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The Role of Cytokines in the Inflammatory Process of Asthma and Response to Therapy

Posted: 2008

Robert G. Townley, M.D.
Professor, Medicine, Medical Microbiology and Immunology
Creighton University
601 N. 30 Street, Suite 3M-100
Omaha, NE 68131
402-280-1839 (phone)
402-280-4115 (fax)

The Contribution of Inflammatory Processes to the Characteristics of Asthma


Asthma is a complex disease involving many different inflammatory cells, cytokines and chemokines that result in structural changes, remodeling and ultimately in the signs and symptoms of asthma. The purpose of this synopsis is to focus on the inflammatory processes contributing to the pathogenesis of asthma, and on the role of corticosteroids on inflammation, remodeling and their effect on profibrotic cytokines and vascular endothelial growth factor (VEGF) in severe asthma. The effect of antigen challenge on the production of proinflammatory cytokines and subsequent reduction in the bronchodilating effect of beta-adrenergic agents is reviewed. (1,2,3) The effect of cytokines, corticosteroids and thermoplasty on airway smooth muscle and the immunological and clinical changes following treatment with omalizumab will be discussed.

The fact that IL-13 causes airway hyperresponsiveness and decreased responsiveness to beta-adrenergic agonists and corticosteroids emphasizes the importance of the development of IL-13 antagonists for asthma therapy. (1,2,4)

Asthma is characterized by bronchoconstriction, bronchial hyperresponsiveness, a decreased response to ß-adrenergic agents and inflammation. The inflammation is marked by pulmonary airway eosinophilia, increased exhaled nitric oxide, and the expression of specific T-cell cytokines including interleukin-4 (IL-4), IL-5, IL-9 and IL-13. (5) Sputum from patients with asthma is characterized by tight spirals of mucus that originate from the small bronchioles and by small mucus plugs that are typical of bronchopulmonary aspergillosis. Bronchial obstruction and bronchoconstriction leads to dyspnea, wheezing and chest cough. In addition to chronic inflammation, asthma is characterized by structural alterations in the airways that together are called airway remodeling. Airway remodeling in the large and small airways includes subepithelial thickening, epithelial denudation with goblet cell metaplasia, increased airway smooth muscle mass, bronchial gland enlargement, angiogenesis and alterations in the extracellular matrix components (5). This remodeling is thought to be initiated by inflammation of the airways. (6)

Complex interactions between airway inflammation, structural changes and airway hyperresponsiveness occur in mice sensitized by chronic exposure to allergens. Patients who exhibit persistent airway hyperresponsiveness with fixed airflow limitation may have significant airway narrowing despite maximal therapy; components of airway remodeling are likely to contribute to airway hyperresponsiveness, airflow limitation, and airway narrowing. (5,6)

The Effect of Corticosteroids on Inflammation and Airway Remodeling

Corticosteroids have been the most extensively evaluated asthma therapy. Epithelial denudation increases the exposure of mucosal nerve endings, enhances the penetration of allergens and reduces mucocilliary clearance. Biopsy studies have demonstrated that corticosteroids partially restore the epithelial lining of the mucosa. (7)

Goblet cell metaplasia and mucus hypersecretion are also characteristic features of asthma, and corticosteroids are effective in reducing goblet cell metaplasia in animal models. Studies of basement membrane components and thickness have been difficult to interpret, and the consequences of basement membrane remodeling in asthma remain controversial. (5,6) Some investigators have shown that the thickness of the collagen is related to airway obstruction and airway responsiveness. Others have argued that these findings are of little consequence. However, fibrosis of airway smooth muscle is more likely to have functional consequences. (6)

The lamina propria may be thickened in asthma, and inhaled corticosteroids are effective in preventing and reversing the enhanced fibronectin deposition that occurs during repeated exposure to allergen. However, treatment with inhaled steroids at low doses or after allergen exposure does not affect fibronectin deposition and suggests that the dose of inhaled corticosteroids may be critical. (5)

Treatment of patients with asthma with inhaled corticosteroids for ten years markedly decreased inflammation. It is interesting however, that this reduced inflammation was not always associated with improvement of bronchial hyperresponsiveness. In a prospective study, three months of therapy with budesonide, a corticosteroid, increased the number of ciliated cells thereby increasing mucosal clearance more than bronchodilator treatment alone in patients with asthma. (5,7,8)

Effect of Corticosteroids on Profibrotic Cytokines and VEGF in Severe Asthma

Patients with moderate and severe asthma have increased amounts of the profibrotic cytokines IL-11, IL-17 and transforming growth factor beta (TGF-ß) when compared to healthy controls and patients with mild asthma. Treatment with two weeks of oral corticosteroids decreases the amounts of IL-11 and IL-17, but not of TGF-ß or collagen. (5) Treatment with corticosteroids affects the extracellular matrix components in asthma, but it is unclear whether this has functional relevance.

