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. Author manuscript; available in PMC: 2012 Mar 15.
Published in final edited form as: J Immunol. 2011 Mar 15;186(6):3283–3288. doi: 10.4049/jimmunol.1003049

A Brief History of IL-9

Ritobrata Goswami 1, Mark H Kaplan 1,1
PMCID: PMC3074408  NIHMSID: NIHMS275281  PMID: 21368237

Abstract

Interleukin-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. Although many biological functions have been attributed to IL-9, it remains an understudied cytokine. A resurgence of interest in IL-9 has been spurred by recent work demonstrating a role for IL-9 in regulating inflammatory immunity, and in defining the transcription factors that activate the Il9 gene in cells that most efficiently produce IL-9. In this review we summarize the characterization of IL-9 biological activities, highlight roles for the cytokine that are clearly defined, and outline questions regarding IL-9 functions that still require further exploration.

Discovery and cloning of IL-9

Interleukin-9 (IL-9) was first purified and characterized as a T-cell and mast cell growth factor respectively termed P40, based on molecular weight, or Mast cell growth-enhancing activity (MEA) (1, 2). The cloning and complete amino acid sequencing of P40 revealed that it is structurally distinct from other T cells growth factors (3, 4) and was renamed IL-9 based on biological effects on both myeloid and lymphoid cells. A 14 kDa peptide was predicted from the cloned sequence encoding a 144 amino acid protein, including leader sequence. The mouse Il9 gene is located on chromosome 13, while the human IL9 gene is located in a syntenic region on chromosome 5 (5). IL9 is 3.2 Mb telomeric from the IL5/IL13/IL4 loci.

IL-9-secreting cells

The major source of IL-9 is T lymphocytes. Initially described as T Cell Growth Factor III, IL-9 is produced by long-term T cell lines, antigen-specific T cell lines and naïve murine T cells (6). However, it was unclear if there were specialized cells programmed for IL-9 production as was being established at the time for other cytokines such as IL-4 and IFNγ in Th2 and Th1 cells respectively.

IL-9 production was first associated with the Th2 phenotype, and many of the preliminary functions of IL-9 were tested in models of Th2-associated immunity. The expression of IL-9 in T cells isolated from Leishmania major-infected Balb/c mice, which generate a Th2-biased immune response, provided the initial basis for defining IL-9 as a Th2 cytokine (7). However, other T helper subsets also appear to have the potential for IL-9 production. Th17 cells, which are defined by secretion of IL-17A and IL-17F, may also secrete IL-9 in vitro and ex vivo (8, 9). Human Th17 cells can secrete IL-9, and long-term Th17 cultures have the ability to co-express IL-17A and IL-9 (10). In contrast, IL-23, a cytokine required for maintenance of the IL-17-secreting phenotype has inhibitory effects on IL-9 production (8, 11). T regulatory cells may also produce IL-9. A study linking mast cells to peripheral tolerance demonstrated that natural Tregs (nTregs) and inducible Tregs (iTregs), both Foxp3+ populations, secrete IL-9 (12). There is conflicting evidence regarding production of IL-9 from human Treg cells (10, 13).

Mounting evidence suggests that there may be a specialized subset of T cells dedicated to producing IL-9, where Il9 is regulated by a number of cytokines and transcription factors (Fig. 1). More than fifteen years ago, TGF-β and IL-4 were shown to enhance IL-9 production from activated T cells (14). Naïve CD4+ T cells primed in the combination of TGF-β and IL-4, or Th2 cells additionally cultured in TGF-β, produced high levels of IL-9 and showed diminished expression of other lineage-specific cytokines and transcription factors (15, 16). The ability of IL-4 to inhibit expression of Foxp3 in cultures containing TGF-β that induce iTreg generation, and to promote an IL-9-secreting phenotype, was dependent on STAT6 (15, 16). Similarly, GATA3 was required for the generation of IL-9-secreting cells (15), suggesting that Th2 cells, and the IL-9-secreting population termed Th9 cells, have shared factors in their development. Human T cells also acquire IL-9-secreting potential when cultured with TGF-β and IL-4 (10, 13, 17–19). The stability of the IL-9-secreting phenotype is still not well described, although studies suggest that Th9 cells can be maintained, but retain plasticity to acquire additional cytokine-secreting potential (20).

Figure 1.

Figure 1

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Transcription factor activation of the gene encoding IL-9. In T cells, the most efficient priming of IL-9 production occurs in response to a combination of TGF-β and IL-4. PU.1 may be downstream of the TGF-β signal, and STAT6 and GATA3, both required for the development of IL-9-secreting T cells, are downstream of IL-4. IRF4 expression may be regulated by both signals. It is not known if STAT6 or GATA3 binds the Il9 gene directly. PU.1 and IRF4 bind the Il9 promoter directly in Th9 cells. AP1, and NF-κB bind the promoter in response to TLR stimulation in mast cells, and are likely downstream of IL-1 and IL-25 signaling in T cells.

Recently, two transcription factors were reported to bind directly to the Il9 gene and were required for the development of IL-9-secreting cells. PU.1 is an ETS-family transcription factor known to have a repressive effect on the production of Th2 cytokines (21, 22). Ectopic expression of PU.1 not only represses Th2 cytokines, but also induces IL-9 production (17). PU.1-deficient T cells have greatly diminished IL-9 production, compared to wild type cells, when cultured in the presence of TGF-β and IL-4. PU.1 binds directly to the Il9 gene and histone modifications associated with the Th9 phenotype are dependent upon PU.1. PU.1 is also important for IL-9 production in human T cells as PU.1-specific siRNA results in impaired IL-9 production by human T cells. Importantly, PU.1 is expressed in greater amounts in cells cultured under Th9 conditions, compared to Th2 cells, suggesting that PU.1 is a critical factor in diverting Th2 cells into an IL-9-secreting lineage (17). Interferon-regulatory factor 4 (IRF4) was also shown to be required for Th9 generation (18). Like PU.1, and possibly in concert with PU.1 since IRF4 was originally identified as a PU.1-interacting protein, IRF4 bound the Il9 gene directly (18). Moreover, IRF4 expression is correlated with both human and mouse Th9 differentiation, and is induced by cytokines that promote IL-9 production including IL-4, IL-2 and TGF-β (18). As IRF4 is also required for Th2 and Th17 development (23–25), this transcription factor plays an important role in the cytokine-secreting potential of several Th subsets.

Mast cells also produce IL-9 in response to LPS and IL-1, correlating with the presence of NF-κB binding sites in the Il9 promoter that mediate gene activation (26–28). GATA1 in mast cells promotes IL-9 production and Il9 promoter activation in a manner that is dependent upon p38 MAPK (29). The relative amounts of IL-9 produced by mast cells and T cells, as well as the scenarios where each cell may contribute to IL-9 production in vivo, have not been determined.

Amplifiers of IL-9 production

TGF-β and IL-4 are potent cytokines in promoting the generation of IL-9-secreting cells. Indeed, the ability of TGF-β to promote IL-9 expression is likely responsible for the ability of Treg and Th17 cultures to secrete IL-9 (8, 9), and may have similar affects on both naive and memory cells (10, 13). In addition, other cytokines, and signaling pathways are able to modulate IL-9 production. IL-2 promotes, while IFNγ inhibits IL-9 production (14, 30). IL-25 can enhance IL-9 production by Th9 cells, and promote IL-9 production in vivo (31). These observations are consistent with the ability of NF-κB signaling to promote transcription from the IL9 promoter (28). Addition of other pro-inflammatory cytokines to human Th9 cultures, such as type I interferons, IL-1β, IL-6, IL-10, IL-12, and IL-21 may also enhance IL-9 production (10, 13, 19, 32). The ability of type I interferons to promote IL-9 production is dependent upon IFN-induced IL-21 expression (19). Whether the effects of these accessory cytokines is dependent upon other STAT proteins, or other transcription factors that activate IL9 transcription such as NF-κB or AP-1 (33), has not yet been determined. T cell receptor signaling also induces IL-9, and though cyclosporine A inhibits IL-9 production suggesting a role for NFAT proteins (7), the TCR-induced signals that lead to expression of Il9 are not characterized.

The IL-9 receptor: Signaling and expression

The IL-9R has two subunits: the alpha chain (IL-9Rα) and the common gamma chain receptor shared by other cytokines including IL-2, IL-4, and IL-7 (34, 35). The human IL-9 receptor gene contains 11 exons and encodes a 522-amino acid protein, while the mouse receptor contains 468-amino acids. The IL-9Rα is a member of the hematopoietin superfamily based on the presence of WSXWS motif in the extracellular domain, and the Box1 and Box2 motifs in the intracellular domain. IL-9-mediated signal transduction results in the activation of STAT1, STAT3 and STAT5 (36). A single tyrosine residue (Tyr407) in the IL-9Rα is phosphorylated after ligand binding to the receptor and activation of associated Jak1, and mutation of this residue demonstrates that it is required for IL-9-dependent responses (37). The Box1 intracellular domain between amino acids 338 and 422 including a YLPQ motif is critical for IL-9-induced cell growth, activation of STAT3, and induced gene expression (38). IL-9R signaling also activates MAP kinase and Insulin Receptor Substrate-PI3 kinase pathway (37, 39, 40), though the physiological requirement for these pathways in primary cells has not been well documented.

As expected from its initial identification as a T cell growth factor, IL-9R is expressed on T cells lines, and on effector T cells but not on naïve T cells (41, 42). Among the Th cell subsets, IL-9R has highest expression in Th2 and Th17 cells (9). In asthma patients, IL-9R is found on mast cells and PMNs in the lung (43, 44). Based on the responsiveness of airway epithelial cells, and smooth muscle cells, IL-9R is expressed on non-hematopoietic cells as well. Since γc is unlikely to be expressed in these cells, the exact composition of the receptor on non-hematopoietic cells is not clearly defined.

Cell-type specific functions of IL-9

As suggested by the patterns of receptor expression, IL-9 has biological effects on a number of distinct cell types (Fig. 2). Beyond the first description as T cell or mast cell growth factor, IL-9 may affect other immune cells, as well as resident tissue cells that contribute to the development of inflammation.

Figure 2.

Figure 2

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IL-9 is a pleiotropic cytokine. IL-9 has direct and indirect effects on multiple cell types that affect the development of immunity and inflammation.

T cells

Although IL-9 was originally cloned as a T cell growth factor, its function was more restricted than cytokines with similar functions like IL-2 and IL-4. IL-9 could promote T cell growth, but it functioned preferentially on CD4+ T cells, and not on CD8+ T cells, and was unable to support long-term antigen-independent growth of T helper lines (2, 6). Crossing of IL-9 transgenic mice to Th2 cytokine-deficient mice suggests that some effects of IL-9 in vivo may be due to promoting Th2 cytokine production, though whether these are direct or indirect effects is unclear (45, 46). More recently, IL-9 was shown to promote Th17 development but has variable affects on Treg development (8, 9).

B cells

IL-9 has effects on both B cell development and function. Transgenic expression of IL-9 results in an increase of peritoneal CD11b+ B1 B cells, and can recover the B1 cell numbers, but not natural IgM production, in xid mice (47, 48). IL-9 enhances IL-4-mediated IgE and IgG production from human B cells without having any effect on IgM production (49, 50). IL-9 has similar functions on germinal center B cells, and IL-9Rα expression is greater on germinal center B cells than on other B cells (51).

Mast cells

One of the main functions of IL-9 is to promote mast cell growth and function, though the primary effects are observed in response to pathogens, since basal mast cell numbers are normal in the absence of IL-9 (52). IL-9 can promote the growth of mast cells from bone marrow and mast cell progenitors in concert with Stem cell factor (53). IL-9, alone or in combination with Stem Cell Factor or FcεRI, promotes the expression of mast cell proteases and pro-allergic cytokines in cultured mast cells (1, 54–56).

Hematopoietic progenitor cells

IL-9 has been extensively characterized as a factor that regulates hematopoiesis. IL-9 synergizes with IL-3 in promoting the growth of IL-3-dependent cell lines and can enhance BFU-E, CFU-E and multi-lineage colony formation in combination with other factors including Stem Cell Factor from cord blood and bone marrow precursors (57–60). Human IL-9 also acts as an activator of megakaryocyte progenitor cells (61).

Airway epithelial cells

Transgenic expression of IL-9 in the lung results in changes in gene expression in airway epithelial cells including goblet cell metaplasia (62). Many of the effects of IL-9 in the lung are thought to occur due to indirect effects of IL-13 (46, 63–66). In this scenario, IL-9 promotes allergic inflammation through effects on hematopoietic cells that then produce IL-13 to have direct effects on airway epithelium (64). However, IL-9 can have direct effects on human primary airway epithelial cells and cells lines including the direct induction of mucus genes (67–70). Thus, IL-9 may have both direct and indirect effects in the airway.

Airway smooth muscle cells

In the lung environment, IL-9 also acts on airway smooth muscle cells. Human airway smooth muscle cells express both IL-9 receptor (71), and IL-9 can potentiate the ERK-dependent release of CCL11 and IL-8 from these cells (71, 72). IL-9-mediated CCL11 expression in primary smooth muscle cells is dependent upon STAT3 but not STAT6 (73). IL-9-activated STAT3 binds directly to the Ccl11 promoter (73).

IL-9-dependent regulation of inflammation

IL-9 demonstrates pro-inflammatory activity in several mouse models of inflammation. Transgenic expression of Il9 in the lung results in allergic inflammation that is at least partially dependent on the presence of Th2 cytokines (46, 62). IL-25 also promotes allergic inflammation through an IL-9-dependent mechanism (31). While allergic inflammation can develop in Il9−/− mice using a standard sensitization-challenge model (74), four reports have demonstrated that blockade of IL-9 in a similar model results in decreased allergic inflammation (17, 31, 75, 76). Similarly, blocking IL-9 in a chronic model of lung inflammation inhibits mastocytosis and airway remodeling (44). Moreover, Th9-polarized allergen-specific T cells can promote allergic inflammation that is blocked by anti-IL-9 (18). The reason for the discrepancy between germline disruption of Il9 and acute blockade by anti-IL-9 is not entirely clear. but the immune system may be able to compensate for the germline loss of cytokine. A role for IL-9 in the development of allergic pulmonary inflammation is further supported by the requirement for the T cell expression of IL-9-promoting transcription factors PU.1 and IRF4 in this process (17, 18). In mice with PU.1-deficient T cells, Th2 development is normal, stressing the importance of IL-9-secreting cells for the development of inflammation even in the presence of allergen-specific Th2 responses (17).

IL-9 mediates allergic inflammation in tissues other than the lung. IL-9 provided either by transgene or injection, increases susceptibility to passive or active systemic anaphylaxis (77). However, systemic anaphylaxis occurred in Il9−/− and Il9r−/− mice, suggesting that IL-9 is not absolutely required for anaphylaxis (77, 78). In contrast, deficiency in IL-9 or IL-9R attenuates intestinal anaphylaxis, and transgenic expression of IL-9 in the intestine results in local mastocytosis and increased susceptibility to intestinal anaphylaxis (78, 79). Thus, IL-9 may be required for anaphylaxis caused by allergen challenge at mucosal surfaces but not parenterally administered allergen.

IL-9 provides a protective role in immunity to intestinal parasites. In mice with transgenic expression of IL-9, there is increased clearance of worms following infection with Trichuris muris and Trichinella spiralis (80, 81). Similarly, adoptive transfer of IL-9 transgenic bone marrow derived DC increases immunity to T. spiralis, while anti-IL-9 blocks T. muris immunity (82, 83). Blocking TGF-β signaling, which inhibits the development of Th9 cells, also results in diminished immunity to T. muris (16). In contrast, IL-9-deficient mice were able to control Giardia lamblia and Nippostrongylus brasiliensis infection, and neutralization of IL-9 resulted in enhanced immunity to Leishmania major, owing to blockade of Th2 immunity (52, 84, 85). IL-9 was also not required for granuloma formation following injection with Schistosoma mansoni eggs, though it was important for mastocytosis and goblet cell metaplasia in this model (52). Yet, IL-4 is able to promote intestinal parasite immunity in the absence of IL-9 and other Th2 cytokines (86).

There is also evidence that IL-9 plays a role in regulating immunity to infectious disease. IL-9 negatively impacts clearance of RSV and neutralization of IL-9 may be therapeutic (87). Symptoms of septic shock may also be attenuated by IL-9, which may be through several mechanisms including suppression of inflammatory cytokines and the respiratory burst in monocytes (88, 89).

Although IL-9 is involved in what are classically thought to be Th2 responses, there are conflicting data on how it may be involved in autoimmune inflammation. Adoptive transfer of Th9-polarized cells can promote the development of EAE and EAU, though the inflammation that develops is distinct from Th1- or Th17-mediated immunity (11, 20). In two reports IL-9Rα-deficiency, or treatment with anti-IL9, were either partially protective or resulted in delayed development of EAE (9, 90). Results from another report demonstrated increased severity of EAE in Il9r−/− mice that was correlated with an effect of IL-9 on Treg function (8). The anti-inflammatory role proposed in the latter report is consistent with a described role for IL-9 in promoting mast cell dependent tolerance to transplanted allografts and nephritis (12, 91). IL-9 certainly has effects in the EAE models on T and non-T cells and the effect of blocking IL-9/IL-9R may depend upon the cells present in the microenvironment (9).

IL-9: From the bench to the bedside

Parallel to in vitro studies and experiments in mouse models, IL-9 is correlated with allergic inflammation in patients. IL-9 expression is increased in lungs of asthmatic patients (92, 93), and IL-9R expression is found in the lungs of asthmatic individuals but not healthy controls (94). Seasonal ragweed pollen enhances IL-9 production from peripheral blood mononuclear cells of allergic patients (95). Because of the presence of IL-9 in allergic inflammation, blocking antibodies to IL-9 are being developed as a therapy for atopic disease (96).

Some genetic links between disease and IL-9 signaling have also been identified. SNPs in the IL9R gene, located on the X chromosome, were protective for wheezing in boys, but not girls, and provided a modest protective effect for allergen sensitization (97). IL9 polymorphisms are also linked to sex-restricted differences in lung function, allergen sensitization, IgE levels, and the severity of RSV infection (98, 99). An IL9R polymorphism (rs3093457) has been linked to rheumatoid arthritis (100). Together, these results suggest that changes in IL9 or IL9R expression can impact human disease.

Conclusions

IL-9 is a pleiotropic cytokine that has documented effects on lymphocytes, mast cells and resident lung cells (Figure 2). It has been most frequently associated with allergic inflammation and immunity to extracellular parasites, although developing literature has demonstrated a role for IL-9 or IL-9-responsive cells in Th1/Th17-mediated inflammation and in T regulatory cell responses. The factors required for IL-9 production in T cells are only beginning to be elucidated and require the integration of signals from multiple cytokines (Figure 1). The next challenges will be to develop a more detailed understanding of Il9 regulation, and to define the relevant IL-9-target cells in various inflammatory diseases. Although IL-9 has been understudied, recent advances in defining IL-9 biology will likely promote greater attention.

Acknowledgments

This work was supported in part, by Public Health Service Award AI057459.

References

  • 1.Hultner L, Druez C, Moeller J, Uyttenhove C, Schmitt E, Rude E, Dormer P, Van Snick J. Mast cell growth-enhancing activity (MEA) is structurally related and functionally identical to the novel mouse T cell growth factor P40/TCGFIII (interleukin 9) Eur J Immunol. 1990;20:1413–1416. doi: 10.1002/eji.1830200632. [DOI] [PubMed] [Google Scholar]
  • 2.Uyttenhove C, Simpson RJ, Van Snick J. Functional and structural characterization of P40, a mouse glycoprotein with T-cell growth factor activity. Proc Natl Acad Sci U S A. 1988;85:6934–6938. doi: 10.1073/pnas.85.18.6934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Van Snick J, Goethals A, Renauld JC, Van Roost E, Uyttenhove C, Rubira MR, Moritz RL, Simpson RJ. Cloning and characterization of a cDNA for a new mouse T cell growth factor (P40) J Exp Med. 1989;169:363–368. doi: 10.1084/jem.169.1.363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Yang YC, Ricciardi S, Ciarletta A, Calvetti J, Kelleher K, Clark SC. Expression cloning ofcDNA encoding a novel human hematopoietic growth factor: human homologue of murine T-cell growth factor P40. Blood. 1989;74:1880–1884. [PubMed] [Google Scholar]
  • 5.Mock BA, Krall M, Kozak CA, Nesbitt MN, McBride OW, Renauld JC, Van Snick J. IL9 maps to mouse chromosome 13 and human chromosome 5. Immunogenetics. 1990;31:265–270. doi: 10.1007/BF00204898. [DOI] [PubMed] [Google Scholar]
  • 6.Schmitt E, Van Brandwijk R, Van Snick J, Siebold B, Rude E. TCGF III/P40 is produced by naive murine CD4+ T cells but is not a general T cell growth factor. Eur J Immunol. 1989;19:2167–2170. doi: 10.1002/eji.1830191130. [DOI] [PubMed] [Google Scholar]
  • 7.Gessner A, Blum H, Rollinghoff M. Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology. 1993;189:419–435. doi: 10.1016/S0171-2985(11)80414-6. [DOI] [PubMed] [Google Scholar]
  • 8.Elyaman W, Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, Bettelli E, Oukka M, van Snick J, Renauld JC, Kuchroo VK, Khoury SJ. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A. 2009;106:12885–12890. doi: 10.1073/pnas.0812530106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Nowak EC, Weaver CT, Turner H, Begum-Haque S, Becher B, Schreiner B, Coyle AJ, Kasper LH, Noelle RJ. IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med. 2009;206:1653–1660. doi: 10.1084/jem.20090246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Beriou G, Bradshaw EM, Lozano E, Costantino CM, Hastings WD, Orban T, Elyaman W, Khoury SJ, Kuchroo VK, Baecher-Allan C, Hafler DA. TGF-beta induces IL-9 production from human Th17 cells. J Immunol. 2010;185:46–54. doi: 10.4049/jimmunol.1000356. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Jager A, Dardalhon V, Sobel RA, Bettelli E, Kuchroo VK. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol. 2009;183:7169–7177. doi: 10.4049/jimmunol.0901906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J, Strom TB, Zheng XX, Noelle RJ. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature. 2006;442:997–1002. doi: 10.1038/nature05010. [DOI] [PubMed] [Google Scholar]
  • 13.Putheti P, Awasthi A, Popoola J, Gao W, Strom TB. Human CD4 memory T cells can become CD4+IL-9+ T cells. PLoS One. 2010;5:e8706. doi: 10.1371/journal.pone.0008706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S, Kuhn R, Muller W, Palm N, Rude E. IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol. 1994;153:3989–3996. [PubMed] [Google Scholar]
  • 15.Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, Mitsdoerffer M, Strom TB, Elyaman W, Ho IC, Khoury S, Oukka M, Kuchroo VK. IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat Immunol. 2008;9:1347–1355. doi: 10.1038/ni.1677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Veldhoen M, Uyttenhove C, vanSnick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9:1341–1346. doi: 10.1038/ni.1659. [DOI] [PubMed] [Google Scholar]
  • 17.Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, Jabeen R, McKinley C, Ahyi AN, Han L, Nguyen ET, Robertson MJ, Perumal NB, Tepper RS, Nutt SL, Kaplan MH. The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol. 2010;11:527–534. doi: 10.1038/ni.1867. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T. Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity. 2010;33:192–202. doi: 10.1016/j.immuni.2010.07.014. [DOI] [PubMed] [Google Scholar]
  • 19.Wong MT, Ye JJ, Alonso MN, Landrigan A, Cheung RK, Engleman E, Utz PJ. Regulation of human Th9 differentiation by type I interferons and IL-21. Immunol Cell Biol. 2010;88:624–631. doi: 10.1038/icb.2010.53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Tan C, Aziz MK, Lovaas JD, Vistica BP, Shi G, Wawrousek EF, Gery I. Antigen-Specific Th9 Cells Exhibit Uniqueness in Their Kinetics of Cytokine Production and Short Retention at the Inflammatory Site. J Immunol. 2010;185:6795–6801. doi: 10.4049/jimmunol.1001676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Chang HC, Han L, Jabeen R, Carotta S, Nutt SL, Kaplan MH. PU.1 regulates TCR expression by modulating GATA-3 activity. J Immunol. 2009;183:4887–4894. doi: 10.4049/jimmunol.0900363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Chang HC, Zhang S, Thieu VT, Slee RB, Bruns HA, Laribee RN, Klemsz MJ, Kaplan MH. PU.1 expression delineates heterogeneity in primary Th2 cells. Immunity. 2005;22:693–703. doi: 10.1016/j.immuni.2005.03.016. [DOI] [PubMed] [Google Scholar]
  • 23.Ahyi AN, Chang HC, Dent AL, Nutt SL, Kaplan MH. IFN regulatory factor 4 regulates the expression of a subset of Th2 cytokines. J Immunol. 2009;183:1598–1606. doi: 10.4049/jimmunol.0803302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Brustle A, Heink S, Huber M, Rosenplanter C, Stadelmann C, Yu P, Arpaia E, Mak TW, Kamradt T, Lohoff M. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol. 2007;8:958–966. doi: 10.1038/ni1500. [DOI] [PubMed] [Google Scholar]
  • 25.Lohoff M, Mittrucker HW, Prechtl S, Bischof S, Sommer F, Kock S, Ferrick DA, Duncan GS, Gessner A, Mak TW. Dysregulated T helper cell differentiation in the absence of interferon regulatory factor 4. Proc Natl Acad Sci U S A. 2002;99:11808–11812. doi: 10.1073/pnas.182425099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Hultner L, Kolsch S, Stassen M, Kaspers U, Kremer JP, Mailhammer R, Moeller J, Broszeit H, Schmitt E. In activated mast cells, IL-1 up-regulates the production of several Th2-related cytokines including IL-9. J Immunol. 2000;164:5556–5563. doi: 10.4049/jimmunol.164.11.5556. [DOI] [PubMed] [Google Scholar]
  • 27.Stassen M, Arnold M, Hultner L, Muller C, Neudorfl C, Reineke T, Schmitt E. Murine bone marrow-derived mast cells as potent producers of IL-9: costimulatory function of IL-10 and kit ligand in the presence of IL-1. J Immunol. 2000;164:5549–5555. doi: 10.4049/jimmunol.164.11.5549. [DOI] [PubMed] [Google Scholar]
  • 28.Stassen M, Muller C, Arnold M, Hultner L, Klein-Hessling S, Neudorfl C, Reineke T, Serfling E, Schmitt E. IL-9 and IL-13 production by activated mast cells is strongly enhanced in the presence of lipopolysaccharide: NF-kappa B is decisively involved in the expression of IL-9. J Immunol. 2001;166:4391–4398. doi: 10.4049/jimmunol.166.7.4391. [DOI] [PubMed] [Google Scholar]
  • 29.Stassen M, Klein M, Becker M, Bopp T, Neudorfl C, Richter C, Heib V, Klein-Hessling S, Serfling E, Schild H, Schmitt E. p38 MAP kinase drives the expression of mast cell-derived IL-9 via activation of the transcription factor GATA-1. Mol Immunol. 2007;44:926–933. doi: 10.1016/j.molimm.2006.03.019. [DOI] [PubMed] [Google Scholar]
  • 30.Houssiau FA, Renauld JC, Fibbe WE, Van Snick J. IL-2 dependence of IL-9 expression in human T lymphocytes. J Immunol. 1992;148:3147–3151. [PubMed] [Google Scholar]
  • 31.Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C. Regulation of IL-9 expression by IL-25 signaling. Nat Immunol. 2010;11:250–256. doi: 10.1038/ni.1846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Schmitt E, Beuscher HU, Huels C, Monteyne P, van Brandwijk R, van Snick J, Ruede E. IL-1 serves as a secondary signal for IL-9 expression. J Immunol. 1991;147:3848–3854. [PubMed] [Google Scholar]
  • 33.Zhu YX, Kang LY, Luo W, Li CC, Yang L, Yang YC. Multiple transcription factors are required for activation of human interleukin 9 gene in T cells. J Biol Chem. 1996;271:15815–15822. doi: 10.1074/jbc.271.26.15815. [DOI] [PubMed] [Google Scholar]
  • 34.Renauld JC, 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 Natl Acad Sci U S A. 1992;89:5690–5694. doi: 10.1073/pnas.89.12.5690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM, Friedmann M, Berg M, McVicar DW, Witthuhn BA, Silvennoinen O, et al. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science. 1994;266:1042–1045. doi: 10.1126/science.7973658. [DOI] [PubMed] [Google Scholar]
  • 36.Bauer JH, Liu KD, You Y, Lai SY, Goldsmith MA. Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis. J Biol Chem. 1998;273:9255–9260. doi: 10.1074/jbc.273.15.9255. [DOI] [PubMed] [Google Scholar]
  • 37.Demoulin JB, Uyttenhove C, Van Roost E, DeLestre B, Donckers D, Van Snick J, Renauld JC. A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9. Mol Cell Biol. 1996;16:4710–4716. doi: 10.1128/mcb.16.9.4710. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Zhu YX, Sun HB, Tsang ML, McMahel J, Grigsby S, Yin T, Yang YC. Critical cytoplasmic domains of human interleukin-9 receptor alpha chain in interleukin-9-mediated cell proliferation and signal transduction. J Biol Chem. 1997;272:21334–21340. doi: 10.1074/jbc.272.34.21334. [DOI] [PubMed] [Google Scholar]
  • 39.Yin T, Keller SR, Quelle FW, Witthuhn BA, Tsang ML, Lienhard GE, Ihle JN, Yang YC. Interleukin-9 induces tyrosine phosphorylation of insulin receptor substrate-1 via JAK tyrosine kinases. J Biol Chem. 1995;270:20497–20502. doi: 10.1074/jbc.270.35.20497. [DOI] [PubMed] [Google Scholar]
  • 40.Demoulin JB, Louahed J, Dumoutier L, Stevens M, Renauld JC. MAP kinase activation by interleukin-9 in lymphoid and mast cell lines. Oncogene. 2003;22:1763–1770. doi: 10.1038/sj.onc.1206253. [DOI] [PubMed] [Google Scholar]
  • 41.Cosmi L, Liotta F, Angeli R, Mazzinghi B, Santarlasci V, Manetti R, Lasagni L, Vanini V, Romagnani P, Maggi E, Annunziato F, Romagnani S. Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines. Blood. 2004;103:3117–3121. doi: 10.1182/blood-2003-09-3302. [DOI] [PubMed] [Google Scholar]
  • 42.Druez C, Coulie P, Uyttenhove C, Van Snick J. Functional and biochemical characterization of mouse P40/IL-9 receptors. J Immunol. 1990;145:2494–2499. [PubMed] [Google Scholar]
  • 43.Abdelilah S, Latifa K, Esra N, Cameron L, Bouchaib L, Nicolaides N, Levitt R, Hamid Q. Functional expression of IL-9 receptor by human neutrophils from asthmatic donors: role in IL-8 release. J Immunol. 2001;166:2768–2774. doi: 10.4049/jimmunol.166.4.2768. [DOI] [PubMed] [Google Scholar]
  • 44.Kearley J, Erjefalt JS, Andersson C, Benjamin E, Jones CP, Robichaud A, Pegorier S, Brewah Y, Burwell TJ, Bjermer L, Kiener PA, Kolbeck R, Lloyd CM, Coyle AJ, Humbles AA. IL-9 Governs Allergen-induced Mast Cell Numbers in the Lung and Chronic Remodeling of the Airways. Am J Respir Crit Care Med. 2010 doi: 10.1164/rccm.200909-1462OC. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Lauder AJ, Jolin HE, Smith P, van den Berg JG, Jones A, Wisden W, Smith KG, Dasvarma A, Fallon PG, McKenzie AN. Lymphomagenesis, hydronephrosis, and autoantibodies result from dysregulation of IL-9 and are differentially dependent on Th2 cytokines. J Immunol. 2004;173:113–122. doi: 10.4049/jimmunol.173.1.113. [DOI] [PubMed] [Google Scholar]
  • 46.Temann UA, Ray P, Flavell RA. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J Clin Invest. 2002;109:29–39. doi: 10.1172/JCI13696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Knoops L, Louahed J, Renauld JC. IL-9-induced expansion of B-1b cells restores numbers but not function of B-1 lymphocytes in xid mice. J Immunol. 2004;172:6101–6106. doi: 10.4049/jimmunol.172.10.6101. [DOI] [PubMed] [Google Scholar]
  • 48.Vink A, Warnier G, Brombacher F, Renauld JC. Interleukin 9-induced in vivo expansion of the B-1 lymphocyte population. J Exp Med. 1999;189:1413–1423. doi: 10.1084/jem.189.9.1413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Dugas B, Renauld JC, Pene J, Bonnefoy JY, Peti-Frere C, Braquet P, Bousquet J, Van Snick J, Mencia-Huerta JM. Interleukin-9 potentiates the interleukin-4-induced immunoglobulin (IgG, IgM and IgE) production by normal human B lymphocytes. Eur J Immunol. 1993;23:1687–1692. doi: 10.1002/eji.1830230743. [DOI] [PubMed] [Google Scholar]
  • 50.Petit-Frere C, Dugas B, Braquet P, Mencia-Huerta JM. Interleukin-9 potentiates the interleukin-4-induced IgE and IgG1 release from murine B lymphocytes. Immunology. 1993;79:146–151. [PMC free article] [PubMed] [Google Scholar]
  • 51.Fawaz LM, Sharif-Askari E, Hajoui O, Soussi-Gounni A, Hamid Q, Mazer BD. Expression of IL-9 receptor alpha chain on human germinal center B cells modulates IgE secretion. J Allergy Clin Immunol. 2007;120:1208–1215. doi: 10.1016/j.jaci.2007.08.022. [DOI] [PubMed] [Google Scholar]
  • 52.Townsend JM, Fallon GP, Matthews JD, Smith P, Jolin EH, McKenzie NA. IL-9-deficient mice establish fundamental roles for IL-9 in pulmonary mastocytosis and goblet cell hyperplasia but not T cell development. Immunity. 2000;13:573–583. doi: 10.1016/s1074-7613(00)00056-x. [DOI] [PubMed] [Google Scholar]
  • 53.Matsuzawa S, Sakashita K, Kinoshita T, Ito S, Yamashita T, Koike K. IL-9 enhances the growth of human mast cell progenitors under stimulation with stem cell factor. J Immunol. 2003;170:3461–3467. doi: 10.4049/jimmunol.170.7.3461. [DOI] [PubMed] [Google Scholar]
  • 54.Eklund KK, Ghildyal N, Austen KF, Stevens RL. Induction by IL-9 and suppression by IL-3 and IL-4 of the levels of chromosome 14-derived transcripts that encode late-expressed mouse mast cell proteases. J Immunol. 1993;151:4266–4273. [PubMed] [Google Scholar]
  • 55.Wiener Z, Falus A, Toth S. IL-9 increases the expression of several cytokines in activated mast cells, while the IL-9-induced IL-9 production is inhibited in mast cells of histamine-free transgenic mice. Cytokine. 2004;26:122–130. doi: 10.1016/j.cyto.2004.01.006. [DOI] [PubMed] [Google Scholar]
  • 56.Lora JM, Al-Garawi A, Pickard MD, Price KS, Bagga S, Sicoli J, Hodge MR, Gutierrez-Ramos JC, Briskin MJ, Boyce JA. FcepsilonRI-dependent gene expression in human mast cells is differentially controlled by T helper type 2 cytokines. J Allergy Clin Immunol. 2003;112:1119–1126. doi: 10.1016/j.jaci.2003.08.042. [DOI] [PubMed] [Google Scholar]
  • 57.Donahue RE, Yang YC, Clark SC. Human P40 T-cell growth factor (interleukin-9) supports erythroid colony formation. Blood. 1990;75:2271–2275. [PubMed] [Google Scholar]
  • 58.Holbrook ST, Ohls RK, Schibler KR, Yang YC, Christensen RD. Effect of interleukin-9 on clonogenic maturation and cell-cycle status of fetal and adult hematopoietic progenitors. Blood. 1991;77:2129–2134. [PubMed] [Google Scholar]
  • 59.Lemoli RM, Fortuna A, Fogli M, Motta MR, Rizzi S, Benini C, Tura S. Stem cell factor (c-kit ligand) enhances the interleukin-9-dependent proliferation of human CD34+ and CD34+CD33-DR-cells. Exp Hematol. 1994;22:919–923. [PubMed] [Google Scholar]
  • 60.Williams DE, Morrissey PJ, Mochizuki DY, de Vries P, Anderson D, Cosman D, Boswell HS, Cooper S, Grabstein KH, Broxmeyer HE. T-cellgrowth factor P40 promotes the proliferation of myeloid cell lines and enhances erythroid burst formation by normal murine bone marrow cells in vitro. Blood. 1990;76:906–911. [PubMed] [Google Scholar]
  • 61.Fujiki H, Kimura T, Minamiguchi H, Harada S, Wang J, Nakao M, Yokota S, Urata Y, Ueda Y, Yamagishi H, Sonoda Y. Role of human interleukin-9 as a megakaryocyte potentiator in culture. Exp Hematol. 2002;30:1373–1380. doi: 10.1016/s0301-472x(02)00966-9. [DOI] [PubMed] [Google Scholar]
  • 62.Temann UA, Geba GP, Rankin JA, Flavell RA. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J Exp Med. 1998;188:1307–1320. doi: 10.1084/jem.188.7.1307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Steenwinckel V, Louahed J, Lemaire MM, Sommereyns C, Warnier G, McKenzie A, Brombacher F, Van Snick J, Renauld JC. IL-9 promotes IL-13-dependent paneth cell hyperplasia and up-regulation of innate immunity mediators in intestinal mucosa. J Immunol. 2009;182:4737–4743. doi: 10.4049/jimmunol.0801941. [DOI] [PubMed] [Google Scholar]
  • 64.Steenwinckel V, Louahed J, Orabona C, Huaux F, Warnier G, McKenzie A, Lison D, Levitt R, Renauld JC. IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells. J Immunol. 2007;178:3244–3251. doi: 10.4049/jimmunol.178.5.3244. [DOI] [PubMed] [Google Scholar]
  • 65.Temann UA, Laouar Y, Eynon EE, Homer R, Flavell RA. IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells. Int Immunol. 2007;19:1–10. doi: 10.1093/intimm/dxl117. [DOI] [PubMed] [Google Scholar]
  • 66.Whittaker L, Niu N, Temann UA, Stoddard A, Flavell RA, Ray A, Homer RJ, Cohn L. Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 T cells and interleukin-9. Am J Respir Cell Mol Biol. 2002;27:593–602. doi: 10.1165/rcmb.4838. [DOI] [PubMed] [Google Scholar]
  • 67.Longphre M, Li D, Gallup M, Drori E, Ordonez CL, Redman T, Wenzel S, Bice DE, Fahy JV, Basbaum C. Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J Clin Invest. 1999;104:1375–1382. doi: 10.1172/JCI6097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Louahed J, Toda M, Jen J, Hamid Q, Renauld JC, Levitt RC, