Targeting Interleukins to Treat Severe Asthma

David Gibeon; Andrew N Menzies-Gow


Expert Rev Resp Med. 2012;6(4):423-429. 

In This Article

The Role of Interleukins in Asthma


IL-1 is a pleiotropic proinflammatory cytokine produced in response to infection that mediates chronic inflammation[11] and plays an important role in respiratory allergy and asthma.[12] It is increased in the bronchoalveolar lavage (BAL) fluid of patients with symptomatic asthma,[13] stimulates IL-5 release from airway smooth muscle cells,[12] and influences eosinophil recruitment and activation. IL-1 receptor type I-deficient mice demonstrate suppressed AHR in a mouse model of asthma,[14] and IL-1 appears to participate in eosinophil priming and augmentation of the late asthmatic response in guinea pigs.[15]

Some of the anti-inflammatory and immunosuppressive actions derived from corticosteroid therapy may be secondary to augmenting the expression of IL-1RII, a decoy receptor for IL-1. Interestingly, the potential beneficial use of methotrexate in severe asthma may be secondary to blocking IL-1 from binding to its receptor and inhibiting the cellular response to IL-1.[16]

There is an ongoing Phase I trial using anakinra, an inhaled IL-1R antagonist that is used in rheumatoid arthritis, in normal volunteers. However, there has not been any further work with regard to IL-1 modulation in human asthma. This may partly be due to infection risk, given that IL-1 plays an important role in the recruitment of inflammatory cells.


IL-2 is primarily produced by activated CD4+ T cells and promotes effector T-cell and Treg responses. It affects Treg cell growth, survival and activity,[17] and acts as a direct chemoattractant for eosinophils.[18] In addition, IL-2 may have an indirect role through IL-5 production.[19]

IL-2 administration is used to enhance T-cell numbers in patients with certain types of malignancy[20,21] and has been trialed in AIDS[22] and chronic graft-versus-host disease.[23] Conversely, the use of IL-2R antibodies has been used to suppress rejection of transplanted organs.[24]

IL-2 administration, particularly when aerosolized, has caused severe cough, dyspnea, bronchoconstriction[25] and obstructive lung function.[26] These patients usually had a previous history of asthma, suggesting that they are a more susceptible group.

IL-2 and sIL-2R are elevated in BAL fluid of symptomatic asthmatic patients[27] and IL-2R-positive lymphocytes are increased in the bronchial mucosa of atopic asthmatics.[28] BAL fluid IL-2 concentration correlates with the degree of airway eosinophilia and forced expiratory volume in 1 s (FEV1) in symptomatic patients with asthma, implying that IL-2 may have an important role in lung physiology via eosinophil recruitment.

Daclizumab is a humanized monoclonal antibody directed against the αCD25 subunit of the IL-2 receptor of CD25+ T cells, leading to blocking of IL-2 binding and subsequent downstream immune activities.[29] IL-2R is expressed by abnormal T cells, such as those seen in lymphoid malignancies, autoimmune diseases and during allograft rejection.[30,31] By contrast, very few normal resting cells exhibit IL-2R expression, making it an interesting target.[32] Furthermore, in vitro studies have shown that daclizumab potentiates the ability of dexamethasone to block T-cell activation,[33] suggesting a potential role as a steroid-sparing agent in severe asthma.

A randomized, double-blinded, placebo-controlled study of daclizumab in 115 patients with moderate-to-severe persistent asthma found a small but statistically significant improvement in FEV1 at day 84 from baseline (4.4 ± 1.80% for daclizumab vs a decrease of 1.5 ± 2.39% for placebo, as a percentage of baseline; p = 0.05) [34]. Daclizumab was associated with reduced daytime asthma symptom scores (p = 0.018) and lower β2 agonist use (p = 0.009). However, during the second phase of the study, which incorporated a tapering of ICS use, these differences were not maintained. Among the 88 patients receiving daclizumab, three developed side effects that were considered to be drug related. These included an anaphylactoid reaction following the first dose that progressed to respiratory failure and required invasive mechanical ventilation, varicella zoster viral meningitis and myelitis following the first dose, and breast carcinoma that developed 4 months after the last infusion of daclizumab.


