The emerging role of the IL-4/IL-3 cytokine receptor IL-4Ralpha in asthma
Summary
Analysts have recently predicted that the market for airway inflammatory diseases will increase by 35% to over $18 billion by 2011. A recent target evaluation report produced for the drug development sector concluded that the TH2-derived cytokines IL-4, and more so IL-13 represent promising targets. Both cytokines activate IL-4Ralpha to produce multiple functional changes observed in asthma patients. A recent report published in the Journal of Immunology elucidates the divergent mechanisms thThe emerging role of the IL-4/IL-3 cytokine receptor IL-4Ralpha in asthma
DailyUpdates 9th July: Analysts have recently predicted that the market for airway inflammatory diseases will increase by 35% to over $18 billion by 2011. A recent target evaluation report produced for the drug development sector concluded that the TH2-derived cytokines IL-4, and more so IL-13 represent promising targets. Both cytokines activate IL-4Ralpha to produce multiple functional changes observed in asthma patients. A recent report published in the Journal of Immunology elucidates the divergent mechanisms through which IL-4Ralpha activation may modulate airway inflammation and mucus hypersecretion
Analysts have recently predicted that the market for airway inflammatory diseases will increase by 35% to over $18 billion by 2011. This growth will be driven, in part, by the increased incidence of asthma over recent years. The lack of effective oral therapies of this condition means that inhalation formulations of combined steroid/beta agonist, rather than novel drug launches will provide the cornerstone of asthma as well as COPD therapeutics in the near-term (click here for an analysis of evolving airway therapeutics).
More distant advances in the treatment of airway inflammation will focus on new molecular targets. Like many inflammatory conditions asthma is a highly complex clinical disorder, characterized by multiple functional changes including airway narrowing, inflammation, and excessive mucus production. Due to the large number of inflammatory mediators contributing to these changes as well as redundancy between these mediators accurate target selection remains a challenge.
A recent target evaluation report produced for the drug development sector evaluated various anti-inflammatory molecules that are candidate targets for future asthma therapeutics (click here for the report). The authors of the report concluded that the TH2-derived cytokines IL-4, and more so IL-13 represent promising targets.
IL-4, which binds to the IL-4Ralpha/gamma receptor complex, is critical for the synthesis of IgE by B-lymphocytes and is also involved in eosinophil recruitment to the airways. IL-4 also promotes the differentiation of Th2 cells. IL-4 is an attractive target for inhibition (for example with neutralizing IL-4 receptors) and this strategy has produced promising results in patients with moderate to severe disease. Patients with mild disease have been shown to be less responsive.
IL-13 also binds to the IL-4Ralpha/gamma receptor complex activating a similar signal transduction pathway to that of IL-4, but in addition may stimulate different intracellular pathways via activation of IL-4Ralpha/IL-13R1 receptor complexes. Exogenous IL-13 produces many asthma-like functional changes including airway hyper-responsiveness, mucus hypersecretion and airway fibrosis, and blocking IL-4Ralpha now represents a more promising strategy than targeting IL-4 alone.
Several laboratories have investigated the role IL-4Ralpha expression plays in regulating inflammatory responses using IL-4Ralpha knockout mice. Mice completely lacking the IL-4Ralpha do not develop allergic airway hyperreactivity, airway mucus production, or inflammation.
Kelly-Welsh and colleagues have recently reported in the Journal of Immunology the mechanism through which IL-4Ralpha mediates airway mucus production and inflammation.
This group confirmed that mice expressing IL-4Ralpha developed a marked eosinophilia following sensitization with ovalbumin. The appearance of eosinophils in the bronchioalveolar fluid was influenced by the expression of IL-4Ralpha both by bone marrow derived cells and by cells of non-bone marrow lineage. Activation of IL-4Ralpha on bone marrow-derived cells played a primary role in this eosinophilia. Further investigation suggested that the bone marrow cells were monocytic cells in the spleen and a subset of eosinophils in the lungs that were able to amplify total eosinophilia.
IL-4Ralpha on non-bone marrow-derived cells appeared to modulate the level of eosinophilia, however the primary effect of activating IL-4Ralpha on these cells (suggested to be lung epithelial cells) appears to be related to the increase in mucus secretion.
Activating IL-4Ralpha on T cells was shown to facilitate both eosinophilia and mucus production and this was proposed to result from the ability of IL-4 or IL-13 to differentiate these T cells into IL-4/IL-13 producing Th2 cells.
Blocking IL-13 activity is emerging as a promising strategy for treating asthma and a full understanding of how the binding of this cytokine to IL-4Ralpha is therefore required. This study is therefore important and in particular it demonstrates how IL-13 can provoke different components of allergic airway inflammation through the binding to IL-4Ralpha on different cell types.
Source DailyUpdates 9th July; for a full abstract of the original papers see J Immunol. 2004 Apr 1;172(7):4545-55.
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