New insights into the role of cytokines in asthma

Asthma is a triad of intermittent airway obstruction, bronchial smooth musc le cell hyperreactivity to bronchoconstrictors, and chronic bronchial infla mmation. From an aetiological standpoint, asthma is a heterogenous disease, but often appears as a form of immediate hypersensitivity. Many patients w ith asthma have other manifestations of atopy, such as rhinitis or eczema. Even among nonatopic patients with asthma, the pathophysiology of airway co nstriction is similar, raising the hypothesis that alternative mechanisms o f mast cell degranulation may underlie the disease. The primary inflammator y lesion of asthma consists of accumulation of CD4(+) T helper type 2 (TH2) lymphocytes and eosinophils in the airway mucosa. TH2 cells orchestrate th e asthmatic inflammation through the secretion of a series of cytokines, pa rticularly interleukin 4 (IL-4), IL-13, IL-5, and IL-9. IL-4 is the major f actor regulating IgE production by B cells, and is required for optimal TH2 differentiation. However, blocking IL-4 is not sufficient to inhibit the d evelopment of asthma in experimental models. In contrast, inhibition of IL- 13, another TH2 cytokine whose signal transduction pathway overlaps with th at 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 a nd epithelial cells, and might be a good target for therapeutic interventio ns. Finally, chemokines, which can be produced by many cell types from infl amed lungs, play a major role in recruiting the mediators of asthmatic infl ammation. Genetic studies have demonstrated that multiple genes are involve d in asthma. Several genome wide screens point to chromosome 5q31-33 as a m ajor susceptibility locus for asthma and high IgE values. This region inclu des 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 chai n 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, th e prototypical TH1 cytokine with inhibitory activities for TH2 lymphocytes. Taken together, both experimental and genetic studies point to TH2 cytokin es, such as IL-4, IL-13, IL-5, and IL-9, as important targets for therapeut ic applications in patients with asthma.