Th2 cytokines and asthma: an introduction
Respiratory Research volume 2, Article number: 64 (2001)
Asthma is a highly complex disease that is still poorly understood and whose cause remains unknown. One of the striking advances in the last decade has been the recognition that cytokines play a critical role in orchestrating, perpetuating and amplifying the inflammatory response in asthma. Indeed the increased and abnormal expression of cytokines in airway cells is one of the major targets of corticosteroid therapy, by far the most effective controller treatment for asthma currently available. Many cytokines and chemokines are involved in the pathophysiology of asthma [1,2]. While some of these cytokines, such as interleukin (IL)-1, tumour necrosis factor-α and IL-6, are involved in many inflammatory diseases, including chronic obstructive pulmonary disease, rheumatoid arthritis and inflammatory bowel disease, others are more specific to allergic inflammation. These cytokines, IL-4, IL-5, IL-9 and IL-13, are derived from T helper type 2 (Th2) cells, although they may also derive from other cell types. Th2 cells are recognised by their secretion of IL-4, IL-5, IL-9 and IL-13, as opposed to Th1 cells, which secrete IL-2 and interferon-γ, although the clear distinction between Th1 and Th2 cells is not as distinct in humans as in mice. Th2 cytokines may play an important role in the pathophysiology of allergic diseases, including asthma. They may be useful therapeutic targets in the future management of allergic diseases, and several approaches to inhibiting these cytokines are now being tested in clinical trials or are in active development .
In this issue of Respiratory Research we focus on Th2 cytokines and their potential role in allergic diseases, such as asthma. John Steinke and Larry Borish  discuss the role of IL-4 in the pathogenesis of asthma and make the point that this is an upstream cytokine that regulates allergic inflammation by promoting Th2 cell differentiation and IgE synthesis. Early studies with an IL-4 antagonist, soluble recombinant IL-4 receptor (altrakincept), show therapeutic benefit as a steroid-replacing agent in moderately severe asthma  and longer term clinical trials are now underway. IL-5 is discussed by Scott Greenfeder and colleagues . IL-5 is a cytokine that is highly specific for eosinophilic inflammation and antibodies that block IL-5 actions are effective in reducing eosinophilic inflammation and airway hyperresponsiveness (AHR) in various species. Recently, studies of a humanised anti-IL-5 monoclonal antibody (mepomizulab) in asthmatic patients have confirmed its extraordinary efficacy in reducing eosinophils in the circulation and the airways, but surprisingly no reduction in response to allergen or in AHR . This result has been confirmed in a preliminary clinical trial of asthmatic patients whose symptoms were not controlled with inhaled corticosteroids and who showed no clinical improvement with anti-IL-5 antibody, despite a marked suppression of circulating eosinophils . These studies confirm the importance of IL-5 in eosinophilic inflammation in man, but question the role of eosinophils in asthma. IL-13 has many actions similar to those of IL-4 and also regulates IgE production but, unlike IL-4, it does not regulate T cell differentiation to Th2 cells and T lymphocytes do not respond to IL-13. The role of IL-13 in asthma was recently reviewed in this journal by Marsha Wills-Carp . IL-9 has been less intensively investigated than the other Th2 cytokines, but appears to amplify Th2-cell-mediated responses, as reviewed by Roy Levitt and colleagues in this issue . They make a persuasive case for this cytokine as a target for inhibition in asthma.
The reason why Th2 cells should be more prominent in allergic diseases such as asthma is still unknown but the hygiene hypothesis is a persuasive theory, suggesting that lack of infection and exposure to endotoxins in dirt may alter the balance between Th1 and Th2 cells. This hypothesis now has increasing support from experimental animals and from epidemiological studies, as will be discussed by Fernando Martinez in the next issue of Respiratory Research. This has important therapeutic implications and suggests that stimulating Th1 cells might suppress Th2 cells and allergic inflammation. Genetic polymorphisms may be one of the factors predisposing to the imbalance between Th1 and Th2 cells, including single nucleotide polymorphisms (SNPs) of the endotoxin receptor CD14. SNPs and predisposition to asthma are also discussed in this issue of Respiratory Research by Lyle Palmer and Bill Cookson , and several SNPs of the genes encoding Th2 cytokines (which are situated together in a cluster on chromosome 5q) and their receptors have now been associated with increased risk of atopy and asthma.
We live in exciting times, when the availability of new molecular and genetic techniques is beginning to elucidate some of the complexities of asthma. It is likely that this will lead to even more effective and specific therapies in the future that may be targeted to individual patients. The prospect of a cure for asthma is coming closer.
Barnes PJ, Chung KF, Page CP: Inflammatory mediators of asthma: an update. Pharmacol Rev. 1998, 50: 515-596.
Chung KF, Barnes PJ: Cytokines in asthma. Thorax. 1999, 54: 825-857.
Barnes PJ: Novel approaches and targets for treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1999, 160: S72-S79.
Steinke JW, Borish L: Th2 cytokines and asthma - Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respiratory Research. 2001, 2: 66-70. 10.1186/rr40.
Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, Garrison L: Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized, placebo-controlled trial. Am J Respir Crit Care Med. 1999, 160: 1816-1823.
Greenfeder S, Umland SP, Cuss FM, Chapman RW, Egan RW: Th2 cytokines and asthma - The role of interleukin-5 in allergic eosinophilic disease. Respiratory Research. 2001, 2: 71-79. 10.1186/rr41.
Leckie MJ, ten Brincke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, Mathur M, Cowley H, Chung KF, Djukanovic RJ, Hansel TT, Holgate ST, Sterk PJ, Barnes PJ: Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyperresponsiveness and the late asthmatic response. Lancet. 2000, 356: 2144-2148. 10.1016/S0140-6736(00)03496-6.
Kips JC, O'Connor BJ, Langley SJ, Woodcock A, Kerstjens HAM, Postma DS, Danzig M, Cuss F, Pauwels RA: Results of a phase I trial with SCH5 a humanized anti-IL-5 antibody in severe persistent asthma [abstract]. Am J Resp Crit Care Med. 5700, 161: A505-
Wills-Karp M: The gene encoding interleukin-13: a susceptibility locus for asthma and related traits. Respiratory Research. 2000, 1: 19-23. 10.1186/rr7.
Zhou Y, McLane M, Levitt RC: Th2 cytokines and asthma - Interleukin-9 as a therapeutic target for asthma. Respiratory Research. 2001, 2: 80-84. 10.1186/rr42.
Palmer LJ, Cookson WOCM: Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma. Respiratory Research. 2001, 2: 102-112. 10.1186/rr45.
About this article
Cite this article
Barnes, P.J. Th2 cytokines and asthma: an introduction. Respir Res 2, 64 (2001). https://doi.org/10.1186/rr39