Strategies targeting the IL-4/IL-13 axes in disease

Abstract

IL-4 and IL-13 are pleiotropic Th2 cytokines produced by a wide variety of different cell types and responsible for a broad range of biology and functions. Physiologically, Th2 cytokines are known to mediate host defense against parasites but they can also trigger disease if their activities are dysregulated. In this review we discuss the rationale for targeting the IL-4/IL-13 axes in asthma, atopic dermatitis, allergic rhinitis, COPD, cancer, inflammatory bowel disease, autoimmune disease and fibrotic disease as well as evaluating the associated clinical data derived from blocking IL-4, IL-13 or IL-4 and IL-13 together.

Introduction

IL-4 was first cloned in 1986 from a mouse T cell line and was known as IgG1 induction factor [1]. In the same year the human IL-4 ortholog was cloned from a concanavalin A-activated human T-cell cDNA library and found to be a 153aa protein with a signal sequence that stimulated helper T cell and anti-IgM activated B cell proliferation [2]. Both human [3] and mouse [4] IL-4 were shown to induce IgE production from B cells and mouse [5] and human IL-4 [6] shown to be secreted by Th2 cells.

IL-13 was similarly cloned in 1989 from concanavalin A-activated mouse T-cells and was initially known as p600 [7], a protein secreted by Th2 cells. The human IL-13 ortholog was cloned by 2 teams [8], [9] from activated human lymphocytes as a 132aa protein with a signal sequence that inhibited LPS-induced IL-6 production by peripheral blood mononuclear cells (PBMC) [8], stimulated PBMC MHC II and CD23 expression and induced B cell proliferation and immunoglobulin production [9]. IL-4 and IL-13 are 20–25% identical but with higher identity in the first and last alpha-helical regions [8] known to be key for IL-4 activity [10].

IL-4 mediates its biological effects by binding to IL-4Rα; subsequently either gamma c or IL-13 receptor alpha 1 (IL-13Rα1) are recruited to form a signaling complex [11]. IL-13 mediates its biological effects by binding to IL-13Rα1 and then recruiting IL-4Rα to form a signaling complex [11], [12]. IL-4:IL-4Rα:γc, IL-4:IL-4Rα:IL-13Rα1, IL-13:IL-13Rα1:IL-4Rα all signal through STAT6 [13]. Studies on the activated IL-4/IL-4Rα complex show that receptor components cluster densely on, and just beneath, the cell membrane in early sorting and recycling cortical endosomes trafficked via a constitutive internalization process [14]. Sources of IL-4 and IL-13 and cell types expressing the receptors are shown in Fig. 1.

Polymorphisms in the IL-4/IL-13 axis exist and modulate function positively and negatively. Q576R IL-4Rα is a cytoplasmic-IL-4Rα mutant associated with atopy [15]; I75V is an extracellular-IL-4Rα mutant that when combined with Q576R mediates enhanced pharmacodynamic effects compared to WT IL-4Rα and is associated with atopy [15] and atopic asthma [16]. R130Q IL-13 has been associated with asthma, atopy and increased serum IgE [17], [18], [19] and shown to activate the signaling of IL-13Rα1 and downstream functions more efficiently, and binding to the decoy receptor (IL-13Rα2) less efficiently, than WT IL-13 [20]. Additionally R130Q IL-13 is more stable in human plasma than WT IL-13; patients homozygous for R130Q have higher serum IL-13 levels than non-homozygotes [21]. Finally R130Q expression causes an elevated pharmacodynamic effect via Q576R I75V IL-4Rα compared with WT IL-4Rα [22]. On the other hand, IL-4δ2 is a polymorphic form of IL-4 generated by deletion of exon 2 from IL-4 mRNA [23] which acts as a functional antagonist of IL-4 at IL-4Rα [24]. Other negative regulators include soluble IL-4Rα, formed by a stop codon in exon 8 of the 12 exons present for the full length protein [25], and membrane IL-13Rα2 which lacks a significant cytoplasmic tail and is generally considered to be a decoy [26], involved in removing IL-13 by internalization [27], particularly in humans [28] where soluble IL-13Rα2 is not present due to lack of a differential splice site [29], [30]. However there is an emerging literature associating IL-13Rα2 with fibrosis [31] and as a receptor for chitinase 3-like 1 [32]. STUB1, an intracellular ubiquitin ligase, has just been shown to interact with IL-4Rα and shuttle it for degradation thereby decreasing IL-4/-13 signaling [33].

Both IL-4 and IL-13 reside on human chromosome 5q23-31 [34], [35] in a cluster of allergy-related genes including GMCSF, IL-3 and IL-5 [36]. This cluster has been repeatedly linked with an increased risk of allergic-disease development (reviewed in [37]). The broad similarity in biological function, signal transduction, gene structure [38] and genomic localization of IL-4 and IL-13 have led to speculation that they may have arisen via gene duplication [39]. It is tempting to speculate that the natural advantage of having a highly active Th2 system is optimal extracellular parasite rejection [40]. In support of this genetic analysis suggests the 5q31 complex is under intense selection pressure in geographical regions with endemic parasites [41] and Schistosoma mansoni egg counts are lower in individuals with the gain of function Q130R IL-13 mutation [42].

Based on the broad biology of these 2 similar cytokines that has clear links to human disease, substantial efforts have been made to develop effective agents to block them. The types of approaches that have been tried and the rationale supporting them in the various disease areas will be covered in the following sections.