New insights into the role of cytokines in asthma

Abstract

Asthma is a triad of intermittent airway obstruction, bronchial smooth muscle cell hyperreactivity to bronchoconstrictors, and chronic bronchial inflammation. From an aetiological standpoint, asthma is a heterogeneous disease, but often appears as a form of immediate hypersensitivity. Many patients with asthma have other manifestations of atopy, such as rhinitis or eczema. Even among non-atopic patients with asthma, the pathophysiology of airway constriction is similar, raising the hypothesis that alternative mechanisms of mast cell degranulation may underlie the disease. The primary inflammatory lesion of asthma consists of accumulation of CD4(+) T helper type 2 (TH2) lymphocytes and eosinophils in the airway mucosa. TH2 cells orchestrate the asthmatic inflammation through the secretion of a series of cytokines, particularly interleukin 4 (IL-4), IL-13, IL-5, and IL-9. IL-4 is the major factor regulating IgE production by B cells, and is required for optimal TH2 differentiation. However, blocking IL-4 is not sufficient to inhibit the development of asthma in experimental models. In contrast, inhibition of IL-13, another TH2 cytokine whose signal transduction pathway overlaps with that of IL-4, completely blocks airway hyperreactivity in mouse asthma models. IL-5 is a key factor for eosinophilia and could therefore be responsible for some of the tissue damage seen in chronic asthma. IL-9 has pleiotropic activities on allergic mediators such as mast cells, eosinophils, B cells and epithelial cells, and might be a good target for therapeutic interventions. Finally, chemokines, which can be produced by many cell types from inflamed lungs, play a major role in recruiting the mediators of asthmatic inflammation. Genetic studies have demonstrated that multiple genes are involved in asthma. Several genome wide screens point to chromosome 5q31--33 as a major susceptibility locus for asthma and high IgE values. This region includes a cluster of cytokine genes, and genes encoding IL-3, IL-4, IL-5, IL-9, IL-13, granulocyte macrophage colony stimulating factor, and the beta chain of IL-12. Interestingly, for some of these cytokines, a linkage was also established between asthma and their receptor. Another susceptibility locus has been mapped on chromosome 12 in a region that contains other potential candidate cytokine genes, including the gene encoding interferon gamma, the prototypical TH1 cytokine with inhibitory activities for TH2 lymphocytes. Taken together, both experimental and genetic studies point to TH2 cytokines, such as IL-4, IL-13, IL-5, and IL-9, as important targets for therapeutic applications in patients with asthma.

Figure 1 Pleiotropic activities of T helper type 2 (TH2)-type cytokines in allergic asthma. Upon recognition of the antigen and activation by antigen presenting cells (APC), naive T cells differentiate into TH2 cells, a process that is promoted by interleukin 4 (IL-4). Activated TH2 cells stimulate B cells to produce IgE antibodies in response to IL-4, and to a lower extend to IL-13 or IL-9. IgE binds the high affinity IgE receptor at the surface of mast cells, the proliferation and differentiation of which is promoted by IL-9, in synergy with other factors such as fibroblast derived mast cell growth factor. At contact with antigen, mast cells release the contents of their granules, including histamine, which will induce a bronchospasm, together with newly synthesised prostaglandins and leukotrienes (PGD₂ and LTC₄). Mast cells also release chemotactic factors that contribute to the recruitment of inflammatory cells, particularly eosinophils, whose proliferation and differentiation from bone marrow progenitors is promoted by IL-5 and IL-9. Finally, epithelial cells upregulate their production of mucus and chemokines in responses to TH2 cytokines such as Il-4, IL-13, and IL-9. The presence of the IL-13 receptor at the surface of smooth muscle cells suggests that this factor can also directly affect smooth muscle contractility, but this remains to be demonstrated.

Figure 2 Signal transduction pathway and polymorphisms of the interleukin 4 (IL-4)/IL-13 receptors. IL-4 can bind to two distinct receptor complexes. On T cells, the IL-4 receptor (IL-4R) consists of γC, a transmembrane protein also shared by the IL-2, IL-7, IL-9, and IL-15 receptors, and IL-4Rα. On other cell types such as B cells, the IL-4R consists of IL-4Rα associated with IL-13Rα1. Tyrosine kinases JAK1 (Janus kinase 1), JAK3, and TYK2 are associated with the membrane proximal domain of these receptors as indicated in the figure. The thin and bold lines on the extracellular domain of IL-4Rα correspond to the four cystein residues and the WSXWS motif, respectively, which are the hallmarks of the haematopoietic receptor superfamily. Signal transduction through IL-4Rα involves activation of insulin receptor substrate 1/2 (IRS1/2) and signal transducer and activator of transcription 6 (STAT6), which lead to cell proliferation and gene activation, respectively. Crucial tyrosines of the intracytoplasmic domain of IL-4Rα are indicated. Genes activated by STAT6 include IgE, MHC II, and CD23. The two main IL-4Rα polymorphisms for which functional studies have suggested a biological relevance are indicated (I50V and G576R). IL-13 binds only to the second type of IL-4 receptor but is thought to activate the same downstream pathway. In addition, IL-13 binds to a distinct receptor, IL-13Rα2, which might be defective for signal transduction and act as a decoy receptor.