Interleukin-4 and Interleukin-13 signaling

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.

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

There are two types of IL4 receptor complex. 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.. 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. It is reported to exist in soluble form and when overexpressed reduces JAK-STAT signaling. 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.

The first step in the formation of IL4R1 (IL4:IL4R:IL2RB) is the binding of IL4 with IL4R. This is also the first step in formation of IL4R2 (IL4:IL4R:IL13RA1). After the initial binding of IL4 and IL4R, IL2RB binds, 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.

Crystal structures of the IL4:IL4R:IL2RG, IL4:IL4R:IL13RA1 and IL13:IL4R:IL13RA1 complexes have been determined. Consistent with these structures, in monocytes IL4R is tyrosine phosphorylated in response to both IL4 and IL13 while IL13RA1 phosphorylation is induced only by IL13 and IL2RG phosphorylation is induced only by IL4.

Both IL4 receptor complexes signal through Jak/STAT cascades. IL4R is constitutively-associated with JAK2 and associates with JAK1 following binding of IL4 or IL13. IL2RG constitutively associates with JAK3. IL13RA1 constitutively associates with TYK2.

IL4 binding to IL4R1 leads to phosphorylation of JAK1 (but not JAK2) and STAT6 activation.

IL13 binding increases activating tyrosine-99 phosphorylation of IL13RA1 but not that of IL2RG. IL4 binding to IL2RG leads to its tyrosine phosphorylation. IL13 binding to IL4R2 leads to TYK2 and JAK2 (but not JAK1) phosphorylation.

Phosphorylated TYK2 binds and phosphorylates STAT6 and possibly STAT1.

A second mechanism of signal transduction activated by IL4 and IL13 leads to the insulin receptor substrate (IRS) family. 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.