Review ArticleIL-4 and IL-13 signaling in allergic airway disease
Introduction
Allergic asthma is a chronic inflammatory disease of the lung, which has been on the rise in recent decades. Currently asthma affects over 300 million people and one of every 250 deaths worldwide is attributed to this disease. Asthma is a reversible airway disease characterized by airway hyperresponsiveness, airway inflammation, and airway remodeling (i.e. mucus cell metaplasia, smooth muscle thickening, sub-epithelial fibrosis) and the main pathophysiological manifestation of the disease-airway hyperresponsiveness. Since the groundbreaking discovery of distinct CD4+ T cell subsets in the late 1980s [1], Th2 cytokine producing cells have been implicated in the pathogenesis of asthma. Indeed, a tremendous amount of evidence in both humans and animal models support a role for Th2 cells in the development of the prominent features of the allergic diathesis [2]. In deciphering the mechanisms by which Th2 cell derived cytokines regulate asthma pathogenesis, extensive efforts have been devoted to defining the role of the prototypical Th2 cytokines, IL-4 and IL-13. As IL-4 and IL-13 are encoded by adjacent genes (chr 5q in humans and chr11 in mice) that share a number of regulatory elements (GATA-3) and transmit signals through a shared functional receptor complex (IL-4Rα/IL-13Rα1), it was originally assumed that they would serve redundant functions in the pathogenesis of allergic asthma [3]. However, despite their many similarities, a series of in vivo functional experiments utilizing mice deficient in cytokines, cytokine-producing cells or lacking specific receptor subunits have shown that IL-4 and IL-13 play distinct roles in allergic asthma in vivo. In particular, IL-4, through its role in regulating Th2 cell proliferation and survival and IgE synthesis has been shown to be essential in the initiation of allergic airway responses and humoral responses, but it does not regulate AHR, mucus production, or subepithelial fibrosis in vivo in the context of allergic inflammation [4], [5], [6], [7], [8], [9], [10]. In contrast, its look-a-like, IL-13 is thought to play a more important role in the effector phase of the response and to be sufficient to induce the main manifestations of allergic disease including AHR, mucus production, airway smooth muscle alterations, and sub-epithelial fibrosis [11], [12], [13], [14], [15]. The precise mechanism(s) by which these two cytokines regulate distinct features of the allergic response, and how these actions either individually or in concert induce the pathophysiological manifestations of disease, still remain a mystery. Herein, we review recent insights into the potential mechanisms underlying their distinct roles in the asthmatic phenotype, the mechanisms by which IL-13 signaling plays a central role in regulating the effector phase of the disease, and the potential of modulating these cytokines for therapeutic benefit in asthma (see Fig. 1, Fig. 2, Fig. 3).
Section snippets
Mechanisms of distinct roles for IL-4 and IL-13 in allergic inflammation
Although the exact mechanisms by which IL-4 and IL-13 mediate different aspects of the asthmatic phenotype are not totally understood, studies examining the contributions of the four receptor chains (IL-4Rα, IL-13Rα1, γc, IL-13Rα2) which make up the type I and type II IL-4R complexes are providing some clues (Fig. 1). IL-4 signaling is initiated via two types of heterodimeric transmembrane receptor complexes: the type I receptor, which exclusively binds IL-4 and is comprised of IL-4Rα and γc
Mechanism(s) of IL-13 regulation of the effector phase of the allergic response
With the preponderance of evidence continuing to support a pivotal role for IL-13 in allergic disorders, attention is now turned toward understanding the mechanisms by which this cytokine may mediate the pathophysiological features of allergic disease. The emerging paradigm is that IL-13 induces features of the allergic response via a complex array of actions on resident airway cells. Below we review our current understanding of the mechanisms by which IL-13 regulates: (1) mucus cell
IL-4 and IL-13 in human asthma
The importance of IL-4 and IL-13 in allergic asthma in humans is supported by numerous reports of exaggerated IL-4 and IL-13 production in asthma. In asthma, both message and protein levels of both cytokines are elevated in bronchial biopsy specimens and BAL cells from allergic individuals when compared with those of control subjects [3], [106]. Conversely, IL-13 levels are reduced in patients with asthma undergoing allergen desensitization treatment regimes or steroid treatment. Moreover, a
Clinical trials targeting IL-4/IL-13 signaling in asthma
Based on the preponderance of evidence implicating IL-4 and IL-13 in mediating asthma pathophysiology, clinical trials are currently underway to investigate the blockade of IL-4, IL-13 and/or both in the treatment of asthma. One of the first studies was designed to evaluate the efficacy of blocking both IL-4 and IL-13 signaling with a recombinant human soluble interleukin-4 receptor on asthma. Although the study was small, it suggested that IL-4Rα blockade might improve FEV1 in asthmatics [117]
Conclusion
In conclusion, the preponderance of information generated in animal models of asthma support the conclusion that the type II cytokines IL-4 and IL-13, in tandem, play an important role in the pathogenesis of allergic asthma. IL-4 playing a pivotal role in Th2 cell proliferation and cytokine production and IgE synthesis, while IL-13 plays a pivotal role in the pathological features of disease (mucus production, AHR, and collagen deposition). Although we do not fully understand the mechanisms by
Acknowledgements
The authors acknowledge support from the following Grants: RO1AI083315, U19AI070235 to MWK, and NIEHST32ES007141 to N. Gour.
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