The type II Interleukin-13 (IL13) receptor complex (IL13R2) forms with IL13 binding to Interleukin-13 receptor alpha subunit 1 (IL13RA1), which is constitutively bound to Non-receptor tyrosine kinase 2 (TYK2), followed by recruitment of Interleukin-4 receptor subunit alpha (IL4R), which is associated with Janus kinase 2 (JAK2) (Wang et al. 2009). IL13RA1 binds IL13 with low affinity (Kd = 2-10 nmol/L) (Miloux et al. 1997).

Interleukin-13 receptor alpha 2 (IL13RA2), sometimes called Interleukin-13 binding protein (IL13BP) is a high affinity receptor for IL13 (Kd = 250 pmol/L) but is not sufficient to render cells responsive to IL13, even in the presence of IL4R (Donaldson et al. 1998). It is reported to exist in soluble form (Zhang et al. 1997); overexpression reduces STAT6 signaling (Kawakami et al. 2001). Its function may be to prevent IL13 signaling via the functional IL4R:IL13RA1 cell surface receptor. IL13BP is overexpressed in some human cancers and enhances cell invasion (Joshi & Puri 2012).

Interleukin-13 receptor alpha subunit (IL13RA1) binds Interleukin-13 (IL13) with a relatively low affinity, but when paired with Interleukin-4 receptor subunit alpha (IL4R), binds with much higher affinity (Kd = 400 pmol/L) and forms a functional IL13 receptor that is capable of signaling (Miloux et al. 1997). This type II IL13 receptor complex is also the alternative type II receptor for IL4.

IL13 inhibits monocyte and macrophage production of Interleukin-1 (IL1), IL6, IL8, Tumor necrosis factor (TNF) and IL12 (de Vries et al. 1998), through a mechanism that partially involves suppression of Nuclear factor NF-kappa-B.

In human peripheral blood, monocytes Interleukin-4 (IL4) and Interleukin-13 significantly downregulate the expression of classical proinflammatory signal transducers, such as Interleukin-1 (IL1), Interleukin-6, Interleukin-8, Interleukin-18, C-C motif chemokine 2 (CCL2) and Tumor necrosis factor (TNF). Expression of Prostaglandin G/H synthase 2 (PTGS2, COX2) and Arachidonate 5-lipoxygenase (ALOX5), enzymes involved in the biosynthesis of the proinflammatory eicosanoids, is also attenuated (Chatidis et al. 2005).
This is a black box event because the mechanism of gene regulation is not fully defined.

Interleukin-4 (IL4) is a principal regulatory cytokine during the immune response, crucially important in allergy and asthma (Nelms et al. 1999). When resting T cells are antigen-activated and expand in response to Interleukin-2 (IL2), they can differentiate as Type 1 (Th1) or Type 2 (Th2) T helper cells. The outcome is influenced by IL4. Th2 cells secrete IL4, which both stimulates Th2 in an autocrine fashion and acts as a potent B cell growth factor to promote humoral immunity (Nelms et al. 1999).

Interleukin-13 (IL13) is an immunoregulatory cytokine secreted predominantly by activated Th2 cells. It is a key mediator in the pathogenesis of allergic inflammation. IL13 shares many functional properties with IL4, stemming from the fact that they share a common receptor subunit. IL13 receptors are expressed on human B cells, basophils, eosinophils, mast cells, endothelial cells, fibroblasts, monocytes, macrophages, respiratory epithelial cells, and smooth muscle cells, but unlike IL4, not T cells. Thus IL13 does not appear to be important in the initial differentiation of CD4 T cells into Th2 cells, rather it is important in the effector phase of allergic inflammation (Hershey et al. 2003). IL4 and IL13 induce “alternative activation” of macrophages, inducing an anti-inflammatory phenotype by signaling through IL4R alpha in a STAT6 dependent manner. This signaling plays an important role in the Th2 response, mediating anti-parasitic effects and aiding wound healing (Gordon & Martinez 2010, Loke et al. 2002) There are two types of IL4 receptor complex (Andrews et al. 2006). Type I IL4R (IL4R1) is predominantly expressed on the surface of hematopoietic cells and consists of IL4R and IL2RG, the common gamma chain. Type II IL4R (IL4R2) is predominantly expressed on the surface of nonhematopoietic cells, it consists of IL4R and IL13RA1 and is also the type II receptor for IL13. (Obiri et al. 1995, Aman et al. 1996, Hilton et al. 1996, Miloux et al. 1997, Zhang et al. 1997). The second receptor for IL13 consists of IL4R and Interleukin-13 receptor alpha 2 (IL13RA2), sometimes called Interleukin-13 binding protein (IL13BP). It has a high affinity receptor for IL13 (Kd = 250 pmol/L) but is not sufficient to render cells responsive to IL13, even in the presence of IL4R (Donaldson et al. 1998). It is reported to exist in soluble form (Zhang et al. 1997) and when overexpressed reduces JAK-STAT signaling (Kawakami et al. 2001). It's function may be to prevent IL13 signalling via the functional IL4R:IL13RA1 receptor. IL13RA2 is overexpressed and enhances cell invasion in some human cancers (Joshi & Puri 2012).