Morphometric studies of bronchi have shown that patients with asthma have more blood vessels in both the large and small airways than patients without asthma.(5) This increase in the number of blood vessels is associated with increased microvascular permeability. Inhaled corticosteroids decrease airway vascularity in patients with asthma, which is associated with a decrease in basement membrane thickness, improvement in forced expiratory volume in one second (FEV1), and airway responsiveness. (7) Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis, and corticosteroids inhibit angiogenesis in part by regulating VEGF. (5,8) Beclomethasone 800 mcg/day decreases the levels of VEGF in induced sputum in asthma and is associated with a decrease of airway narrowing and vascular permeability. It appears that high doses of corticosteroids are necessary to reduce structural changes in airway vessels that are accompanied by decreases in VEGF expression. Fluticasone 700 mcg twice daily reduces the number of VEGF-positive vessels and VEGF receptors and decreases the concentration of angiopoietin 1. (5,8)

Combining salmeterol, a ß2- agonist, with low-dose inhaled steroids decreases vessel density in patients with asthma, and ß2- agonists inhibit plasma exudation and vascular permeability. Results from a mouse model suggest that leukotriene receptor antagonists may decrease vascular permeability and VEGF levels. (7) Two weeks of daily treatment with 400 mcg fluticasone, a corticosteroid, was effective in reducing mucosal blood flow in patients with asthma. (5,7)

Effect of Antigen Challenge and Proinflammatory Cytokines on Beta-Adrenergic Receptor Function

Antigen challenge decreases the adenylate cyclase response and cyclic AMP levels in the T- lymphocytes of asthmatic patients. Antigen challenge in the sensitized guinea pig model decreases ß-adrenergic receptor-mediated relaxation in airway smooth muscle. This was attributed to the proinflammatory cytokines tumor necrosis factor alpha (TNF-α) and IL-1ß, which were also able to significantly reduce the responsiveness to isoproterenol. However, in these studies the contractile response of the trachea to carbachol was not increased (1,2,3). The in vitro response of trachea and airway smooth muscle to muscarinic agonist, such as acetylcholine, methacholine or carbachol, does not correlate with the in vivo airway hyperresponsiveness to methacholine as seen in patients with asthma, however the postulated mechanisms for this difference are controversial. Interestingly, decreased ß-adrenergic bronchodilator activity and associated hypersensitivity to mediators were theorized as potential pathophysiologic mechanisms several decades before the role of cytokines in asthma was known. (9)

In an in vivo mouse model, treatment of nonsensitized mice with a combination of IL-1 and TNF-α significantly impaired the ability of ß2 agonists to prevent bronchial hyperresponsiveness (3). These results demonstrate that the proinflammatory cytokines, IL-1ß and TNF-α, attenuate bronchodilator responses to ß2 agonists by decreasing cyclic AMP production. Although TNF-α, IL-1ß and IL-13 are increased in the bronchi of asthmatic patients, the interrelationship of the effects of these cytokines is not clear. (2) IL-13 inhibits inflammation and the production of IL-1ß and TNF-α from monocytes and alveolar macrophages (1,3).

Airway Smooth Muscle Proliferation and Airway Hyperresponsiveness: Role of Cytokines, Corticosteroids and Thermoplasty

Increased airway smooth muscle due to hyperplasia and hypertrophy is presumed to be a major determinant of enhanced bronchoconstriction and airway hyperresponsiveness (AHR), (5,6) although the increase in proliferation of airway smooth muscle has not been confirmed in humans in vivo. Contractile agonists, cytokines, growth factors and extracellular matrix proteins can all contribute to airway smooth muscle proliferation. (5) Corticosteroids can exert a direct effect on airway smooth muscle cells in addition to modulating the secretion of chemokines and cytokines involved in airway smooth muscle proliferation. (7) In vitro studies demonstrate that corticosteroids arrest human airway smooth muscle cells in the G-1 phase of the cell cycle and inhibit some of the proliferation of airway smooth muscle cells induced by growth factors. There is some evidence that a combination of inhaled corticosteroids and ß2-adrenoceptor agonists is more efficacious than glucocorticoids alone in controlling remodeling events; (5) however, there are no longitudinal studies evaluating the effect of pharmacologic treatment on the structure of airway smooth muscle in asthma.

Thermoplasty, which involves ablation of the airway smooth muscle, has been proposed as a treatment for asthma. Some evidence has indicated that bronchial thermoplasty reduces airway smooth muscle and increases airway compliance. The first (uncontrolled) study suggested that thermoplasty led to improvements in FEV1 and airway hyperresponsiveness. (5) Recently, the results of a controlled, randomized trial in patients with moderate to severe asthma indicated that thermoplasty reduces the number of mild exacerbations and improves morning expiratory peak flow and symptom scores, but has no effect on FEV1 and airway hyperresponsiveness after one year of follow-up. (5)

Tumor necrosis factor α (TNF-α) and other inflammatory mediators of asthma are upregulated in patients with refractory asthma. This is the basis for treatment with anti-TNF-α antibodies. In two studies, etanercept, an anti-TNF-α antibody, decreased asthma symptoms and bronchial hyperresponsiveness and increased lung function. (10,11) Infliximab, which binds to and neutralizes TNF-α, decreases the number of moderate exacerbations and sputum cytokine levels, but does not affect lung function parameters. IL-4 and IL-5 antagonists, which may decrease markers of inflammation, have not been proven to improve airway hyperreactivity.

IL-13 may be a more attractive target than TNF-α with regard to airway remodeling because it is present in the bronchial mucosa and sputum of asthmatics and is thought to have profibrotic activity. (1) IL-13-transgenic mice have markedly increased fibrosis, eosinophilia, airway hyperresponsiveness and goblet cell mucus production. (12) IL-13 knockout mice have reduced airway collagen, goblet cell metaplasia and mucus staining. Therefore, IL-13 is a reasonable target for preventing airway remodeling.

Both IL-13 and the proinflammatory cytokines IL-1ß and TNF-α have been found in airway smooth muscle and are increased in the airway lining fluid of subjects with asthma. These cytokines decrease the relaxation response to ß-adrenergic agonists in airway smooth muscle. (1,3) However, IL-13 is both necessary and sufficient to produce the characteristics of asthma (1) and is a central mediator of allergic asthma. IL-13 elicits decreased adrenergic bronchodilator activity and associated hypersensitivity to mediators (9), thus supporting its role in the pathogenesis of asthma (2).

Immunological and Clinical Changes in Allergic Asthmatics Following Treatment with Omalizumab

Cytokines, including IL-13, also appear to contribute to allergic asthma. The anti-IgE antibody omalizumab reduces exacerbations and the requirement for steroids in allergic asthmatics. (13,14) This therapeutic effect of omalizumab can be at least partially attributed to the anti-inflammatory effect of decreasing IgE levels. Noga and colleagues examined whether treatment with omalizumab for 16 weeks leads to changes in inflammatory mediators and clinical symptoms in patients with moderate to severe allergic asthma. (15) They observed that omalizumab significantly decreased ß2-agonist use and wheal reactions to skin-prick tests. They also measured circulating levels of IL-5, IL-6, IL-8, IL-10, IL-13 and s-ICAM before and after 16 weeks of treatment with omallizumab. IL-13 decreased significantly in the omalizumab group compared to the placebo group, and IL-5 and IL-8 decreased in the omalizumab group compared to baseline. The levels of other circulating cytokines did not change. The release of histamine from blood basophils and the peripheral blood eosinophil count both decreased significantly. Because omalizumab binds free circulating IgE and prevents the interaction between IgE and its receptors on inflammatory cells (13), these studies point to IgE as a key mediator of allergic reactions in the upper and lower airways. (14)

IL-13: A Cause of AHR in Asthma and Decreased Response to ß-adrenergic Agonists

IL-13 induces AHR, IgE production, eosinophilia and goblet cell mucus production in the airways of mice. IL-13 produces AHR through its effect on the IL-4 receptor α chain and STAT-6, independently of IL-5 and eotaxin (1), and the blockade of IL-13 decreases the characteristic features of asthma in a mouse model of allergen sensitization and challenge(1). A single administration of exogenous IL-13Rα2 can inhibit the AHR induced by IL-13 by reducing the amount available to endogenous receptors (2,3). The use of IL-13R-α2 decoy receptors and an IL-13 mutant (IL-13E13K) are therefore potential approaches to the treatment of asthma (2). Ongoing clinical trials in patients with asthma include several IL-13 receptor antagonists as well as IL-13 monoclonal antibodies. Wenzel and colleagues reported that a monoclonal antibody that blocks the binding of IL-4 and IL-13 to IL-4 receptor complexes significantly inhibited the early and late reactions to allergen challenge in subjects with asthma (16).

