Interleukin-13 signaling and its role in asthma

Abstract

Asthma affects nearly 300 million people worldwide. The majority respond to inhaled corticosteroid treatment with or without beta-adrenergic agonists. However, a subset of 5 to 10% with severe asthma do not respond optimally to these medications. Different phenotypes of asthma may explain why current therapies show limited benefits in subgroups of patients. Interleukin-13 is implicated as a central regulator in IgE synthesis, mucus hypersecretion, airway hyperresponsiveness, and fibrosis. Promising research suggests that the interleukin-13 pathway may be an important target in the treatment of the different asthma phenotypes.

Figure 1

IL-13 signaling. Step 1, the binding of IL-13 to IL-13Rα1 leads to step 2, heterodimer formation with IL-4Rα1 and formation of the type 2 IL-4 receptor. Step 3 leads to Janus Kinase activation (JAK), followed by step 4, STAT6 phosphorylation, dimerization, and translocation to the nucleus. In step 5, Stat 6 heterodimers affect IL-13-dependent gene transcription. IL-13Rα2 is an IL-13 dependent gene. IL-13 can bind IL-13Rα2 that leads to sequestration of IL-13 or IL-13 signaling by TGF-β induction or AP-1 signaling. Mouse models suggest that suppressor of cytokine signaling (SOCS)1 is an IL-13 dependent gene that interacts with JAK2 to negatively regulate JAK2 association with IL-13Rα1 [14]. In a mouse model, SOCS5 targets IL-4Rα1 and impairs STAT6 signaling [15].

Figure 2

Arachidonic acid metabolic pathways and the role of IL-13. The prostaglandin pathway (red), the leukotriene pathway (blue), and the lipoxin pathway (green). PGE2 has inhibitory effects on leukotriene production including inhibition of 5-LO translocation from the cytoplasm to the nucleus and abrogation of leukotriene synthesis [24]. IL-13 down-regulates PGE2 both directly and indirectly through effects on PGES and COX-2. IL-13 also induces 15-LO that is correlated with asthma severity. IL-13 induction of 15-LO stimulates formation of 15-HETE and a metabolite of this enhances MUC5AC expression in human airway epithelial cells.