Interleukin 5 (colony-stimulating factor, eosinophil)
|Crystal structure of human IL-5|
|RNA expression pattern|
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 .
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.
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 .
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.
- ↑ Milburn MV, Hassell AM, Lambert MH, Jordan SR, Proudfoot AE, Graber P et al. A novel dimer configuration revealed by the crystal structure at 2.4 A resolution of human interleukin-5. Nature 1993; 363(6425):172-176.
- ↑ Lee JS, Campbell HD, Kozak CA, Young IG. The IL-4 and IL-5 genes are closely linked and are part of a cytokine gene cluster on mouse chromosome 11. Somat Cell Mol Genet 1989; 15(2):143-152.
- ↑ van Leeuwen BH, Martinson ME, Webb GC, Young IG. Molecular organization of the cytokine gene cluster, involving the human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromosome 5. Blood 1989; 73(5):1142-1148.
- ↑ Dubucquoi S, Desreumaux P, Janin A, Klein O, Goldman M, Tavernier J et al. Interleukin 5 synthesis by eosinophils: association with granules and immunoglobulin-dependent secretion. J Exp Med 1994; 179(2):703-708.
- ↑ Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R et al. Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am J Respir Cell Mol Biol 1994; 10(5):471-480.
- ↑ Kaminuma O, Mori A, Kitamura N, Hashimoto T, Kitamura F, Inokuma S et al. Role of GATA-3 in IL-5 gene transcription by CD4+ T cells of asthmatic patients. Int Arch Allergy Immunol 2005; 137 Suppl 1:55-9. Epub;%2005 Jun 2.:55-59.
- ↑ Shen HH, Ochkur SI, McGarry MP, Crosby JR, Hines EM, Borchers MT et al. A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse. J Immunol 2003; 170(6):3296-3305.
- ↑ Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood 1992; 79(12):3101-3109.
- ↑ Geijsen N, Koenderman L, Coffer PJ. Specificity in cytokine signal transduction: lessons learned from the IL-3/IL-5/GM-CSF receptor family. Cytokine Growth Factor Rev 2001; 12(1):19-25.
- ↑ Tavernier J, Devos R, Cornelis S, Tuypens T, Van der HJ, Fiers W et al. A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF. Cell 1991; %20;66(6):1175-1184.
- ↑ Ogata N, Kouro T, Yamada A, Koike M, Hanai N, Ishikawa T et al. JAK2 and JAK1 constitutively associate with an interleukin-5 (IL-5) receptor alpha and betac subunit, respectively, and are activated upon IL-5 stimulation. Blood 1998; 91(7):2264-2271.
- ↑ Takaki S, Kanazawa H, Shiiba M, Takatsu K. A critical cytoplasmic domain of the interleukin-5 (IL-5) receptor alpha chain and its function in IL-5-mediated growth signal transduction. Mol Cell Biol 1994; 14(11):7404-7413.
- ↑ Martinez-Moczygemba M, Huston DP. Biology of common beta receptor-signaling cytokines: IL-3, IL-5, and GM-CSF. J Allergy Clin Immunol 2003; 112(4):653-665.
- ↑ Quelle FW, Sato N, Witthuhn BA, Inhorn RC, Eder M, Miyajima A et al. JAK2 associates with the beta c chain of the receptor for granulocyte-macrophage colony-stimulating factor, and its activation requires the membrane-proximal region. Mol Cell Biol 1994; 14(7):4335-4341.
- ↑ Li Y, Shen BF, Karanes C, Sensenbrenner L, Chen B. Association between Lyn protein tyrosine kinase (p53/56lyn) and the beta subunit of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors in a GM-CSF-dependent human megakaryocytic leukemia cell line (M-07e). J Immunol 1995; 155(4):2165-2174.
- ↑ Sato N, Sakamaki K, Terada N, Arai K, Miyajima A. Signal transduction by the high-affinity GM-CSF receptor: two distinct cytoplasmic regions of the common beta subunit responsible for different signaling. EMBO J 1993; 12(11):4181-4189.
- ↑ Giembycz MA, Lindsay MA. Pharmacology of the eosinophil. Pharmacol Rev 1999; 51(2):213-340.
- ↑ Lopez AF, Begley CG, Williamson DJ, Warren DJ, Vadas MA, Sanderson CJ. Murine eosinophil differentiation factor. An eosinophil-specific colony-stimulating factor with activity for human cells. J Exp Med 1986; 163(5):1085-1099.
|IL-1 superfamily||IL-1 (IL-1Ra) - IL-18 - IL-33|
|IL-6 like/gp130 utilizing||IL-6 - IL-11 - IL-27 - IL-30 - IL-31|
|IL-10 family||IL-10 - IL-19 - IL-20 - IL-22 - IL-24 - IL-26|
|Interferon type III||IL-28 - IL-29|
|Common γ-chain family||IL-2/IL-15 - IL-3 - IL-4 - IL-7 - IL-9 - IL-13 - IL-21|
|IL-12 family||IL-12 - IL-23 - IL-27 - IL-35|
|Other||IL-5 - IL-8 - IL-14 - IL-16 - IL-17/IL-25 (A) - IL-32|
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