Interleukin-4 receptor explained

Symbol:	IL4Ra_N
Interleukin-4 receptor alpha chain, N-terminal
Pfam:	PF09238
Interpro:	IPR015319
Scop:	1iar

The interleukin 4 receptor is a type I cytokine receptor. It is a heterodimer, that is, composed of two subunits. IL4R is the human gene coding for IL-4Rα, the subunit which combines with either common gamma chain (γc, forming the type I IL4 receptor) or with IL-13Rα1 (forming the type II IL4 receptor).^[1]

Function

This gene encodes the alpha chain of the interleukin-4 receptor, a type I transmembrane protein that can bind interleukin 4 and interleukin 13 to regulate IgE antibody production in B cells. Among T cells, the encoded protein also can bind interleukin 4 to promote differentiation of Th2 cells. A soluble form of the encoded protein can be produced by an alternate splice variant or by proteolysis of the membrane-bound protein, and this soluble form can inhibit IL4-mediated cell proliferation and IL5 upregulation by T-cells. Allelic variations in this gene have been associated with atopy, a condition that can manifest itself as allergic rhinitis, sinusitis, asthma, or eczema. Two transcript variants encoding different isoforms, a membrane-bound and a soluble form, have been found for this gene.^[2] Interactions of IL-4 with TNFα promote structural changes to vascular endothelial cells, thus playing an important role in tissue inflammation.^[3]

The binding of IL-4 or IL-13 to the IL-4 receptor on the surface of macrophages results in the alternative activation of those macrophages. Alternatively activated macrophages (AAMΦ) downregulate inflammatory mediators such as IFNγ during immune responses, particularly with regards to helminth infections.^[4]

Interactions

Interleukin-4 receptor has been shown to interact with SHC1.^{[5] [6]}

Structure

The N-terminal (extracellular) portion of interleukin-4 receptor is related in overall topology to fibronectin type III modules and folds into a sandwich comprising seven antiparallel beta sheets arranged in a three-strand and a four-strand beta-pleated sheet. They are required for binding of interleukin-4 to the receptor alpha chain, which is a crucial event for the generation of a Th2-dominated early immune response.^[7]

See also

• Macrophage-activating factor
• Macrophage polarization
• Cluster of differentiation
• Fibronectin type III domain

Further reading

• Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE . The IL-4 receptor: signaling mechanisms and biologic functions . Annual Review of Immunology . 17 . 1 . 701–738 . 1999 . 10358772 . 10.1146/annurev.immunol.17.1.701 .
• Jiang H, Harris MB, Rothman P . IL-4/IL-13 signaling beyond JAK/STAT . The Journal of Allergy and Clinical Immunology . 105 . 6 Pt 1 . 1063–1070 . June 2000 . 10856136 . 10.1067/mai.2000.107604 . free .

External links

• • PDBe-KB provides an overview of all the structure information available in the PDB for Human Interleukin-4 receptor subunit alpha

Notes and References

1. McCormick SM, Heller NM . Commentary: IL-4 and IL-13 receptors and signaling . Cytokine . 75 . 1 . 38–50 . September 2015 . 26187331 . 4546937 . 10.1016/j.cyto.2015.05.023 .
2. Web site: Entrez Gene: IL4R interleukin 4 receptor.
3. Thornhill MH, Wellicome SM, Mahiouz DL, Lanchbury JS, Kyan-Aung U, Haskard DO . Tumor necrosis factor combines with IL-4 or IFN-gamma to selectively enhance endothelial cell adhesiveness for T cells. The contribution of vascular cell adhesion molecule-1-dependent and -independent binding mechanisms . Journal of Immunology . 146 . 2 . 592–598 . January 1991 . 1702807 . 10.4049/jimmunol.146.2.592 . free .
4. Tundup S, Srivastava L, Harn DA . Polarization of host immune responses by helminth-expressed glycans . Annals of the New York Academy of Sciences . 1253 . 1 . E1–E13 . April 2012 . 22974465 . 10.1111/j.1749-6632.2012.06618.x . 43256244 . 2012NYASA1253E...1T .
5. Ikizawa K, Yanagihara Y . Possible involvement of Shc in IL-4-induced germline epsilon transcription in a human B cell line . Biochemical and Biophysical Research Communications . 268 . 1 . 54–59 . February 2000 . 10652211 . 10.1006/bbrc.2000.2080 .
6. Kashiwada M, Giallourakis CC, Pan PY, Rothman PB . Immunoreceptor tyrosine-based inhibitory motif of the IL-4 receptor associates with SH2-containing phosphatases and regulates IL-4-induced proliferation . Journal of Immunology . 167 . 11 . 6382–6387 . December 2001 . 11714803 . 10.4049/jimmunol.167.11.6382 . free .
7. Hage T, Sebald W, Reinemer P . Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface . Cell . 97 . 2 . 271–281 . April 1999 . 10219247 . 10.1016/S0092-8674(00)80736-9 . 18795930 . free .