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Interleukin 5 (colony-stimulating factor, eosinophil)

Crystal structure of human IL-5
Available structures
1hul
Identifiers
Symbols IL5; EDF; IL-5; TRF
External IDs OMIM147850 MGI96557 HomoloGene679 GeneCards: IL5 Gene
RNA expression pattern
PBB GE IL5 207952 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3567 16191
Ensembl ENSG00000113525 ENSMUSG00000036117
UniProt P05113 Q05A89
RefSeq (mRNA) NM_000879 NM_010558
RefSeq (protein) NP_000870 NP_034688
Location (UCSC) Chr 5:
131.91 - 131.91 Mb
Chr 11:
53.56 - 53.57 Mb
PubMed search [1] [2]

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) , 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 GATA-3 [6].

Contents

Clinical significance

Interleukin-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma where 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, particularly, allergic asthma pathology, it has been widely speculated that eosinophils have an important role in the pathology of this disease [8].

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.

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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].

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. Like 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].

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.

Interactions

Interleukin 5 has been shown to interact with Interleukin 5 receptor alpha subunit.[19][20][21]

References

  1. ^ 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.
  2. ^ 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.
  3. ^ 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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.
  8. ^ Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood 1992; 79(12):3101-3109.
  9. ^ 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ Giembycz MA, Lindsay MA. Pharmacology of the eosinophil. Pharmacol Rev 1999; 51(2):213-340.
  18. ^ 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.
  19. ^ 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. PMID 7957082.  
  20. ^ 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. ISSN 0021-9258. PMID 7721873.  
  21. ^ 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. ISSN 0022-1007. PMID 1732409.  

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