The first step in the formation of IL4R1 (IL4:IL4R:IL2RB) is the binding of IL4 with IL4R (Hoffman et al. 1995, Shen et al. 1996, Hage et al. 1999). This is also the first step in formation of IL4R2 (IL4:IL4R:IL13RA1). After the initial binding of IL4 and IL4R, IL2RB binds (LaPorte et al. 2008), to form IL4R1. Alternatively, IL13RA1 binds, forming IL4R2. In contrast, the type II IL13 complex (IL13R2) forms with IL13 first binding to IL13RA1 followed by recruitment of IL4R (Wang et al. 2009).

Crystal structures of the IL4:IL4R:IL2RG, IL4:IL4R:IL13RA1 and IL13:IL4R:IL13RA1 complexes have been determined (LaPorte et al. 2008). Consistent with these structures, in monocytes IL4R is tyrosine phosphorylated in response to both IL4 and IL13 (Roy et al. 2002, Gordon & Martinez 2010) while IL13RA1 phosphorylation is induced only by IL13 (Roy et al. 2002, LaPorte et al. 2008) and IL2RG phosphorylation is induced only by IL4 (Roy et al. 2002).

Both IL4 receptor complexes signal through Jak/STAT cascades. IL4R is constitutively-associated with JAK2 (Roy et al. 2002) and associates with JAK1 following binding of IL4 (Yin et al. 1994) or IL13 (Roy et al. 2002). IL2RG constitutively associates with JAK3 (Boussiotis et al. 1994, Russell et al. 1994). IL13RA1 constitutively associates with TYK2 (Umeshita-Suyama et al. 2000, Roy et al. 2002, LaPorte et al. 2008, Bhattacharjee et al. 2013).

IL4 binding to IL4R1 leads to phosphorylation of JAK1 (but not JAK2) and STAT6 activation (Takeda et al. 1994, Ratthe et al. 2007, Bhattacharjee et al. 2013).

IL13 binding increases activating tyrosine-99 phosphorylation of IL13RA1 but not that of IL2RG. IL4 binding to IL2RG leads to its tyrosine phosphorylation (Roy et al. 2002). IL13 binding to IL4R2 leads to TYK2 and JAK2 (but not JAK1) phosphorylation (Roy & Cathcart 1998, Roy et al. 2002).

Phosphorylated TYK2 binds and phosphorylates STAT6 and possibly STAT1 (Bhattacharjee et al. 2013).

A second mechanism of signal transduction activated by IL4 and IL13 leads to the insulin receptor substrate (IRS) family (Kelly-Welch et al. 2003). IL4R1 associates with insulin receptor substrate 2 and activates the PI3K/Akt and Ras/MEK/Erk pathways involved in cell proliferation, survival and translational control. IL4R2 does not associate with insulin receptor substrate 2 and consequently the PI3K/Akt and Ras/MEK/Erk pathways are not activated (Busch-Dienstfertig & González-Rodríguez 2013).

Signal transducer and activator of transcription 6 (STAT6) may function as a signaling molecule and as a transcription factor. The canonical activation of STAT6 in IL4 and IL13 signaling pathways is mediated by the tyrosine kinases JAK (Hebenstreit D et al. 2006). Virus-induced STAT6 activation was found to be cytokine- and JAK-independent (Chen H et al. 2011). Infection of human cells with RNA or DNA viruses resulted in an interaction of STAT6 with STING. The kinase TBK1 was shown to phosphorylate STAT6, which in turn induced STAT6 dimerization and translocation to the nucleus, leading to induction of chemokines CCL2, CCL20, and CCL26 in IFN-independent manner (Chen H et al. 2011).

RNA virus infection triggers STAT6 activation through STING, TBK1 and adaptor protein MAVS interaction (Chen H et al. 2011).

Interleukin 13 receptor subunit alpha 1 or 2