HGNC Approved Gene Symbol: IL9R
Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:155,997,696-156,013,020 (from NCBI)
Interleukin-9 (IL9; 146931) was originally identified as a growth factor for murine T helper cell clones, murine mast cell lines, and a human megakaryoblastic leukemia line. Subsequently, additional biologic targets were discovered, including human T-cell lines and human erythroid and myeloid precursors. Moreover, involvement of IL9 in tumorigenesis was suggested by the observation that lymph nodes from patients with Hodgkin disease or large-cell anaplastic lymphoma express IL9 constitutively. Renauld et al. (1992) reported the expression cloning and sequencing of a cDNA encoding the murine IL9 receptor. They used this cDNA to identify a human homolog. Sequence analysis showed that the IL9 receptor belongs to the hematopoietin receptor superfamily and is expressed in membrane-bound and soluble forms.
Chang et al. (1994) determined that the IL9R gene encodes a 522-amino acid type I transmembrane protein. They also found evidence for alternatively spliced isoforms of the protein.
Russell et al. (1993) suggested that the interleukin receptor common gamma chain, or gamma-c (IL2RG; 308380), may be shared with the IL9 receptor.
Demoulin et al. (1996) expressed mutated IL9R molecules and showed that a single tyrosine at position 116 in the receptor's intracellular domain is phosphorylated after IL9 binding and mediates the activation of STAT1, STAT3 (102582), and STAT5 (601511). They also showed that JAK1 is constitutively associated with IL9R and that activation of JAK1 depends on a distinct intracellular domain of IL9R.
Ihle and Kerr (1995) reviewed the activation cascade involving cytokines, cytokine receptors, the Janus kinases (see JAK1; 147795), and the signal transducers and activators of transcription, or STATs (see STAT1; 600555).
IL9R is expressed on many hemopoietic cells, including T cells, mast cells, and macrophages. By RT-PCR analysis, Abdelilah et al. (2001) detected expression of IL9R in polymorphonuclear neutrophils (PMNs) from all asthmatic patients tested but in only some controls. Flow cytometric analysis demonstrated surface expression of IL9R on PMNs of all asthmatics tested, with less intense expression on neutrophils of some controls. Immunohistochemical analysis revealed surface and intracytoplasmic expression in all asthmatic PMNs and bronchoalveolar lavage cells, but little or no expression in control PMNs. Functional analysis showed that recombinant IL9 could induce PMNs from asthmatic patients to produce IL8 (146930), a proinflammatory cytokine, at higher levels than from control PMNs.
Using flow cytometry and RT-PCR analysis, Gounni et al. (2004) found that human airway smooth muscle (ASM) cells expressed IL9R mRNA constitutively and IL9R protein on their surface. Incubation of ASM cells with IL9 induced dose-dependent, IL13 (147683)- and IL4 (147780)-independent secretion of CCL11 (601156), which in turn recruited eosinophils. IL9 had no effect on the release of CCL17 (601520). Gounni et al. (2004) concluded that IL9-dependent activation of ASM cells via IL9R contributes to eosinophilic inflammation observed in asthma.
Chang et al. (1994) isolated the genomic clone of the IL9R gene, based on its sequence homology with a human IL9R cDNA isolated from a human megakaryocyte cell line. It consists of 10 exons spread over approximately 13.7 kb.
Kermouni et al. (1995) also characterized the genomic structure of IL9R and noted an eleventh exon in a gene which spans about 17 kb of DNA.
Kermouni et al. (1995) used PCR analysis of somatic cell hybrid DNAs for chromosome assignment and fluorescence in situ hybridization to map the IL9R gene to the pseudoautosomal regions at Xq28 and Yq12. A CA repeat in intron 8 was shown to be the same as a sequence identified by Kvaloy et al. (1994) which was mapped about 20 kb from the Xq and Yq telomeres. This entire region represents about 320 kb of DNA and has an L1 element at its proximal border. IL9R was reportedly the first gene to be mapped to the long-arm pseudoautosomal region; a considerable number of genes had previously been mapped to the pseudoautosomal region of Xp and Yp. Kermouni et al. (1995) speculated that some of the phenotypic features associated with Yq deletions, such as short stature, azoospermia, learning disabilities, and facial dysmorphism, may be the result of loss of IL9R or other adjacent loci in the long-arm pseudoautosomal region.
Kermouni et al. (1995) found pseudogenes for IL9R at the subtelomeric regions 9q34, 10p15, 16p13.3, and 18p11.3. They proposed that the pseudogenes may have arisen from translocations at the end of the X or Y chromosomes possibly involving an Alu repeat located in the second intron.
Two genes located in the pseudoautosomal region on the short arm of the X and Y chromosomes, CFS2RA (306250) and IL3RA, are autosomal in mice, suggesting that this region is of autosomal origin. Vermeesch et al. (1997) investigated the origin of the long arm pseudoautosomal region (PAR). They showed that the IL9R gene, which is located within the human Xq/Yq homology region, maps to murine chromosome 11. Thus, the Xq/Yq PAR represents a second region on the human X chromosome that is not X-linked in mice. Furthermore, they showed that IL9R is absent on the Y of great apes. IL9R is thus exceptional among X/Y genes in that it is X-linked in some mammals, but autosomal or pseudoautosomal in others. Genes located on the X and the Y generally escape X-inactivation. An exception to this rule is XYBL1 (300053), a gene located in the Xq PAR. XYBL1 is X-inactivated and is inactive on the Y chromosome. In contrast, Vermeesch et al. (1997) showed that IL9R expression does occur from the Y, and from both the active and the inactive X chromosomes. This finding raised the question of how transcriptional regulation of the genes within Xq PAR occurs and how the X-inactivation status of IL9R has evolved the autosome-to-X and the X-to-X/Y translocation.
Kauppi et al. (2000) studied the possible role of the IL9R gene in the development of asthma. They found that the sDF2*10 allele of the IL9R gene was more frequently transmitted than untransmitted to asthmatic offspring (34 vs 16), that the allele was found to be homozygous more often than expected in asthma patients, and that a specific X-chromosome haplotype was found to be associated with asthma.
Nowak et al. (2009) showed that mouse T cells or Th17 cells (see 603149) stimulated with Tgfb (190180) produced Il9. Neutralization of Il9 ameliorated experimental autoimmune encephalomyelitis (EAE) in mice, and EAE was delayed and attenuated in mice lacking Il9r. Less severe EAE correlated with decreases in Th17 cells and macrophages producing Il6 (147620) in the central nervous system, as well as mast cells in regional lymph nodes. Nowak et al. (2009) proposed that IL9 is a Th17-derived cytokine that contributes to inflammatory disease.
Yoshimura et al. (2020) found that Il9r -/- mice developed severe EAE with increased numbers of pathogenic Gmcsf (CSF2; 138960)-producing Cd4 (186940)-positive T cells and inflammatory dendritic cells (DCs) in central nervous system (CNS). Treatment with exogenous Il9 alleviated EAE by suppressing pathogenic Gmcsf-producing Cd4-positive T cells and inflammatory DCs in CNS of Il9r -/- mice. Transfer of wildtype DCs suppressed EAE in Il9r -/- mice, whereas transfer of Il9r -/- DCs enhanced EAE in wildtype mice, indicating that Il9r -/- DCs induced Gmcsf in Cd4-positive T cells and contributed to disease worsening. The authors concluded that Il9-Il9r signaling has a protective role in EAE by suppressing Gmcsf-production by T cells through modulation of inflammatory DCs.
Abdelilah, S. G., Latifa, K., Esra, N., Cameron, L., Bouchaib, L., Nicolaides, N. C., Levitt, R. C., Hamid, Q. Functional expression of IL-9 receptor by human neutrophils from asthmatic donors: role in IL-8 release. J Immun. 166: 2768-2774, 2001. [PubMed: 11160343] [Full Text: https://doi.org/10.4049/jimmunol.166.4.2768]
Chang, M., Engel, G., Benedict, C., Basu, R., McNinch, J. Isolation and characterization of the human interleukin-9 receptor gene. Blood 83: 3199-3205, 1994. [PubMed: 8193355]
Demoulin, J.-B., Uyttenhove, C., Van Roost, E., de Lestre, B., Donckers, D., Van Snick, J., Renauld, J.-C. A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. Molec. Cell. Biol. 16: 4710-4716, 1996. [PubMed: 8756628] [Full Text: https://doi.org/10.1128/MCB.16.9.4710]
Gounni, A. S., Hamid, Q., Rahman, S. M., Hoeck, J., Yang, J., Shan, L. IL-9-mediated induction of eotaxin1/CCL11 in human airway smooth muscle cells. J. Immun. 173: 2771-2779, 2004. [PubMed: 15294996] [Full Text: https://doi.org/10.4049/jimmunol.173.4.2771]
Ihle, J. N., Kerr, I. M. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet. 11: 69-74, 1995. [PubMed: 7716810] [Full Text: https://doi.org/10.1016/s0168-9525(00)89000-9]
Kauppi, P., Laitinen, T., Ollikainen, V., Mannila, H., Laitinen, L. A., Kere, J. The IL9R region contribution in asthma is supported by genetic association in an isolated population. Europ. J. Hum. Genet. 8: 788-792, 2000. [PubMed: 11039580] [Full Text: https://doi.org/10.1038/sj.ejhg.5200541]
Kermouni, A., Van Roost, E., Arden, K. C., Vermeesch, J. R., Weiss, S., Godelaine, D., Flint, J., Lurquin, C., Szikora, J.-P., Higgs, D. R., Marynen, P., Renauld, J.-C. The IL-9 receptor gene (IL9R): genomic structure, chromosomal localization in the pseudoautosomal region of the long arm of the sex chromosomes, and identification of IL9R pseudogenes at 9qter, 10pter, 16pter, and 18pter. Genomics 29: 371-382, 1995. [PubMed: 8666384] [Full Text: https://doi.org/10.1006/geno.1995.9992]
Kvaloy, K., Galvagni, F., Brown, W. R. A. The sequence organization of the long arm pseudoautosomal region of the human sex chromosomes. Hum. Molec. Genet. 3: 771-778, 1994. [PubMed: 8081364] [Full Text: https://doi.org/10.1093/hmg/3.5.771]
Nowak, E. C., Weaver, C. T., Turner, H., Begum-Haque, S., Becher, B., Schreiner, B., Coyle, A. J., Kasper, L. H., Noelle, R. J. IL-9 as a mediator of Th17-driven inflammatory disease. J. Exp. Med. 206: 1653-1660, 2009. [PubMed: 19596803] [Full Text: https://doi.org/10.1084/jem.20090246]
Renauld, J.-C., Druez, C., Kermouni, A., Houssiau, F., Uyttenhove, C., Van Roost, E., Van Snick, J. Expression cloning of the murine and human interleukin 9 receptor cDNAs. Proc. Nat. Acad. Sci. 89: 5690-5694, 1992. [PubMed: 1376929] [Full Text: https://doi.org/10.1073/pnas.89.12.5690]
Russell, S. M., Keegan, A. D., Harada, N., Nakamura, Y., Noguchi, M., Leland, P., Friedmann, M. C., Miyajima, A., Puri, R. K., Paul, W. E., Leonard, W. J. Interleukin-2 receptor gamma-chain: a functional component of the interleukin-4 receptor. Science 262: 1880-1883, 1993. [PubMed: 8266078] [Full Text: https://doi.org/10.1126/science.8266078]
Vermeesch, J. R., Petit, P., Kermouni, A., Renauld, J.-C., Van Den Berghe, H., Marynen, P. The IL-9 receptor gene, located in the Xq/Yq pseudoautosomal region, has an autosomal origin, escapes X inactivation and is expressed from the Y. Hum. Molec. Genet. 6: 1-8, 1997. [PubMed: 9002663] [Full Text: https://doi.org/10.1093/hmg/6.1.1]
Yoshimura, S., Thome, R., Konno, S., Mari, E. R., Rasouli, J., Hwang, D., Boehm, A., Li, Y., Zhang, G.-X., Ciric, B., Rostami, A. IL-9 controls central nervous system autoimmunity by suppressing GM-CSF production. J. Immun. 204: 531-539, 2020. [PubMed: 31852750] [Full Text: https://doi.org/10.4049/jimmunol.1801113]