 stimulation, this increase did not reach significance. Peripheral blood eosinophils of asthmatic patients were shown to be primed compared to those of healthy subjects [40–42] which may render them more susceptible to IL-17 effect. Our results suggest that IL-17 cytokines enhance pro-fibrotic activity of activated, such as in the case of allergic and auto-immune diseases, but not resting eosinophils. Furthermore, our data indicated that asthmatic eosinophils may express higher levels of IL-17R than those of healthy controls (Figure 2A). IL-23 was shown to increase expression of IL-17RA and IL-17RC in eosinophils  and hence this observed potential increase in IL-17R in asthmatic eosinophils could be due to increased serum IL-23 in those patients. Serum levels of IL-23 were shown to inversely correlate with level of pulmonary function (FEV1) of asthmatic patients in various reports [43, 44]. This may indicate that, due to the expected increase in serum IL-23 with asthma severity, eosinophils isolated from mild and moderate asthmatic patients may express higher levels of IL-17 receptors than eosinophils of healthy controls but lower than those of severe asthmatic patients. Understanding the correlation between asthmatic patients’ IL-23 serum levels, the expression of IL-17R on peripheral blood eosinophils, and the severity of asthma requires further investigations.
Eosinophils are known to produce IL-17 cytokines  and IL-23 was shown to stimulate the expression of IL-17A cytokine . This may indicate that IL-23 could stimulate eosinophils release of pro-fibrotic cytokines indirectly by triggering their release of IL-17A. This possibility, however, needs to be further investigated.
Stimulating eosinophils with IL-17 cytokines at a physiologically relevant concentration (25 ng/ml) resulted in an increase in TGF-β and IL-11 production although not to a significant levels (Figure 3). While stimulating eosinophils with either IL-17A or F alone did not enhance a significant increase in pro-fibrotic cytokines, using a combination of both cytokines did indicating an additive effect. Since both IL-17A and IL-17 F share the same IL-17R receptor , a concentration of around 25 ng/ml or more of each IL-17 cytokine seems to be required for efficient eosinophil derived pro-fibrotic cytokine release. This is more likely to be achieved in vivo through the additive effect of IL-17A and F rather than a high concentration of a single IL-17 cytokine alone.
Accumulating evidences from various reports indicate for a key role of p38 MAPK pathway in IL-17 cytokine activity on structural and inflammatory cells in asthma [15, 36]. Binding of IL-17A and F to the IL-17RA and RC receptors on target cells triggers the recruitment of the U-box E3 ubiquitin ligase Act1 (CIKS). Act1 will in turn recruit TGF-β activated kinase that serves as the template for the activation of the transcription factors NF-kB, CEBPb (beta), as well as the MAPK pathways ERK1/ERK2 and p38 MAPK . P38 MAPK, ERK, and JNK pathways were shown to regulate TGF-β transcription each in response to different stimuli . Our data suggest that IL-17 cytokines stimulate TGF-β transcription via the activation of p38 MAPK but not PI3K or ERK1/2 MAPK (data not shown) pathways. IL-23, however, seems to use another mechanism as inhibiting those pathways did not affect its ability to stimulate TGF-β and IL-11 production.
Data presented herein suggest a new role for Th17 cytokines in airway remodeling during asthma. IL-17 cytokines seem to contribute to airway tissue fibrosis by enhancing production of eosinophil derived pro-fibrotic cytokines. This role of IL-17 was dependent on p38 MAPK activation. Therefore, upstream activators of p38 MAPK within the IL-17R pathway may represent an attractive target in corticosteroid-unresponsive diseases [49, 50]. Preventing the release of TGF-β by blocking the effect of IL-17 on eosinophils may also prove efficient in controlling fibrosis for disorders with IL-17 driven inflammation such as allergic and autoimmune diseases.
This study was supported by a grant from the National Plan for Sciences and Technology, King Saud University, Riyadh, Saudi Arabia (grant number 09-BIO907-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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