Interleukin 5
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 human, 133 in the mouse) -long TH2 cytokine that is part of the hematopoietic family. Unlike other members of this cytokine family (namely IL-3 and GM-CSF) , this glycoprotein in its active form is a homodimer.[1] 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),[2][3] which are often co-expressed in TH2 cells. Interleukin-5 is also expressed by eosinophils [4] and has been observed in the mast cells of asthmatic airways by immunohistochemistry.[5] IL-5 expression is regulated by several transcription factors including GATA3.[6]
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[edit] Clinical significance
Interleukin-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma, wherein a large increase in the number of circulating, airway tissue, and induced sputum eosinophils have been observed.[7] Given the high concordance of eosinophils and, in particular, allergic asthma pathology, it has been widely speculated that eosinophils have an important role in the pathology of this disease.[8]
[edit] 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.
[edit] α-subunit
The IL-5Rα chain is exclusively expressed by eosinophils, some basophils and murine B1 cells or B cell precursors.[9] 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 bα-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.[10] 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.[11][12]
[edit] 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.[13] Therefore, it is known as the common β receptor or βc. As with the IL-5Rα subunit, the β subunit’s cytoplasmic domain is constitutively associated with JAK2,[14] as well as LYN,[15] another tyrosine kinase, which are both essential for IL-5 signal transduction.[16]
[edit] 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.[17] 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,[18] is a major regulator of eosinophil accumulation in tissues, and can modulate eosinophil behavior at every stage from maturation to survival.
[edit] Interactions
Interleukin 5 has been shown to interact with Interleukin 5 receptor alpha subunit.[19][20][21]
[edit] References
- ^ 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.
- ^ Woodcock, J M; Zacharakis B, Plaetinck G, Bagley C J, Qiyu S, Hercus T R, Tavernier J, Lopez A F (Nov. 1994). "Three residues in the common beta chain of the human GM-CSF, IL-3 and IL-5 receptors are essential for GM-CSF and IL-5 but not IL-3 high affinity binding and interact with Glu21 of GM-CSF". EMBO J. (ENGLAND) 13 (21): 5176–85. ISSN 0261-4189. PMC 395466. PMID 7957082. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=395466.
- ^ Johanson, K; Appelbaum E, Doyle M, Hensley P, Zhao B, Abdel-Meguid S S, Young P, Cook R, Carr S, Matico R (Apr. 1995). "Binding interactions of human interleukin 5 with its receptor alpha subunit. Large scale production, structural, and functional studies of Drosophila-expressed recombinant proteins". J. Biol. Chem. (UNITED STATES) 270 (16): 9459–71. doi:10.1074/jbc.270.16.9459. ISSN 0021-9258. PMID 7721873.
- ^ Murata, Y; Takaki S, Migita M, Kikuchi Y, Tominaga A, Takatsu K (Feb. 1992). "Molecular cloning and expression of the human interleukin 5 receptor". J. Exp. Med. (UNITED STATES) 175 (2): 341–51. doi:10.1084/jem.175.2.341. ISSN 0022-1007. PMC 2119102. PMID 1732409. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2119102.
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