The Interleukin 13 Receptor Complex

Interleukin 13 (IL-13) is closely related to IL-4. They display overlapping functions, and the genes for the human proteins are both found on chromosome 5q. IL-13 is produced by activated Th0, Th1-like cells, Th2-like cells and CD8-positive T cells. The murine homolog is referred to as P600. IL-13 has multiple effects on the differentiation and functions of monocytes/macrophages. It can suppress the cytotoxic functions of monocytes/ macrophages, production of pro-inflammatory cytokines and upregulate the production of IL-1ra. IL-13 also plays a role in asthma [1, 2]. The similarities and overlapping functions between IL-4 and IL-13 led to interest in the components of the IL-13 receptor (IL-13R) complex and the relationship of IL-13R to the IL-4 receptor (IL-4R). The IL-4Rα chain plays an important role in IL-13 signaling, despite the observation that it has a low affinity for IL-13. The common γ chain also plays a role in the IL-13R complex. Although it does not bind IL-13, it may participate in signaling. Additionally, two novel proteins, termed IL-13R alpha 1 (IL-13Rα1) and IL-13R alpha 2 (IL-13Rα2), have been cloned and shown to play roles in the IL-13R complex. The IL-13R complex is more complicated than at first appreciated [3-5]. IL-13Rα1, previously called NR4, IL-13Rα and IL-13Rα′, is a hemopoietin receptor family member that was cloned on the basis of its conserved WSXWS motif. Human and mouse IL-13Rα1, which share 76% amino acid sequence identity, each bind IL-13 with low affinity. In addition, human IL-13Rα1 binds IL-4 with low affinity (in the absence of the IL-4Rα chain). Cells transfected with mouse IL-13Rα1 only, bind mouse IL-13 with low affinity. Cells expressing both mouse IL-13Rα1 and IL-4Rα form a high affinity IL-13R complex, capable of transducing an IL-13- or IL-4-dependent proliferative signal. These results suggest that mouse IL-13Rα1, in addition to its role as an IL-13 binding subunit, could serve as an alternative to the common γ chain for IL-4 signaling [6-11]. IL-13Rα2, previously called IL-13R and IL-13Rα, is also a hemopoietin receptor family member and was originally cloned from the Caki-1 human renal carcinoma cell line. In contrast to IL-13Rα1, this protein binds IL-13 with high affinity, but does not bind IL-4. Mouse and human IL-13Rα2 display 59% amino acid sequence identity, and the cytoplasmic domains of each lack box-1 and -2 signaling motifs. Human IL-13Rα2 contains a putative consensus phosphorylation site that may interact with SH2-containing signaling molecules. The amino-terminal 27 amino acid residues of human and mouse IL-13Rα2 are nearly identical to that of a soluble mouse IL-13 binding protein purified from mouse serum and urine [6-11]. IL-13Rα1, IL-13Rα2, IL-4Rα, and γ chain are proposed to form four types of IL-13R complexes. The type of IL-13R complex expressed depends upon the cell and which of the possible receptor components are present. As a result, different cells can display different binding properties for IL-13 and IL-4 (Table 1). IL-13R Complexes* *For references to the data presented in the table, see references 3-5 and 10. IL-13R Complexes* *For references to the data presented in the table, see references 3-5 and 10. The specific role of each chain in IL-13 signaling is unclear. Donaldson et al. [11] observed that Ba/F3 cells transfected with IL-13Rα1 displayed a mitogenic response to IL-13, but cells transfected with mouse IL-13Rα2 did not. A soluble IL-13Rα2/Fc fusion protein blocked the mitogenic response to IL-13. They suggested that IL-13Rα2 could serve as a dominant negative inhibitor or decoy receptor for IL-13. Wills-Karp et al. [2] found that administration of IL-13 was sufficient to induce airway hyper-responsiveness (AHR), which is found in allergic asthma. In vivo administration of soluble IL-13Rα2 completely reversed IL-13-mediated AHR. Grünig et al. [1] found that neutralization of IL-13 activity prevented development of experimental asthma. Both the human and mouse IL-13Rα1 and IL-13Rα2 genes are located on the X chromosome [11], possibly suggesting a role in X-linked immune diseases. Research focusing on IL-13 and the IL-13R complex could have significant impacts into the understanding and treatment of X-linked immune diseases, allergen-induced asthma and experimental asthma.