The interleukin-13 receptor α2 chain: an essential component for binding and internalization but not for interleukin-13–induced signal transduction through the STAT6 pathway

Abstract

IntroductionInterleukin-13 (IL-13) and IL-4 are related multifunctional cytokines with similar biological activities on human B cells and monocytes. [1][2][3][4][5][6][7] The cognate receptors for these cytokines are complex and have been shown to share 2 chains with each other. [8][9][10][11][12] The IL-4 receptor system is well characterized and has been shown to be composed of a primary IL-4 binding protein, IL-4R␣ (also known as IL-4R␤). 13 This chain forms a heterodimer with either the IL-2R␥ c chain (type I IL-4R) or IL-13R␣1 (also known as IL-13R␣Ј) (type II IL-4R) for signaling. 11,[14][15][16][17] In some situations, all 3 chains (IL-4R␣, IL-2R␥ c , and IL-13R␣1) may constitute the IL-4R complex; however, whether all 3 chains are simultaneously required for IL-4 function is not known.In contrast, the receptor for IL-13 is less well characterized. We have studied the structure of IL-13R in various cell types and reported that IL-13 binds to 2 isoforms of an approximate 65-kDa protein in human renal cell carcinoma cells. [8][9][10][11][12] One of these proteins also binds 14 On the basis of the binding characteristics, cross-linking, and displacement of radiolabeled IL-4 and IL-13 in various cell types, we hypothesized that, as is the case for the IL-4R system, IL-13R may also be composed of 3 different types. [9][10][11][12] More recently, 2 different chains of the IL-13R system have been cloned. The murine and human IL-13R␣1 chain was first cloned. 14,18 This chain can bind IL-13 with low affinity, but, when coupled with the IL-4R␣ chain, the heterodimer binds IL-13 with high affinity and mediates IL-13-induced signaling. 14,18 The second chain of the IL-13R, termed IL-13R␣2 (also known as IL-13R␣), has also been cloned from a human renal cell carcinoma cell line (Caki-1). This chain shares approximately 50% homology with the IL-5R at the DNA level. It contains a very short intracellular domain and binds IL-13 with high affinity. 19 On the basis of the above studies, we have proposed that the type I IL-13R complex is composed of both chains of IL-13R (IL-13R␣1 and IL-13R␣2) and IL-4R␣ chain. Although IL-13 binds to all 3 chains, only the IL-13R␣1 and IL-4R␣ chains form a productive complex. Because of this arrangement, IL-13 binds to these cells strongly. Only IL-13, not IL-4, is able to displace the binding of 125 I-IL-13. In the type II IL-13R system, IL-13R␣2 is not present, and the IL-13R␣1 chain forms a complex with the IL-4R␣ chain. In these cells both interleukins compete for the binding of their radiolabeled cognaters. 12 The structure of the type III IL-13R is similar to that of type II receptors except that these cells also express the IL-2R␥ c chain. Although it appears that the IL-2R␥ c chain does not bind IL-13, it does affect IL-13 binding and function in some cell types. 20,21 After binding to their receptors, both IL-4 and IL-13 signal through phosphorylation-dependent activation of Jak kinases and signal transduction and activator of transcription (STAT) protein. 11,17,22 In particular,...

Adenoviral vector–mediated gene transfer of IL‐13Rα2 chain followed by IL‐13 cytotoxin treatment offers potent targeted therapy for cytotoxin‐resistant cancers

“…Previous studies have demonstrated that the attachment of radiolabeled IL-13 to the functional heterodimer receptor can be competed by IL-4 as well as IL-13, [30][31][32]49 whereas its attachment to IL-13R 2 is competed by IL-13 but not IL-4. 2,9,10,15,33,36 To confirm that the cytotoxicity of IL-13 cytotoxin was specifically mediated through IL-13R 2 chain delivered by Ad-IL-13R 2 vector, A549 cells were infected with Ad-IL-13R 2 at MOI 10 followed by treatment with IL-13 cytotoxin (10 ng/ml) in the presence of a 50-fold dose of human IL-13 or IL-4. As shown in Figure 4, IL-13 and IL-4 did not affect the growth of uninfected or Ad-LacZ-infected cells, regardless of treatment with IL-13 cytotoxin.…”

“…Therefore, IL-13R 1 chain requires the recruitment of IL-4R chain [30][31][32]35 to form a high-affinity heterodimer receptor complex, which mediates the IL-13 signaltransduction pathway. IL-13R 2 chain by itself can bind IL-13 with higher affinity, but it does not mediate IL-13 signaling 35,36 because it has a very short cytoplasmic domain that lacks the conserved signaling motifs. In particular, IL-13R 2 chain has a unique property of ligand internalization after binding, 36,37 which has also been identified as a soluble protein in mouse serum and urine; 38 thus, it can be a specific inhibitor of IL-13 signaling or a decoy receptor for IL-13.…”

“…IL-13R 2 chain by itself can bind IL-13 with higher affinity, but it does not mediate IL-13 signaling 35,36 because it has a very short cytoplasmic domain that lacks the conserved signaling motifs. In particular, IL-13R 2 chain has a unique property of ligand internalization after binding, 36,37 which has also been identified as a soluble protein in mouse serum and urine; 38 thus, it can be a specific inhibitor of IL-13 signaling or a decoy receptor for IL-13. [39][40][41] Moreover, IL-13R 2 chain may inhibit IL-13-mediated biologic functions in tumor growth and recurrence.…”

IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer

“…On the other hand, IL13Ra2 does not seem to require IL-4Ra and by itself binds IL-13 with high affinity, internalizes and also mediates signal transduction. [8][9][10][11] To determine the significance of IL-13Ra2 expression', we have discovered that over-expression of IL13Ra2 increases cancer invasion and metastasis and shortens survival time of mice with human pancreatic cancer. 12 Whether this novel function of IL-13Ra2 is extendable to other human cancers is not known.…”

Gene transfer of interleukin 13 receptor α2 chain dramatically enhances the antitumor effect of IL-13 receptor–targeted cytotoxin in human prostate cancer xenografts

“…23 IL -13R 1 chain can form a productive complex with IL-4R chain ( also known as IL -4R ) for IL-13 signal transduction. 22,24 Based on these studies, it has been proposed that IL -13R can exist in at least three different forms. 19,25 In the first form IL -13 binds to IL -13R 2, IL-13R 1, and IL -4R chains.…”