IL-5 is produced by Th2 cells, mast cells, eosinophils, natural killer (NK) cells and nonhematopoietic cells such as epithelial cells.[35–37] Its receptor, IL-5R, is expressed by eosinophils, basophils and a subgroup of B lymphocytes.[38]

IL-5 has a modulatory role in the development and function of basophils and mast cells. Furthermore, IL-5 promotes the proliferation, differentiation, recruitment and survival of eosinophils.[39,40] The eosinophil plays an important role in asthma, and it has been suggested as the key effector cell causing chronic airway inflammation.[41] Eosinophils have been observed in the airway of asthmatic patients and detected in peripheral blood, BAL fluid and endobronchial biopsies.[42]

Sputum eosinophilia is a common finding in asthma, present in up to 50% of asthmatic patients on ICS and between 60 and 80% of symptomatic untreated asthmatics.[43,44] High eosinophil counts are associated with poor asthma control,[45,46] and greater healthcare utilization,[47] and titrating ICS therapy alongside sputum eosinophil counts has led to a reduction in the number of subjects experiencing an exacerbation[48,49] – factors that make blocking IL-5 a particularly exciting treatment modality.

Animal studies have supported a role of IL-5 in asthma. IL-5 gene-deficient or IL-5Rα-deficient mice exhibit reduced AHR and less pulmonary eosinophilia following antigen sensitization and aeroallergen challenge.[50,51] The administration of anti-IL-5 before antigen inhalation in mice,[52] guinea pig[53] and monkey[54] models of asthma suppresses AHR.

In humans, IL-5 expression is elevated in BAL fluid and in bronchial biopsies[55] from asthmatic patients, and levels correlate with disease severity.[56] An in vivo study noted that IL-5 induces eosinophil infiltration and activation in asthmatic airways. Eight patients with mild atopic asthma underwent two bronchoscopies before and 24 h after the administration of IL-5 and saline to different sublobar segments. No significant difference was noted in the saline-treated segments. By contrast, the IL-5-treated segments exhibited a significant eosinophilia and raised eosinophil cationic protein levels, which is used as a marker of eosinophil activation in the BAL fluid and bronchial mucosa.[57]

Anti-IL-5 therapy in mild atopic asthmatics reduces eosinophil-associated TGF-β1 expression and decreases reticular basement membrane expression of extracellular matrix proteins linked to airway remodeling.[58] Another study using three intravenous doses of anti-IL-5 therapy found a 100% median decrease from baseline for blood eosinophils, 52% for bone marrow eosinophils and 55% for airway eosinophils.[59] This discrepancy, showing different levels of depletion in different tissue compartments, may result from altered tissue penetration, the inability to act systemically, altered receptor expression and receptor downregulation, or the ability of other cytokines to sustain tissue eosinophilia.[59]

Mepolizumab and reslizumab are two monoclonal antibodies directed against IL-5 that have been trialed in asthma.

Early trials using anti-IL-5 therapy in asthma failed to show efficacy,[60,61] despite a significant reduction in blood and sputum eosinophil counts. However, these were short exploratory trials designed primarily to look at cellular responses and safety profiles. A subsequent multicenter, randomized, double-blind placebo-controlled trial of mepolizumab in 362 patients with moderate persistent asthma did not demonstrate any differences in spirometry, symptom scores or exacerbation rates.[62] However, this cohort was not phenotyped, and the authors suggested that future studies should target patients with persistent airway eosinophilia.

Recent trials have been more promising and mepolizumab has been associated with significant decreases in exacerbations, reductions in oral corticosteroid burden and improved asthma quality of life scores.[63,64]

A randomized, double-blind, placebo-controlled study with reslizumab in 106 patients with poorly controlled, eosinophilic asthma (sputum eosinophil count ≥3%) over 4 months demonstrated that the active arm displayed significant reductions in sputum eosinophils, improvements in airway function and a trend towards greater asthma control.[65]

The relationship between asthma, nasal polyposis and anti-IL-5 treatment is an area that requires further definition.[66] Patients with polyps who are asthmatic exhibit greater polyp eosinophilia,[67] and anti-IL-5 therapy can reduce nasal polyp size in a group of patients with elevated nasal concentrations of IL-5.[68] Both conditions are linked by eosinophilic inflammation,[67] and patients with both may represent a subset of eosinophilic asthma patients that experience greater benefit from anti-IL-5 therapy.

Benralizumab (MEDI-563) is a monoclonal antibody that targets the α-chain of IL-5R, depleting circulating and tissue eosinophils and basophils,[69] and augments eosinophil apoptosis in vitro.[70] Single, increasing doses of MEDI-563 in six mild atopic asthmatics decreased peripheral blood eosinophil levels within 24 h in a dose-dependent manner that lasted up to 12 weeks.[70] In total, 25 asthmatic patients received three monthly subcutaneous MEDI-563 doses (25, 100 or 200 mg, or placebo) in a Phase II study. Peripheral blood eosinophil levels were depleted in all active cohorts by day 7, and this was maintained for at least 161 days with an acceptable safety profile.[71]

Phase II/III trials using mepolizumab, reslizumab and benralizumab are currently in process, and anti-IL-5 therapy remains a promising therapeutic option.