The development of allergen-induced airway hyperreactivity, the decreased response to ß-adrenergic agonists and the ability of IL-13 R-α2 to block this effect in mouse airway smooth muscle all support a critical role for IL-13 in asthma (1,2). In IL-13 knockout mice, ongoing challenge with allergen does not elicit AHR and airway mucus changes. Administration of recombinant IL-13 results in airway hyperresponsiveness and goblet cell mucus changes. (1, 17) .The initiation of TH2 immune responses to allergen is induced by IL-4; the main characteristics of asthma, such as AHR, airway fibrosis and mucus hypersecretion, are induced by IL-13 alone (1). IL-13 switches on the production of IgE and increases eosinophilic inflammation and mucus cell hyperplasia even in naïve, nonimmunized mice (1). In this regard, IL-13 is both necessary and sufficient to produce both characteristics of asthma (1). In addition, IL-13 markedly decreases the relaxation of mouse trachea in response to ß-agonists in vitro and also markedly diminishes the protective effect of albuterol in vivo against methacholine-induced bronchoconstriction (2).

IL-13 has many diverse effects on a variety of cell types that are involved in the pathogenesis of allergic disorders (see table Functions of IL-13 on Inflammatory cells in Asthma). IL-13 induces VCAM-1 and enhances proliferation and cholinergic-induced contraction of airway smooth muscle cells in vitro.(1) IL-13 also increases collagen deposition and fibrosis. Furthermore it increases the expression of chemokines, including eotaxin and CCR5. (12) It is also a potent stimulator of matrix metalloproteinases in the lung. The expression of IL-13 (12) in transgenic mice results in emphysematous changes and mucus metaplasia. It therefore appears that IL-13 is an important molecule, not only in asthma, but also in chronic obstructive pulmonary disease phenotypes. (12)

IL-13 and Corticosteroid-Resistant Asthma

It was reported that the effect of fluticasone and/or ß-agonists on airway hyperresponsiveness in mice is markedly diminished through treatment with IL-13 (2, 4,18), both in vivo and in vitro. IL-13 also suppresses the airway response to glucocorticoids. During the preparation of this manuscript, another paper supporting the "finding" that IL-13 induces airway inflammation and a corticosteroid resistant model of severe asthma has been published. (19) Glucocorticoids remain the most effective therapy for asthma, primarily through their suppression of airway inflammation, but glucocorticoids do not affect airway hyperresponsiveness or the expression of goblet cell hyperplasia induced by IL-13. Corticosteroids inhibit IL-13 production by mast cells and peripheral blood mononuclear cells (i.e., TH2 cells) but have little or no effect on IL-13 once it is released. When IL-13 was administered to nonsensitized mice, administration of fluticasone by inhalation did not protect against methacholine bronchial challenges. In contrast, fluticasone and other corticosteroids were effective in protecting against AHR in ovalbumin-sensitized mice (2,4, 18,19).

Table. Functions of Interleukin-13 (IL-13) on Inflammatory Cells in Asthma

Target Tissues/cells Effects of IL-13
Respiratory epithelium Increases chemokine expression, mucus hypersecretion, and goblet cell metaplasia
Airway smooth muscle Increases smooth muscle proliferation
Increases sensitivity to bronchoconstrictor agents
B-lymphocyte Induces immunoglobulin (Ig)E production
  • In macrophages, increases low-affinity IgE receptors
  • In mast cells, modulates the high-affinity IgE receptor and IgE priming
Upregulates the IgE receptor
Eosinophils Recruits and activates
Increases the numbers of eosinophils
Vascular endothelium Induces the expression of vascular cell adhesion molecules
Increases chemokine expression, e.g. CCR5
Fibroblasts Increases collagen and fibrosis remodeling in airways? E.g. via TGF-ß

Other mechanisms by which IL-13 induces the features of asthma have been summarized by Wills-Karp (1), including signaling through the adenosine, acidic mammalian chitinase, leukotriene and arginase signaling cascades (1). During the pathogenesis of asthma (3), IL-13 can elicit the loss of adrenergic bronchodilator activity associated with hypersensitivity to mediators, as put forth by Szentivanyi 40 years ago. (9,2) IL-13 thus affects a variety of genes in the cells of the airways, including smooth muscle cells, epithelial and endothelial cells, goblet cells, fibroblasts and monocytes, macrophages, B-cells, basophils and mast cells and eosinophils. The role of the chemokine CCR5 in the pathogenesis of IL-13 -induced inflammation and remodeling has been reported.(12) (See figure)


The pathogenesis of asthma involves inflammatory processes that result in structural airway changes and remodeling. The effect of the proinflammatory cytokines TNF-α and IL-1ß and especially IL-13 reduce the effect of endogenous and exogenous bronchodilators. The striking effect of IL-13 on rapidly inducing AHR and suppressing of the effect of corticosteroids emphasizes the importance of clinical trials of IL-13 or IL-13 receptors antagonists in asthma that are currently underway.


  1. Wills-Karp M.: "Interleukin-13 in Asthma Pathogenesis". Immunol Rev 2004;202:175- 190.
  2. Townley R.: "IL-13 and ?-adrenergic Blockade Theory of Asthma Revisited 40 Years Later". Ann Allergy Asthma Immunol 2007; 99 (3):215-224.
  3. Townley RG, Horiba M. "Airway Hyperresponsiveness: Story of Mice and Men and Cytokines". Clin Rev Allergy Immunol 2003;24 (1):85-110.
  4. Townley R G, Gendapodi P, Romero FA "Effect of Fluticasone and/or ?-agonists on Airway Hyperresponsiveness (AHR) in Mice Either Sensitized to Allergen or Pre-Treated with IL-13". J Allergy Clin Immunol 2007;119:S295. (abstract)
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  9. Szentivanyi A: ‚ The ß-adrenergic theory of the atopic abnormality in bonchial asthma. J Allergy 1968;42:203-233.
  10. Erin E, Leaker BR, Nicholson GC, Tan AJ, Green, LM , Neighbour H, Zacharasiewicz AS, Turner J, Barnathan ES, Kon OM, Barnes PJ,Hansel TH.: The Effects of a Monoclonal Antibody Directed against Tumor Necrosis Factor- in Asthma Am. J. Respir. Crit. Care Med. 2006; 174: 753-762.
  11. Berry MA, et al: Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006; 354(7):697-708.
  12. Ma B, Liu W, Homer RJ, Lee PJ, Coyle AJ, Lora JM, Lee CG, Elias JA. Role of CCR5 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling. J Immunol 2006 176: 4968-4978.
  13. Soler M, Matz J, Townley R, Buhl R, O'Brien J, Fox H et al. The anti-IgE antibody Omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J 2001; 18(2): 254-61.
  14. Stokes J, Casale TB. Rationale for new treatments aimed at IgE immunomodulation.
  15. Ann Allergy Asthma Immunol. 2004 Sep;93(3):212-7; quiz 217-9, 271.
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  17. Wenzel S, Wilbraham D, Fuller R, Getz, EB, Longphre M: "Effect of an Interleukin-4 Variant on Late Phase Asthmatic Response to Allergen Challenge in Asthmatic Patients: Results of Two Phase II Studies". Lancet, 2007;370(9596):1396-8.
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  19. Townley RG, Gendapodi PR, Romero FA, Qutna N, Abel P.: IL-13 Induces Bronchial Hyperresponsiveness and Decreases the Bronchoprotective Effect of Beta-Adrenergic Bronchodilators and Corticosteroids. Ann allergy Asthma & Immunol (in press)
  20. Therien AG, Bernier V, Weicker S, Tawa P, Falgueyret JP, Mathieu MC, Honsberger J, Pomerleau V, Robichaud A, Stocco R, Dufresne L, Houshyar H, Lafleur J, Ramachandran C, O'Neill GP, Slipetz D, Tan CM. Adenovirus IL-13-induced airway disease in mice: a corticosteroid-resistant model of severe asthma. Am J Respir Cell Mol Biol. 2008 Jul; 39(1):26-35.

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