Interleukin 5

Overview
Interleukin 5 or IL-5 is an interleukin produced by T helper-2 cells and mast cells. Its functions are to stimulate B cell growth and increase immunoglobulin secretion. It is also a key mediator in eosinophil activation. IL-5 is a 115 amino acid (in man, 133 in the mouse) long TH2 cytokine which is part of the hematopoietic family. Unlike other members of this cytokine family (namely IL-3 and GM-CSF), in its active form, this glycoprotein is a homodimer. The IL-5 gene is located on chromosome 11 (in the mouse, chromosome 5 in humans) in close proximity to the genes encoding IL-3, IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) which are often co-expressed in TH2 cells. Interleukin-5 is also expressed by eosinophils and has been observed in the mast cells of asthmatic airways by immunohistochemistry. IL-5 expression is regulated by several transcription factors including GATA-3.

Clinical significance
Interleukin-5 has long been associated with several allergic diseases including allergic rhinitis and asthma where a large increase in the number of circulating, airway tissue, and induced sputum eosinophil numbers have been observed. Given the high concordance of eosinophils and, particularly, allergic asthma pathology, it has been widely speculated that eosinophils have an important role in the pathology of this disease.

The IL-5 Receptor
The IL-5 receptor (IL-5R) belongs to the type I cytokine receptor family and is a heterodimer composed of two polypeptide chains, one α subunit which binds IL-5 and confers upon the receptor cytokine specificity, and one β subunit which contains the signal transduction domains.

α-subunit
The IL-5Rα chain is exclusively expressed by eosinophils, some basophils and murine B1 cells or B cell precursors. Like many other cytokine receptors, alternative splicing of the α-chain gene results in expression of either a membrane bound or soluble form of the α-chain. The soluble form does not lead to signal transduction and therefore has an antagonistic effect on IL-5 signaling. Both monomeric forms of IL-5Rα are low affinity receptors, while dimerization with the β-chain produces a high affinity receptor. In either case, the α-chain exclusively binds IL-5 and the intra-cellular portion of IL-5Rα is associated with Janus kinase (JAK) 2, a protein tyrosine-kinase essential in IL-5 signal transduction.

β-subunit
The β-subunit of the IL-5 receptor is responsible for signal transduction and contains several intracellular signaling domains. Unlike the α-chain, the β-chain does not bind IL-5, is not specific to this cytokine, and is expressed on practically all leukocytes. In fact, the β-subunit of the IL-5 receptor is also found in IL-3 and GM-CSF receptors where it is associated the IL-3Rα and GM-CSFRα subunits respectively. Therefore it is known as the common β receptor or βc. Like the IL-5Rα subunit, the β subunit’s cytoplasmic domain is constitutively associated with JAK2, as well as LYN , another tyrosine kinase, which are both essential for IL-5 signal transduction.

Effect of IL-5 on Eosinophils
Eosinophils are terminally differentiated granulocytes found in most mammals. The principal role of these cells, in a healthy host, is the elimination of antibody bound parasites through the release of cytotoxic granule proteins. Given that eosinophils are the primary IL-5Rα expressing cells, it is not surprising that this cell type responds to IL-5. In fact, IL-5 was originally discovered as an eosinophil colony stimulating factor, is a major regulator of eosinophil accumulation in tissues, and can modulate eosinophil behavior at every stage from maturation to survival.