interleukin 9

{{Short description|Protein-coding gene in the species Homo sapiens}}

Interleukin 9, also known as IL-9, is a pleiotropic cytokine (cell signalling molecule) belonging to the group of interleukins.{{cite web | title = Entrez Gene: IL9 interleukin 9 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3578 }} IL-9 is produced by variety of cells like mast cells, NKT cells, Th2, Th17, Treg, ILC2, and Th9 cells in different amounts. Among them, Th9 cells are regarded as the major CD4+ T cells that produce IL-9.{{cite book | vauthors = Rojas-Zuleta WG, Sanchez E | chapter = IL-9: Function, Sources, and Detection | title = Th9 Cells | volume = 1585 | pages = 21–35 | date = 2017 | pmid = 28477184 | doi = 10.1007/978-1-4939-6877-0_2 | series = Methods in Molecular Biology | isbn = 978-1-4939-6876-3 | hdl = 10161/14730 }}

Functions

Il-9 is a cytokine secreted by CD4+ helper cells that acts as a regulator of a variety of hematopoietic cells.{{cite journal | vauthors = Perumal NB, Kaplan MH | title = Regulating IL9 transcription in T helper cells | journal = Trends in Immunology | volume = 32 | issue = 4 | pages = 146–150 | date = Apr 2011 | pmid = 21371941 | pmc = 3070825 | doi = 10.1016/j.it.2011.01.006 }} This cytokine stimulates cell proliferation and prevents apoptosis. It functions through the interleukin-9 receptor (IL9R), which activates different signal transducer and activator (STAT) proteins namely STAT1, STAT3 and STAT5 and thus connects this cytokine to various biological processes. The gene encoding this cytokine has been identified as a candidate gene for asthma. Genetic studies on a mouse model of asthma demonstrated that this cytokine is a determining factor in the pathogenesis of bronchial hyperresponsiveness.

Interleukin-9 has also been shown to inhibit melanoma growth in mice.

{{cite journal | vauthors = Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X, Jetten AM, Khoury SJ, Fuhlbrigge RC, Kuchroo VK, Clark RA, Kupper TS | title = Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells | journal = Nature Medicine | volume = 18 | issue = 8 | pages = 1248–1253 | date = August 2012 | pmid = 22772464 | pmc = 3518666 | doi = 10.1038/nm.2856 }}

{{lay source |template = cite web|url = https://medicalxpress.com/news/2012-07-scientists-molecule-immune-dangerous-skin.html|title = Scientists find molecule in immune system that could help treat dangerous skin cancer|date = July 8, 2012 |website = MedicalXpress }}

Additionally, it gives rise to the multiplication of hematologic neoplasias and also Hodgkin's lymphoma in humans but IL-9 also has antitumor properties in solid tumors, for example melanoma.

Discovery

IL-9 was first described in the late 1980s as a member of a growing number of cytokines that had pleiotropic functions in the immune system. IL-9 remains an understudied cytokine despite the attribution of many biological functions to it. IL-9 was first purified and characterized as a T cell and mast cell growth factor and termed as P40, based on its molecular weight, or MEA, based on its mast cell growth-enhancing activity. The cloning and complete amino acid sequencing of P40 disclosed that it is structurally different from other T cell growth factors. It was therefore named IL-9 based on its biological effects on both myeloid and lymphoid cells.{{cite journal | vauthors = Goswami R, Kaplan MH | title = A brief history of IL-9 | journal = Journal of Immunology | location = Baltimore, Md. | volume = 186 | issue = 6 | pages = 3283–3288 | date = March 2011 | pmid = 21368237 | pmc = 3074408 | doi = 10.4049/jimmunol.1003049 }}

The identification and cloning was first done by Yang and colleagues as a mitogenic factor for a human megakaryoblastic leukemia. The same human cDNA was isolated again by cross-hybridization with the mouse IL-9 probe.{{cite book | vauthors = Renauld JC | chapter = Interleukin-9: Structural characteristics and biologic properties | title = Cytokines: Interleukins and Their Receptors | volume = 80 | pages = 287–303 | date = 1995 | pmid = 8821582 | doi = 10.1007/978-1-4613-1241-3_11 | publisher = Springer, Boston, MA | isbn = 978-1-4612-8528-1 | series = Cancer Treatment and Research | language = en }}

Gene location

The human IL-9 gene is located on the long arm of human chromosome 5 at band 5q31-32, a region which is not found in a number of patients with acquired chromosome 5q deletion syndrome.{{cite journal | vauthors = Kelleher K, Bean K, Clark SC, Leung WY, Yang-Feng TL, Chen JW, Lin PF, Luo W, Yang YC | title = Human interleukin-9: genomic sequence, chromosomal location, and sequences essential for its expression in human T-cell leukemia virus (HTLV)-I-transformed human T cells | journal = Blood | volume = 77 | issue = 7 | pages = 1436–1441 | date = Apr 1991 | pmid = 1901233 | doi = 10.1182/blood.V77.7.1436.1436 | url = http://www.bloodjournal.org/content/bloodjournal/77/7/1436.full.pdf | doi-access = free }}