TPI ASM8 is a drug containing two oligonucleotides directed against the β subunit of IL-3, IL-5, and the GM-CSF receptor, and downregulates CCR3.[72] This results in an attenuation of airway eosinophil influx and AHR. A single-center, open-label, stepwise-ascending study in 14 stable, mild allergic asthmatics found that TPI ASM8 reduced sputum eosinophilia by 60.9% at 7 h and attenuated the early and late airway responses by 45 and 59%, respectively.[73] At present, there are no further clinical studies using TPI ASM8.

IL-4 & IL-13

IL-4 and IL-13 are produced by Th2 cells and are functionally and structurally related. Both have been detected in BAL fluid of asthmatics and can be induced by allergen challenge.[74] Their receptors also share a close similarity. Large numbers of high-affinity IL-4 receptors are present on activated B and T cells. In addition, they are also found on macrophages, mast cells, endothelial cells, epithelial cells, fibroblasts, muscle cells and hematopoietic progenitor cells.[75,76] Both interleukins have a high affinity to the receptor complex IL-4Rα/IL-13Rα1, and following signaling via STAT6[77] they play an important role in the allergic cascade.

IL-4 and IL-13 induce B cells to produce IgE[78–80] and the production of chemokines from structural cells of the lung.[81] IL-4 levels are raised in the serum of atopic individuals and peripheral blood mononuclear cells display increased IL-4 production in response to dust mite antigens.[82] IL-4 gene-deleted mice demonstrate a marked attenuation of antigen-induced eosinophil recruitment[83] and murine models of asthma have shown that both IL-4 and IL-13 induce AHR and mucus hyperproduction.[84–86]

Both IL-4 and IL-13 are associated with subepithelial fibrosis and airway remodeling,[87] partly relating to increased TGF-β production following IL-13 binding to receptors on fibroblasts.[88] Fibrocytes, cells contributing to the fibrotic changes seen in severe asthma, secrete greater amounts of extracellular matrix molecules following stimulation with IL-4 or IL-13.[89] In addition, IL-13 induces bronchial epithelial cells to secrete periostin, a matricellular protein originally isolated from an osteoblast cell line that is upregulated in bronchial epithelial cells of asthmatics and associated with subepithelial fibrosis.[90–92]

Blocking IL-13 in a murine model of allergic asthma significantly reduced AHR, eosinophil infiltration, serum IgE, proinflammatory cytokine production and airway remodeling.[93,94] An anti-IL-13 monoclonal antibody inhibits disease progression in a chronic mouse model of persistent asthma.[95]

Murine studies have been promising, with early work showing that STAT6-knockout mice demonstrated abrogation of AHR, reduced mucus-containing cells and virtually undetectable IgE levels following antigen provocation.[96,97] IL-4R blockade resulted in reduced AHR, a reduction in BAL fluid lymphocyte numbers and almost complete ablation of eosinophils.[98] Furthermore, mice lacking IL-4 and IL-13,[99] and those treated with IL-4 antagonists,[100] exhibited significant reductions in serum IgE levels. A placebo-controlled trial of inhaled recombinant human IL-4 in eight patients with atopic asthma led to greater AHR and sputum eosinophilia.[101]

A randomized, double-blind, placebo-controlled study of lebrikizumab (a monoclonal antibody to IL-13), given as a monthly infusion over 6 months in 219 adults with poorly controlled asthma despite inhaled glucocorticoids, found that treatment was associated with small improvements in lung function at 12 weeks that were not maintained at 24 weeks. Subgroup analysis revealed that subjects with high levels of baseline periostin, a matricellular protein first identified in osteoblasts, were associated with greater improvements in lung function. However, these changes were moderate and did not persist throughout the trial. Lebrukizumab was associated with a reduction in fractional exhaled nitric oxide (FENO; 19% mean decline) after 12 weeks, compared with a 10% increase with placebo. No significant differences were noted in asthma symptom scores, change in rescue medications, exacerbation rates or frequency of nocturnal awakening.[92] This study demonstrates the possibility for personalized medicine in severe asthmatics stratified according to serum periostin, and the results of Phase III studies are awaited.

Pascolizumab is a humanized anti-IL-4 monoclonal antibody that inhibits IL-4 binding and leads to reduced IL-5 synthesis, Th2 cell activation and IgE upregulation.[102] Early trials in cynomolgus monkeys were promising; however, a subsequent Phase I trial of 24 patients with mild/moderate asthma did not demonstrate clinical efficacy, and further development of pascolizumab has been discontinued.[103]

Inhaled recombinant human IL-4 receptor fragment (altrakincept and nuvance), which competitively inhibits IL-4 binding, showed promise in early trials involving mild-to-moderate asthmatics. Following a single dose, patients exhibited a small but significant improvement in FEV1 by day 4 and a reduction in FENO.[104] A subsequent randomized, double-blind, placebo-controlled study in 62 subjects receiving 12 once-weekly nebulized IL-4R or placebo demonstrated that the active arm maintained their FEV1 following corticosteroid withdrawal and displayed a trend towards improved asthma symptom scores.[105] However, subsequent studies failed to show these benefits, and drug development has been halted.[106]

The similarities and complimentary differences in the actions of IL-4 and IL-13 may explain why targeting IL-4 individually has failed to make progress, and has led to the view that a combined approach may lead to better inhibition of allergic inflammation.[103,107] This is supported by the demonstration of single nucleotide polymorphisms (SNPs) of IL-4Rα connecting asthma, atopy, severe exacerbations, lower lung function and increased mast cell-related tissue inflammation.[108,109]

A Phase II, randomized, double-blind, placebo-controlled study of AMG 317, an IL-4Rα antagonist, in moderate-to-severe asthmatics randomized 292 patients to receive three different concentrations versus placebo, given subcutaneously weekly for 12 weeks. Dose-related reductions in IgE and a trend towards improved asthma control test scores, FEV1 and morning peak flow were noted. However, the study failed to demonstrate clinical efficacy.[110]

Pitrakinra (Aerovant™, Aerovance, Inc., CA, USA) is a recombinant form of IL-4 that binds to IL-4Rα1 and prevents IL-4 and IL-13 binding,[111] and is currently in Phase II studies. Chronic administration of pitrakinra in a monkey model of asthma led to inhibition of AHR.[112] However, no significant effect on lung eosinophilia was seen and subsequent studies have shown that repeated dosing is associated with the development of IgG anti-pitrakinra antibodies.

Two Phase IIa double-blind placebo-controlled parallel group studies used subcutaneous and inhaled pitrakinra for 4 weeks in patients with atopic asthma. Both studies led to improved FEV1 levels but only the inhaled formulation proved to be significant compared with the placebo, and this group exhibited a significant reduction in FENO levels. No significant difference in AHR to methacholine was seen in either group.[111,113]

A Phase IIb study of inhaled pitrakinra recruited 534 patients with uncontrolled, moderate-to-severe asthma. Following a 1-month run-in period on salmeterol and fluticasone, patients were randomized to receive three concentrations of pitrakinra or placebo for a 12-week period. Salmeterol and subsequently fluticasone were withdrawn after 4 and 6 weeks, respectively. Although the study failed to show efficacy in the whole study population, three subpopulations did demonstrate benefit: eosinophilic asthma, the GG homozygous allele of the rs8832 SNP of the IL-4R, and the upper tertile FENO subgroups all exhibited a relative reduction in exacerbation incidence when treated with the highest dose of pitrakinra, compared with the overall study population.[114] This suggests that particular phenotypes of asthma may benefit from IL-4/IL-13 inhibition.


IL-6 is produced by many cells, including B cells, macrophages, dendritic cells, fibroblasts and epithelial cells. IL-6 acts by binding to its receptor, IL-6R, and subsequently recruits two membrane-spanning glycoprotein 30 (gp130) molecules to form the active IL-6R complex.[115] It is a pleiotropic cytokine that has been viewed as a marker of airway inflammation in asthma rather than a regulatory cytokine that alters the immune response.[116] However, IL-6 appears to have a more functional role through the promotion of Th2 and suppression of Th1 differentiation, while having a role in determining the adaptive immune response.[117,118] Furthermore, IL-6 may also promote Th17 differentiation.[119]

BAL fluid exhibits increased levels of sIL-6R in allergic asthma, and blocking the receptor in a mouse model of asthma inhibits Th2 cytokine production and pushes CD4+ cells to a Th1 pathway.[115] By contrast, IL-6-deficient mice exhibit increased airway inflammation, pulmonary eosinophilia, raised proinflammatory BAL cytokines (including IL-4, IL-5, IL-13 and eotaxin) and AHR. These findings were supported by opposite findings in transgenic mice where IL-6 is overexpressed in the airway,[120] suggesting that IL-6 has an anti-inflammatory role in allergic airways disease.

In mild-to-moderate asthma, induced sputum IL-6 levels are higher than in healthy controls,[118] and levels show an inverse correlation with predicted FEV1%.[121] Therefore, in contrast to murine studies, IL-6 appears to be proinflammatory in human asthma, contributing towards airways obstruction.

IL-6 blockade, potentially via monoclonal antibodies or by targeting gp130, may be a potential therapeutic target in asthma.


IL-8 induces the migration of neutrophils, monocytes and eosinophils to sites of infection, injury or inflammation.[122] In asthma, levels are raised in sputum [123], BAL fluid[124] and endobronchial biopsies.[125]

To date, IL-8 modulation has not been assessed in asthmatic patients. However, a Phase II randomized, double-blind, placebo-controlled study using intravenous infusions of ABX-IL-8, given over a 3-month period, in 109 moderate-to-severe patients with chronic obstructive pulmonary disease found that the active group exhibited a significant improvement in transition dyspnea index at 2 weeks, which was maintained at 2 months. However, no significant differences were observed in terms of lung function, health status and 6-min walking distance.[126]

An antagonist of the IL-8 receptor CXCR2, SCH527123, has been developed that inhibits neutrophil activation and causes a significant attenuation of ozone-induced airway neutrophilia in healthy subjects.[127] A randomized, double-blind, parallel study using SCH527123 in 22 patients with severe neutrophilic asthma (sputum neutrophils >40%) compared with 12 patients receiving placebo, noted a 57% reduction in sputum neutrophils over 4 weeks and fewer mild exacerbations.[128]

Despite this, blocking IL-8 is not an attractive therapeutic option in asthma, mainly due to its importance in eliciting a host-defense response to infections. However, there may be a potential role in modulating upstream targets that influence IL-8 secretion from epithelial cells.


IL-9 was originally identified as a growth factor that stimulated T cells and mast cells in mice.[129] Production by CD4+ T cells is enhanced by IL-2, IL-4 and TGF-β and inhibited by IFN-γ.[130] Genetic studies have found a link between polymorphisms at the site of IL-9 expression and the IL-9 receptor gene and AHR and IgE levels in asthmatics.[131]

IL-9 transgenic mice, which overexpress IL-9, exhibit increased AHR, pulmonary eosinophilia and raised IgE levels compared to healthy controls.[132] The intratracheal administration of IL-9 in naive B6 mice, which express low levels, results in BAL eosinophilia and raised serum total IgE levels.[133] The reduction of IL-9 producing cells, predominantly TH9 cells, is associated with reduced allergic inflammation.[134] Human PBMCs exposed to anti-IL-9 antibodies and activated by IL-4 and IL-7 exhibit reduced IgE production.[135]

In asthmatic human subjects, IL-9 induces mucus hypersecretion,[136] and allergen challenge causes a lymphocyte-induced increase in IL-9 production in BAL fluid.[137] IL-9 mRNA expression is significantly higher in bronchial biopsies from asthmatic subjects compared with healthy controls, patients with chronic bronchitis and those with sarcoidosis.[138] Furthermore, in this particular study the mRNA levels correlated with AHR.

Two Phase I dose-escalation trials using a monoclonal antibody against IL-9 (MEDI-528) have revealed an acceptable safety profile for both intravenous (n = 24) and subcutaneously (n = 29) delivered forms.[139] Two subsequent Phase IIa studies in subjects with asthma have been conducted. The first randomized 36 subjects with mild asthma to receive three different concentrations of MEDI-528 or placebo subcutaneously, twice a week for 4 weeks. The second trial recruited nine patients, seven of whom received MEDI-528, and was halted prematurely due to a serious adverse event – an abnormal brain MRI that was subsequently found to be an artefact. The active arm in the first study exhibited a trend towards fewer exacerbations, whereas the second study elicited a trend in the reduction of mean maximum decrease in FEV1 postexercise compared with placebo. Both studies noted a trend towards an improvement in asthma control questionnaires.[140]

IL-9 and Th9 cells play an important role in promotion and regulation of allergic asthma, and are a potential therapeutic target. Further trials in asthmatic patients are awaited.


IL-10 is an anti-inflammatory cytokine secreted by monocytes, macrophages, dendritic cells, epithelial cells, T cells, B cells, granulocytes and mast cells.[141] It inhibits the release of proinflammatory cytokines, such as TNF-α, IL-1, IL-6 and IL-12. In addition, it inhibits Th1 cytokine secretion, deactivates macrophages[142] and limits the differentiation and proliferation of macrophages, T cells and B cells.[141,143,144] IL-10 modulates IL-4-induced IgE production in favor of IgG4,[145] and may promote induction of IL-10-secreting regulatory T cells.[146]

In asthma, IL-10 inhibits the action of mast cells, eosinophils and the ability of antigen-presenting cells such as dendritic cells to activate T cells.[147] These effects lead to attenuation of eosinophilic airway inflammation. IL-10 levels in BAL fluid, mainly produced by alveolar macrophages,[148] are reduced in asthmatic patients compared with healthy controls.[149]

In a mouse model of asthma, adenovirus-expressing IL-10 and IL-12 prevented AHR, reduced pulmonary infiltration of eosinophils and neutrophils, and suppressed BAL fluid IL-4, IL-5 and eotaxin.[150] A study looking at acute virus-induced asthma found that sputum eosinophil counts were lower and IL-10 gene expression was increased in this group compared with nonasthmatic virus infection and stable asthmatics. This trend was supported in the 'recovery phase' where sputum eosinophilia returned in conjunction with reduced IL-10 gene expression.[151]

Therapeutic strategies with IL-10 in asthma have focused on its induction and have found that glucocorticoids (both inhaled[152] and oral,)[153] vitamin D3 and immunotherapy[154] promote IL-10 synthesis. CD4+ T cells from steroid-resistant asthmatics exhibit a blunted response to dexamethasone with regard to IL-10 synthesis compared with their glucocorticoid-sensitive counterparts,[155] which appears to be overcome with the addition of vitamin D3.[156]

Although allergen immunotherapy cannot be used in severe asthma due to potential severe allergic reactions or anaphylaxis, other strategies to augment IL-10 levels could be used to improve disease control, such as the addition of vitamin D3 in patients on glucocorticoids. A small proof-of-concept study in three steroid-resistant asthmatics found that steroid sensitivity was restored in vitro following ingestion of vitamin D3 for 1 week.[156]


IL-12 is a macrophage-derived cytokine that modulates the balance between Th1 and Th2 cells, and can suppress allergic and eosinophilic inflammation.[157] Adults with allergic asthma exhibit lower blood IL-12 levels than healthy controls,[158] and this predisposes to increased IgE synthesis,[159] higher IL-5 levels[160] and eosinophilic airway inflammation.

A double-blind, randomized trial in mild allergic asthma using recombinant human IL-12 at increasing weekly injections or placebo in 39 subjects noted that the active arm exhibited reduced blood and sputum eosinophilia. No significant effects were seen on AHR or the late asthmatic reaction following inhaled allergen challenge. Four of the 19 subjects receiving IL-12 withdrew; two experienced cardiac arrhythmias, one abnormal liver function tests and one suffered with severe flu-like symptoms.[161] Other adverse events have occurred with IL-12 use that has prevented further drug development. A Phase II study in advanced renal cell carcinoma found that over 70% of patients (12 out of 17) who received recombinant human IL-12 intravenous injections were hospitalized and two patients died.[162] These events were felt to be secondary to drug toxicity secondary to the drug scheduling, and otherstudies using IL-12 therapy in several hundred subjects did not experience such problems.[162] To reduce the adverse events profile while maintaining beneficial effects, it has been suggested that IL-12 could be coadministered with IL-10 or linked to polyethylene glycol moieties.[150,163]


IL-17 is a proinflammatory cytokine, and its release is induced by IL-23. It acts via the IL-17R receptor and is associated with allergic responses, inducing the production of cytokines such as IL-6, GM-CSF, IL-1β, TGF-β and TNF-α.

Th17 cells have only recently been recognized as a distinct subgroup of T lymphocytes[8] and, among other cytokines, secrete IL-17.[3] They have been isolated from bronchial biopsies taken from patients with severe asthma[164] and IL-17F is expressed in the airways of asthmatics and correlates with disease severity. Elevated levels of IL-17 have been found in sputum, BAL and peripheral blood of allergic asthmatic patients,[165–167] and overproduction is associated with airway neutrophilia, hyper-reactivity, mucus hypersecretion and correlates with steroid resistance[168] and disease severity.[167,169]

IL-17−/− mice exhibit reduced AHR and T-cell-dependent antibody production.[170] By contrast, exogenous IL-17A administration reduced allergen-induced production of eotaxin and IL-5, and decreased airway inflammation and AHR.[171]

IL-17 acts on human bronchial epithelial cells in vitro to increase the production and release of CXCL8, a potent neutrophil chemoattractant.[172] Furthermore, 16HBE cells pretreated with IL-17A exhibited significantly reduced sensitivity of TNF-α-induced IL-8 production to budesonide. The IL-17-induced glucocorticoid insensitivity in airway epithelial cells appears to be PI3K mediated and related to reduction of histone deacetylase 2 activity.[173]

Therefore, IL-17 appears to have a particular role in neutrophilic asthma and also in Th2 forms of asthma that are corticosteroid insensitive.

Secukinumab (AIN457), an anti-IL-17 monoclonal antibody that selectively neutralizes IL-17A, is entering into Phase II trials in patients with asthma that is not adequately controlled with ICS and long-acting β2-agonists.


IL-22 is a member of the IL-10 cytokine family and has a role in the development of allergic airway inflammation. It is produced by many cells including NK cells, Th1, Th17 and a recently described group of T cells termed Th22 cells.[174] It acts through its receptor complex, which consists of IL-22R1, which is found on epithelial cells, and IL-10R2, which is found on immune cells.[175] IL-22 has an indirect action on immune cells[176] and mainly acts on nonhematopoietic tissue cells such as lung epithelial cells, inducing the secretion of antimicrobial peptides to provide protection from extracellular pathogens[177] and maintaining cellular integrity through injury prevention and accelerating cellular repair.[10]

Murine studies have produced some contrasting results. IL-22 has a proinflammatory role in bleomycin-induced airway inflammation, but only in the presence of IL-17A. Furthermore, IL-22 has a protective role when given to IL-17A-deficient mice – a process that is reversed with the coadministration of IL-17A.[178] Conversely, IL-22 gene delivery prior to airway challenge in a mouse model of asthma suppressed the immune response, including eosinophilic airway inflammation, a process that was abrogated with IL-22-binding protein.[176]

IL-22 exerts both pro- and anti-inflammatory effects depending on the background inflammatory state. Its anti-inflammatory role in human lungs remains poorly investigated and its potential role in allergic asthma is unclear.


IL-25 is a member of the IL-17 cytokine family and is expressed by Th2 cells and activated mast cells. IL-25 induces gene expression of IL-4 and IL-13, leading to increased serum IgE,[179] and the systemic administration of IL-25 causes eosinophilia via the production of IL-5.[180]

The airways of presensitized mice exposed to inhaled antigen express IL-25 mRNA, and neutralization of IL-25 inhibits antigen-induced airway recruitment of eosinophils and CD4+ T cells.[181] Blocking IL-25 in a mouse model of allergic asthma led to a significant reduction in BAL fluid IL-5 and -13, serum IgE levels and eosinophilia, and prevented AHR.[182]

The ability of IL-25 antibodies to reduce Th2-mediated inflammation and to prevent AHR in animal models suggests that it may be a promising target in humans.


IL-33 is an IL-1-like, proinflammatory cytokine[183] released from necrotic cells. When cells subsequently undergo apoptosis, they cleave IL-33, and this appears to reduce its proinflammatory activity.[184] The receptor for IL-33, ST2, is an IL-1 receptor-related protein expressed on mast cells and, to a lesser extent, on macrophages, hematopoeic stem cells, NK T cells, eosinophils, basophils, nuocytes and fibroblasts.[185–187] There are two forms of ST2 with different functions. The first is membrane bound, expressed on hematopoietic tissues and lung, and it exerts proinflammatory effects via NF-κB and MAPK pathways. By contrast, the second is a soluble isoform that may act through reducing the Th2 response by functioning as a decoy receptor.[183,188]

IL-33 stimulates the development of IL-5-generating Th2 cells and acts as a chemoattractant for Th2 cells to lymph nodes and tissue.[189,190] In addition, IL-33 enhances dendritic cell maturation and activity, induces GM-CSF expression in the bone marrow and stimulates mast cell cytokine production.[191,192]

Intraperitoneal administration of IL-33 in mice led to enhanced Th2 activity and cytokine production, resulting in raised IgE levels and pulmonary eosinophilic inflammation.[183] In a murine model of allergic asthma, anti-T1/ST2 antibody treatment led to reduced AHR, reduced mucus production and reduced Th2 cytokine production and airway inflammation.[193]

In humans, in vitro studies have identified ST2 expression on eosinophils, while IL-33 appears to enhance eosinophil survival and stimulate eosinophil production of proinflammatory cytokines including CXCL8 and IL-6.[194] IL-33 has been detected in BAL fluid and is increased in asthma compared with healthy controls.[195]

The role of IL-33 in asthma focuses on its proinflammatory properties. An infective or environmental trigger causing epithelial cell necrosis results in increased IL-33 production, leading to a Th2 response. This is counteracted by ST2 secretion by fibroblasts, which may dampen down the immune response. In the event of a potent inflammatory trigger or a reduced ST2 effect, increased IL-5 and IL-13 production would result in eosinophilic recruitment to the lungs and a proinflammatory cycle. This may explain why the inhibition of cytokines such as IL-4 and IL-5 have not been that successful, and may also highlight the potential for targeting IL-33 as a therapeutic target in asthma.[188]

Other Interleukins

IL-11 is a pleiotropic cytokine produced by various cell types, including stromal cells, fibroblasts, endothelial cells and epithelial cells. The expression of IL-11 in the airways of asthmatics correlates with disease severity and may influence chronic airway remodeling.[196]

IL-15 is a Th1-related cytokine that regulates the activation and cytokine release of mast cells, NK cells, B cells and T cells.[197] IL-15 mRNA expression in bronchial biopsies is not raised in asthmatics compared with healthy controls,[198] and IL-15 polymorphisms have revealed an association with asthmatic children.[197] Rhinovirus-induced IL-15 production in alveolar macrophages was reduced in asthma compared with normal subjects, and BAL fluid levels of IL-15 were lower. IL-15 levels appeared to relate to AHR, lower respiratory symptom severity and virus load following rhinovirus infection in vivo,[199] suggesting that IL-15 may be a novel target for therapy or exacerbation prevention in asthma.

IL-16 is secreted by CD4+ T cells, eosinophils, mast cells and epithelial cells. Levels are higher in the sputum and serum of allergic asthmatics compared with healthy controls.[200] Expression in epithelial cells[201] and BAL fluid increased following antigen challenge in asthmatic humans and murine models of allergic asthma.[202] Intraperitoneal delivery of IL-16 antibodies suppressed IgE upregulation and reduced AHR in a murine model of allergic asthma.[203]

IL-18 influences the Th1/Th2 balance and is involved in allergic asthma through the induction of B-cell production of IgE, and also the production of IL-4 and IL-13. Levels in serum of asthmatic patients are raised compared with healthy controls,[204] and a meta-analysis has identified an IL-18 polymorphism that is associated with an increased risk of developing asthma.[205]

IL-19 is a proinflammatory cytokine produced by inflammatory cells such as activated macrophages and bronchial epithelial cells.[206] Its expression is increased in serum from asthmatic patients.[207]

IL-21 is a pleiotropic cytokine expressed by activated CD4+ T cells that regulates the growth, differentiation and function of B cells, T cells and NK cells. It induces Th17 cell differentiation, can downregulate IgE production from IL-4 stimulated B cells, and the IL-21 gene has been associated with atopic asthma.[208] In a mouse model of asthma, intranasal administration of IL-21 significantly reduced the number of sneezes, serum IgE and reduced local expression of IL-4, IL-5 and IL-13.[209] Furthermore, IL-21 inhibited nasal fibroblast production of eotaxin, suggesting a role in the attenuation of eosinophil infiltration. By contrast, IL-21R-deficient mice exhibited reduced AHR despite increased IgE levels, suggesting that IL-21 may play different roles depending on the immune setting and in combination with different cytokines, or may potentially act via different receptors.[210]

IL-23, a member of the IL-12 family, plays an important role in the maintenance of Th17 cells and enhances both neutrophil and eosinophil recruitment in the airways.[211]

IL-27 is produced by activated monocytes, dendritic cells and macrophages following exposure to microbial pathogens,[212] and IL-27 SNPs have been linked to an increased susceptibility to asthma.[213] In mice, neutralization of IL-27 completely inhibited IFN-γ/lipopolysaccharide-induced AHR, while IL-27/IFN-γ-mediated AHR was resistant to dexamethasone therapy. This suggests that IL-27 plays an important role in the regulation of steroid-resistant AHR.[214] In humans, IL-27 levels in sputum appear to correlate to neutrophilic asthma[214] and may be a potential therapeutic avenue for this phenotype.

IL-28 and IL-29 are a new family of cytokines that are also called λ-interferons or type III interferons.[215] IL-28 is produced by antigen-presenting cells following viral infection or Toll-like receptor ligation, and the receptor, IL-28Rα, is found on bronchial epithelial cells, dendritic cells and macrophages. IL-28Rα−/− mice develop marked allergic airway inflammation with increased eosinophilic and neutrophilic infiltration, while wild-type mice treated with IL-28 exhibit significant reductions in Th2 and Th17 responses.[215] IL-29 appears to play an important role in host defense against viral infections, may be the main interferon protein secreted by alveolar type II epithelial cells in response to influenza A infection,[216] and plays a role in the severity of rhinovirus infection, the major cause of asthma exacerbations.[217]

IL-31 is raised in the serum of asthmatics,[218] and its receptor is upregulated in a murine model of asthma, while IL-31RA-knockout mice demonstrate an exacerbated pulmonary inflammatory response.[219]

IL-32 does not currently belong to a group of cytokines, is proinflammatory and its receptor is yet to be described. It has been detected in sputum, and serum levels predict a positive treatment response in asthmatic patients. IL-32 may play a role in the suppression of angiogenesis in asthmatic patients, potentially preventing irreversible airway remodeling.[220]

IL-35 is a newly identified anti-inflammatory/immunosuppressive cytokine that inhibits important Th2-mediated inflammation in allergic asthma and suppresses allergen-specific and total IgE production in mice.[221]