# Interleukin 9

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**Interleukin 9**, also known as **IL-9**, is a [pleiotropic](/source/Pleiotropy) [cytokine](/source/Cytokine) (cell signalling molecule) belonging to the group of [interleukins](/source/Interleukin).[1] IL-9 is produced by variety of cells like [mast cells](/source/Mast_cell), [NKT](/source/Natural_killer_T_cell) cells, [Th2](/source/T_helper_cell), [Th17](/source/T_helper_17_cell), [Treg](/source/Regulatory_T_cell), [ILC2](/source/ILC2), and Th9 cells in different amounts. Among them, [Th9 cells](/source/T_helper_cell) are regarded as the major [CD4+ T cells](/source/CD4%2B_helper_cells) that produce IL-9.[2]

## Functions

Il-9 is a [cytokine](/source/Cytokine) secreted by [CD4+ helper cells](/source/CD4%2B_helper_cells) that acts as a regulator of a variety of [hematopoietic cells](/source/Hematopoietic_cell).[3] This cytokine stimulates [cell proliferation](/source/Cell_proliferation) and prevents [apoptosis](/source/Apoptosis). It functions through the [interleukin-9 receptor](/source/Interleukin-9_receptor) (IL9R), which activates different signal transducer and activator ([STAT](/source/STAT_protein)) proteins namely [STAT1](/source/STAT1), [STAT3](/source/STAT3) and [STAT5](/source/STAT5) and thus connects this cytokine to various biological processes. The gene encoding this cytokine has been identified as a candidate gene for [asthma](/source/Asthma). Genetic studies on a mouse model of asthma demonstrated that this cytokine is a determining factor in the pathogenesis of [bronchial hyperresponsiveness](/source/Bronchial_hyperresponsiveness).[1]

Interleukin-9 has also been shown to inhibit [melanoma](/source/Melanoma) growth in mice. [4]

Additionally, it gives rise to the multiplication of [hematologic neoplasias](/source/Hematologic_neoplasms) and also [Hodgkin's lymphoma](/source/Hodgkin's_lymphoma) in humans but IL-9 also has antitumor properties in solid tumors, for example [melanoma](/source/Melanoma).[2]

## Discovery

IL-9 was first described in the late 1980s as a member of a growing number of [cytokines](/source/Cytokines) that had [pleiotropic](/source/Pleiotropy) functions in the [immune](/source/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](/source/T_cell) and [mast cell](/source/Mast_cell) growth factor and termed as P40, based on its [molecular weight](/source/Molecular_weight), or MEA, based on its mast cell growth-enhancing activity. The [cloning](/source/Cloning) and complete [amino acid](/source/Amino_acid) sequencing of P40 disclosed that it is structurally different from other [T cell](/source/T_cell) growth factors. It was therefore named IL-9 based on its biological effects on both [myeloid](/source/Myeloid_cells) and [lymphoid](/source/Lymphoid_cells) cells.[5]

The identification and [cloning](/source/Cloning) was first done by Yang and colleagues as a [mitogenic factor](/source/Mitogenic_factor) for a human megakaryoblastic leukemia. The same human [cDNA](/source/CDNA) was isolated again by cross-hybridization with the mouse IL-9 probe.[6]

## Gene location

The human IL-9 gene is located on the long arm of human [chromosome 5](/source/Chromosome_5_(human)) at band 5q31-32, a region which is not found in a number of patients with acquired [chromosome 5q deletion syndrome](/source/Chromosome_5q_deletion_syndrome).[7]

## Protein structure

Human IL-9 [protein](/source/Protein) sequence contains 144 residues with a typical [signal peptide](/source/Signal_peptide) of 18 [amino acids](/source/Amino_acid). There is also the presence of 9 [cysteines](/source/Cysteine) in mature [polypeptide](/source/Polypeptide) and 4 [N-linked glycosylation](/source/N-linked_glycosylation) sites.[6] Until recently, IL-9 was thought to be evolutionary related to IL-7.[8] However, we know now that IL-9 is closer to IL-2 and IL-15 than to IL-7,[9] at both the tertiary and amino acid sequence levels.

## Production

[Interleukin 33](/source/Interleukin_33) (IL-33) induces IL-9 expression and secretion in [T cells](/source/T_cell), which was confirmed by the results obtained in mice by using Human *[in vitro](/source/In_vitro)* system.[10] Whereas the report of others confirms that [TGF-β](/source/TGF-b) is an essential factor for IL-9 induction.[11] 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](/source/Cell_culture) 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](/source/Gene) level.[12]

## IL-9 expression

The analysis of IL-9 expression in different types of [tumours](/source/Tumours) such as Large cell anaplastic lymphoma (LCAL) and [Hodgkin's Disease (HD)](/source/Hodgkin's_Disease) by [Northern blot analysis](/source/Northern_blot) and [in situ hybridization](/source/In_situ_hybridization) has shown that IL-9 is not involved as an autocrine growth factor in the [pathogenesis](/source/Pathogenesis) of most [B and T-cell lymphomas](/source/B-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](/source/In_vivo) [overexpression](/source/Gene_expression) of IL-9 might show the unique [symptoms](/source/Symptom) related to [eosinophilia](/source/Eosinophilia) which was recently reported for [Interleukin 5](/source/Interleukin_5) positive cases of HD.[13]

IL-9 was found to be the first physiological stimulus triggering *[BCL3](/source/BCL3)* expression in [T cells](/source/T_cell) and [mast cells](/source/Mast_cell) by the analysis done in mouse.[14]

## References

1. ["Entrez Gene: IL9 interleukin 9"](https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3578)

1. Rojas-Zuleta WG, Sanchez E (2017). "IL-9: Function, Sources, and Detection". *Th9 Cells*. Vol. 1585. Methods in Molecular Biology. pp. 21–35. [doi:10.1007/978-1-4939-6877-0_2](https://doi.org/10.1007/978-1-4939-6877-0_2). [hdl:10161/14730](https://hdl.handle.net/10161/14730). ISBN 978-1-4939-6876-3. [PMID 28477184](https://pubmed.ncbi.nlm.nih.gov/28477184)

1. Perumal NB, Kaplan MH (Apr 2011). "Regulating IL9 transcription in T helper cells". *Trends in Immunology*. **32** (4): 146–150. [doi:10.1016/j.it.2011.01.006](https://doi.org/10.1016/j.it.2011.01.006). [PMC 3070825](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070825). [PMID 21371941](https://pubmed.ncbi.nlm.nih.gov/21371941)

1. Purwar R, Schlapbach C, Xiao S, Kang HS, Elyaman W, Jiang X, Jetten AM, Khoury SJ, Fuhlbrigge RC, Kuchroo VK, Clark RA, Kupper TS (August 2012). "Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells". *Nature Medicine*. **18** (8): 1248–1253. [doi:10.1038/nm.2856](https://doi.org/10.1038/nm.2856). [PMC 3518666](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3518666). [PMID 22772464](https://pubmed.ncbi.nlm.nih.gov/22772464) *

1. Goswami R, Kaplan MH (March 2011). "A brief history of IL-9". *Journal of Immunology*. **186** (6): 3283–3288. [doi:10.4049/jimmunol.1003049](https://doi.org/10.4049/jimmunol.1003049). [PMC 3074408](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074408). [PMID 21368237](https://pubmed.ncbi.nlm.nih.gov/21368237)

1. Renauld JC (1995). "Interleukin-9: Structural characteristics and biologic properties". *Cytokines: Interleukins and Their Receptors*. Vol. 80. Cancer Treatment and Research. Springer, Boston, MA. pp. 287–303. [doi:10.1007/978-1-4613-1241-3_11](https://doi.org/10.1007/978-1-4613-1241-3_11). ISBN 978-1-4612-8528-1. [PMID 8821582](https://pubmed.ncbi.nlm.nih.gov/8821582)

1. Kelleher K, Bean K, Clark SC, Leung WY, Yang-Feng TL, Chen JW, Lin PF, Luo W, Yang YC (Apr 1991). ["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"](http://www.bloodjournal.org/content/bloodjournal/77/7/1436.full.pdf). *Blood*. **77** (7): 1436–1441. [doi:10.1182/blood.V77.7.1436.1436](https://doi.org/10.1182/blood.V77.7.1436.1436). [PMID 1901233](https://pubmed.ncbi.nlm.nih.gov/1901233)

1. Boulay JL, Paul WE (1993-09-01). "Hematopoietin sub-family classification based on size, gene organization and sequence homology". *Current Biology*. **3** (9): 573–581. [Bibcode:1993CBio....3..573B](https://ui.adsabs.harvard.edu/abs/1993CBio....3..573B). [doi:10.1016/0960-9822(93)90002-6](https://doi.org/10.1016/0960-9822(93)90002-6). [ISSN 0960-9822](https://www.worldcat.org/issn/0960-9822). [PMID 15335670](https://pubmed.ncbi.nlm.nih.gov/15335670). [S2CID 42479456](https://api.semanticscholar.org/CorpusID:42479456)

1. Reche PA (2019-02-01). "The tertiary structure of γc cytokines dictates receptor sharing". *Cytokine*. **116**: 161–168. [doi:10.1016/j.cyto.2019.01.007](https://doi.org/10.1016/j.cyto.2019.01.007). [ISSN 1096-0023](https://www.worldcat.org/issn/1096-0023). [PMID 30716660](https://pubmed.ncbi.nlm.nih.gov/30716660). [S2CID 73449371](https://api.semanticscholar.org/CorpusID:73449371)

1. Humphreys NE, Xu D, Hepworth MR, Liew FY, Grencis RK (February 2008). "IL-33, a potent inducer of adaptive immunity to intestinal nematodes". *Journal of Immunology*. **180** (4): 2443–2449. [doi:10.4049/jimmunol.180.4.2443](https://doi.org/10.4049/jimmunol.180.4.2443). [PMID 18250453](https://pubmed.ncbi.nlm.nih.gov/18250453)

1. Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, Orban T, Elyaman W, Khoury SJ, Kuchroo VK, Baecher-Allan C, Hafler DA (July 2010). "TGF-beta induces IL-9 production from human Th17 cells". *Journal of Immunology*. **185** (1): 46–54. [doi:10.4049/jimmunol.1000356](https://doi.org/10.4049/jimmunol.1000356). [PMC 2936106](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936106). [PMID 20498357](https://pubmed.ncbi.nlm.nih.gov/20498357)

1. Blom L, Poulsen BC, Jensen BM, Hansen A, Poulsen LK (2011-07-06). "IL-33 induces IL-9 production in human CD4+ T cells and basophils". *PLOS ONE*. **6** (7). [Bibcode:2011PLoSO...621695B](https://ui.adsabs.harvard.edu/abs/2011PLoSO...621695B). [doi:10.1371/journal.pone.0021695](https://doi.org/10.1371/journal.pone.0021695). [PMC 3130774](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130774). [PMID 21765905](https://pubmed.ncbi.nlm.nih.gov/21765905)

1. Merz H, Houssiau FA, Orscheschek K, Renauld JC, Fliedner A, Herin M, Noel H, Kadin M, Mueller-Hermelink HK, Van Snick J (Sep 1991). ["Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma"](http://www.bloodjournal.org/content/78/5/1311). *Blood*. **78** (5): 1311–1317. [doi:10.1182/blood.V78.5.1311.1311](https://doi.org/10.1182/blood.V78.5.1311.1311). [PMID 1908723](https://pubmed.ncbi.nlm.nih.gov/1908723)

1. Richard M, Louahed J, Demoulin JB, Renauld JC (Jun 1999). ["Interleukin-9 regulates NF-kappaB activity through BCL3 gene induction"](http://www.bloodjournal.org/content/93/12/4318). *Blood*. **93** (12): 4318–4327. [doi:10.1182/blood.V93.12.4318](https://doi.org/10.1182/blood.V93.12.4318). [PMID 10361130](https://pubmed.ncbi.nlm.nih.gov/10361130)

## Further reading

- Renauld JC, Houssiau F, Louahed J, Vink A, Van Snick J, Uyttenhove C (1993). "Interleukin-9". *Advances in Immunology*. Vol. 54. pp. 79–97. [doi:10.1016/S0065-2776(08)60533-7](https://doi.org/10.1016/S0065-2776(08)60533-7). ISBN 978-0-12-022454-8. [PMID 8379467](https://pubmed.ncbi.nlm.nih.gov/8379467)
- Knoops L, Renauld JC (December 2004). "IL-9 and its receptor: from signal transduction to tumorigenesis". *Growth Factors*. **22** (4): 207–215. [doi:10.1080/08977190410001720879](https://doi.org/10.1080/08977190410001720879). [PMID 15621723](https://pubmed.ncbi.nlm.nih.gov/15621723). [S2CID 40523692](https://api.semanticscholar.org/CorpusID:40523692)
- Modi WS, Pollock DD, Mock BA, Banner C, Renauld JC, Van Snick J (1991). "Regional localization of the human glutaminase (GLS) and interleukin-9 (IL9) genes by in situ hybridization". *Cytogenetics and Cell Genetics*. **57** (2–3): 114–116. [doi:10.1159/000133126](https://doi.org/10.1159/000133126). [PMID 1680606](https://pubmed.ncbi.nlm.nih.gov/1680606)
- Kelleher K, Bean K, Clark SC, Leung WY, Yang-Feng TL, Chen JW, Lin PF, Luo W, Yang YC (April 1991). "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". *Blood*. **77** (7): 1436–1441. [doi:10.1182/blood.V77.7.1436.1436](https://doi.org/10.1182/blood.V77.7.1436.1436). [PMID 1901233](https://pubmed.ncbi.nlm.nih.gov/1901233)
- Holbrook ST, Ohls RK, Schibler KR, Yang YC, Christensen RD (May 1991). "Effect of interleukin-9 on clonogenic maturation and cell-cycle status of fetal and adult hematopoietic progenitors". *Blood*. **77** (10): 2129–2134. [doi:10.1182/blood.V77.10.2129.2129](https://doi.org/10.1182/blood.V77.10.2129.2129). [PMID 1903074](https://pubmed.ncbi.nlm.nih.gov/1903074)
- Merz H, Houssiau FA, Orscheschek K, Renauld JC, Fliedner A, Herin M, Noel H, Kadin M, Mueller-Hermelink HK, Van Snick J (September 1991). "Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma". *Blood*. **78** (5): 1311–1317. [doi:10.1182/blood.V78.5.1311.1311](https://doi.org/10.1182/blood.V78.5.1311.1311). [PMID 1908723](https://pubmed.ncbi.nlm.nih.gov/1908723)
- Renauld JC, Goethals A, Houssiau F, Merz H, Van Roost E, Van Snick J (June 1990). "Human P40/IL-9. Expression in activated CD4+ T cells, genomic organization, and comparison with the mouse gene". *Journal of Immunology*. **144** (11): 4235–4241. [doi:10.4049/jimmunol.144.11.4235](https://doi.org/10.4049/jimmunol.144.11.4235). [PMID 1971295](https://pubmed.ncbi.nlm.nih.gov/1971295). [S2CID 30151082](https://api.semanticscholar.org/CorpusID:30151082)
- Renauld JC, Goethals A, Houssiau F, Van Roost E, Van Snick J (January 1990). "Cloning and expression of a cDNA for the human homolog of mouse T cell and mast cell growth factor P40". *Cytokine*. **2** (1): 9–12. [doi:10.1016/1043-4666(90)90037-T](https://doi.org/10.1016/1043-4666(90)90037-T). [hdl:2078.1/11464](https://hdl.handle.net/2078.1/11464). [PMID 2129501](https://pubmed.ncbi.nlm.nih.gov/2129501)
- Yang YC, Ricciardi S, Ciarletta A, Calvetti J, Kelleher K, Clark SC (November 1989). "Expression cloning of cDNA encoding a novel human hematopoietic growth factor: human homologue of murine T-cell growth factor P40". *Blood*. **74** (6): 1880–1884. [doi:10.1182/blood.V74.6.1880.1880](https://doi.org/10.1182/blood.V74.6.1880.1880). [PMID 2508790](https://pubmed.ncbi.nlm.nih.gov/2508790)
- Yin T, Keller SR, Quelle FW, Witthuhn BA, Tsang ML, Lienhard GE, Ihle JN, Yang YC (September 1995). "Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases". *The Journal of Biological Chemistry*. **270** (35): 20497–20502. [doi:10.1074/jbc.270.35.20497](https://doi.org/10.1074/jbc.270.35.20497). [PMID 7544789](https://pubmed.ncbi.nlm.nih.gov/7544789)
- Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, Meyers DA, Levitt RC (October 1995). "Genetic susceptibility to asthma--bronchial hyperresponsiveness coinherited with a major gene for atopy". *The New England Journal of Medicine*. **333** (14): 894–900. [doi:10.1056/NEJM199510053331402](https://doi.org/10.1056/NEJM199510053331402). [PMID 7666875](https://pubmed.ncbi.nlm.nih.gov/7666875)
- Le Beau MM, Espinosa R, Neuman WL, Stock W, Roulston D, Larson RA, Keinanen M, Westbrook CA (June 1993). "Cytogenetic and molecular delineation of the smallest commonly deleted region of chromosome 5 in malignant myeloid diseases". *Proceedings of the National Academy of Sciences of the United States of America*. **90** (12): 5484–5488. [Bibcode:1993PNAS...90.5484B](https://ui.adsabs.harvard.edu/abs/1993PNAS...90.5484B). [doi:10.1073/pnas.90.12.5484](https://doi.org/10.1073/pnas.90.12.5484). [PMC 46745](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC46745). [PMID 8516290](https://pubmed.ncbi.nlm.nih.gov/8516290)
- Demoulin JB, Uyttenhove C, Van Roost E, DeLestré B, Donckers D, Van Snick J, Renauld JC (September 1996). "A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9". *Molecular and Cellular Biology*. **16** (9): 4710–4716. [doi:10.1128/mcb.16.9.4710](https://doi.org/10.1128/mcb.16.9.4710). [PMC 231471](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC231471). [PMID 8756628](https://pubmed.ncbi.nlm.nih.gov/8756628)
- Nicolaides NC, Holroyd KJ, Ewart SL, Eleff SM, Kiser MB, Dragwa CR, Sullivan CD, Grasso L, Zhang LY, Messler CJ, Zhou T, Kleeberger SR, Buetow KH, Levitt RC (November 1997). "Interleukin 9: a candidate gene for asthma". *Proceedings of the National Academy of Sciences of the United States of America*. **94** (24): 13175–13180. [Bibcode:1997PNAS...9413175N](https://ui.adsabs.harvard.edu/abs/1997PNAS...9413175N). [doi:10.1073/pnas.94.24.13175](https://doi.org/10.1073/pnas.94.24.13175). [PMC 24282](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC24282). [PMID 9371819](https://pubmed.ncbi.nlm.nih.gov/9371819)
- Demoulin JB, Van Roost E, Stevens M, Groner B, Renauld JC (September 1999). "Distinct roles for STAT1, STAT3, and STAT5 in differentiation gene induction and apoptosis inhibition by interleukin-9". *The Journal of Biological Chemistry*. **274** (36): 25855–25861. [doi:10.1074/jbc.274.36.25855](https://doi.org/10.1074/jbc.274.36.25855). [PMID 10464327](https://pubmed.ncbi.nlm.nih.gov/10464327)
- Lejeune D, Demoulin JB, Renauld JC (January 2001). "Interleukin 9 induces expression of three cytokine signal inhibitors: cytokine-inducible SH2-containing protein, suppressor of cytokine signalling (SOCS)-2 and SOCS-3, but only SOCS-3 overexpression suppresses interleukin 9 signalling". *The Biochemical Journal*. **353** (Pt 1): 109–116. [doi:10.1042/0264-6021:3530109](https://doi.org/10.1042/0264-6021:3530109). [PMC 1221548](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1221548). [PMID 11115404](https://pubmed.ncbi.nlm.nih.gov/11115404)
- Little FF, Cruikshank WW, Center DM (September 2001). "Il-9 stimulates release of chemotactic factors from human bronchial epithelial cells". *American Journal of Respiratory Cell and Molecular Biology*. **25** (3): 347–352. [doi:10.1165/ajrcmb.25.3.4349](https://doi.org/10.1165/ajrcmb.25.3.4349). [PMID 11588013](https://pubmed.ncbi.nlm.nih.gov/11588013)
- Toda M, Tulic MK, Levitt RC, Hamid Q (February 2002). "A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma". *The Journal of Allergy and Clinical Immunology*. **109** (2): 246–250. [doi:10.1067/mai.2002.121555](https://doi.org/10.1067/mai.2002.121555). [PMID 11842292](https://pubmed.ncbi.nlm.nih.gov/11842292)
- Pilette C, Ouadrhiri Y, Van Snick J, Renauld JC, Staquet P, Vaerman JP, Sibille Y (April 2002). "IL-9 inhibits oxidative burst and TNF-alpha release in lipopolysaccharide-stimulated human monocytes through TGF-beta". *Journal of Immunology*. **168** (8): 4103–4111. [doi:10.4049/jimmunol.168.8.4103](https://doi.org/10.4049/jimmunol.168.8.4103). [PMID 11937570](https://pubmed.ncbi.nlm.nih.gov/11937570)

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Adapted from the Wikipedia article [Interleukin 9](https://en.wikipedia.org/wiki/Interleukin_9) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Interleukin_9?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.