Protein structure

Human IL-9 protein sequence contains 144 residues with a typical signal peptide of 18 amino acids. There is also the presence of 9 cysteines in mature polypeptide and 4 N-linked glycosylation sites. Until recently, IL-9 was thought to be evolutionary related to IL-7.{{cite journal | vauthors = Boulay JL, Paul WE | title = Hematopoietin sub-family classification based on size, gene organization and sequence homology | journal = Current Biology | volume = 3 | issue = 9 | pages = 573–581 | date = 1993-09-01 | pmid = 15335670 | doi = 10.1016/0960-9822(93)90002-6 | issn = 0960-9822 | bibcode = 1993CBio....3..573B | s2cid = 42479456 }} However, we know now that IL-9 is closer to IL-2 and IL-15 than to IL-7,{{cite journal | vauthors = Reche PA | title = The tertiary structure of γc cytokines dictates receptor sharing | journal = Cytokine | volume = 116 | pages = 161–168 | date = 2019-02-01 | pmid = 30716660 | doi = 10.1016/j.cyto.2019.01.007 | issn = 1096-0023 | s2cid = 73449371 }} at both the tertiary and amino acid sequence levels.

Production

Interleukin 33 (IL-33) induces IL-9 expression and secretion in T cells, which was confirmed by the results obtained in mice by using Human in vitro system.{{cite journal | vauthors = Humphreys NE, Xu D, Hepworth MR, Liew FY, Grencis RK | title = IL-33, a potent inducer of adaptive immunity to intestinal nematodes | journal = Journal of Immunology | location = Baltimore, Md. | volume = 180 | issue = 4 | pages = 2443–2449 | date = February 2008 | pmid = 18250453 | doi = 10.4049/jimmunol.180.4.2443 | doi-access = free }} Whereas the report of others confirms that TGF-β is an essential factor for IL-9 induction.{{cite journal | vauthors = Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, Orban T, Elyaman W, Khoury SJ, Kuchroo VK, Baecher-Allan C, Hafler DA | title = TGF-beta induces IL-9 production from human Th17 cells | journal = Journal of Immunology | location = Baltimore, Md. | volume = 185 | issue = 1 | pages = 46–54 | date = July 2010 | pmid = 20498357 | pmc = 2936106 | doi = 10.4049/jimmunol.1000356 }} For the first time (Lars Blom, Britta C. Poulsen, Bettina M. Jensen, Anker Hansen and Lars K. Poulsen published a journal online in 2011 Jul 6),indicating that TGF-β may be important for production of IL-9 but it is not only the definite requirement for IL-9 induction, since cultures with IL-33 without TGF-β have noticeably increased secretion of IL-9, suggesting an important role of IL-33, even though that the effect was not found significant on the gene level.{{cite journal | vauthors = Blom L, Poulsen BC, Jensen BM, Hansen A, Poulsen LK | title = IL-33 induces IL-9 production in human CD4+ T cells and basophils | journal = PLOS ONE | volume = 6 | issue = 7 | pages = e21695 | date = 2011-07-06 | pmid = 21765905 | pmc = 3130774 | doi = 10.1371/journal.pone.0021695 | bibcode = 2011PLoSO...621695B | doi-access = free }}

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IL-9 expression

The analysis of IL-9 expression in different types of tumours such as Large cell anaplastic lymphoma (LCAL) and Hodgkin's Disease (HD) by Northern blot analysis and in situ hybridization has shown that IL-9 is not involved as an autocrine growth factor in the pathogenesis of most B and T-cell lymphomas, but it may have a part in HD and LCAL autocrine growth.

The further investigation could be done to conclude another probability, that, the in vivo overexpression of IL-9 might show the unique symptoms related to eosinophilia which was recently reported for Interleukin 5 positive cases of HD.{{cite journal | vauthors = Merz H, Houssiau FA, Orscheschek K, Renauld JC, Fliedner A, Herin M, Noel H, Kadin M, Mueller-Hermelink HK, Van Snick J | title = Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma | journal = Blood | volume = 78 | issue = 5 | pages = 1311–1317 | date = Sep 1991 | pmid = 1908723 | doi = 10.1182/blood.V78.5.1311.1311 | url = http://www.bloodjournal.org/content/78/5/1311 | doi-access = free }}

IL-9 was found to be the first physiological stimulus triggering BCL3 expression in T cells and mast cells by the analysis done in mouse.{{cite journal | vauthors = Richard M, Louahed J, Demoulin JB, Renauld JC | title = Interleukin-9 regulates NF-kappaB activity through BCL3 gene induction | journal = Blood | volume = 93 | issue = 12 | pages = 4318–4327 | date = Jun 1999 | pmid = 10361130 | doi = 10.1182/blood.V93.12.4318 | url = http://www.bloodjournal.org/content/93/12/4318 | url-access = subscription }}