Interleukin 13 (IL-13) is closely related to interleukin 4 (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 mouse 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, the 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 of IL-4 and IL-13 led to interest in the components of the IL-13 receptor (IL-13 R) complex and the relationship of IL-13 R to the IL-4 receptor (IL-4 R). The IL-4 R alpha chain plays an important role in IL-13 signaling, despite the observation that it has a low affinity for IL-13. The common gamma chain also plays a role in the IL-13 R complex. Although it does not bind IL-13, it may participate in signaling. Additionally, two novel proteins, termed IL-13 receptor alpha one and two (IL-13 R alpha 1 and IL-13 R alpha 2), have been cloned and shown to play roles in the IL-13 R complex. The IL-13 R complex is more complicated than at first appreciated.
IL-13 R alpha 1, previously called NR4, IL-13 R alpha, and IL-13 R alpha', is a hemopoietin receptor family member that was cloned on the basis of its conserved WSXWS motif. Human and mouse IL-13 R alpha 1, which share 76% amino acid sequence identity, each bind IL-13 with low affinity. In addition, human IL-13 R alpha 1 binds IL-4 with low affinity (in the absence of the IL-4 R alpha chain). Cells transfected with mouse IL-13 R alpha 1 only, bind mouse IL-13 with low affinity. Cells expressing both mouse IL-13 R alpha 1 and IL-4 R alpha form a high affinity IL-13 receptor complex, capable of transducing an IL-13- or IL-4-dependent proliferative signal. These results suggest that mouse IL-13 R alpha 1, in addition to its role as an IL-13 binding subunit, could serve as an alternative to the common gamma chain for IL-4 signaling.3-8
IL-13 R alpha 2, previously called IL-13 R and IL-13 R alpha, is also a hemopoietin receptor family member and was originally cloned from the Caki-1 human renal carcinoma cell line. In contrast to IL-13 R alpha 1, this protein binds IL-13 with high affinity, but it does not bind IL-4. Mouse and human IL-13 R alpha 2 display 59% amino acid sequence identity, and the cytoplasmic domains of each lack box-1 and -2 signaling motifs. Human IL-13 R alpha 2 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-13 R alpha 2 are nearly identical to that of a soluble mouse IL-13 binding protein purified from mouse serum and urine.3-8
IL-13 R alpha 1, IL-13 R alpha 2, IL-4 R alpha , and gamma chain are proposed to form four types of IL-13 R complexes. The type of IL-13 R 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 (see Table 1).
The specific role of each chain in IL-13 signaling is unclear. Donaldson et al.8 observed that BaF/3 cells transfected with IL-13 R alpha 1 displayed a mitogenic response to IL-13, but cells transfected with mouse IL-13 R alpha 2 did not. A soluble IL-13 R alpha 2/Fc fusion protein blocked the mitogenic response to IL-13. They suggested that IL-13 R alpha 2 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-13 R alpha 2 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-13 R alpha 1 and IL-13 R alpha 2 genes are located on the X chromosome,8 possibly suggesting a role in X-linked immune diseases. Research focusing on IL-13 and the IL-13 R complex could have significant impacts into the understanding and treatment of X-linked immune diseases, allergen-induced asthma, and experimental asthma.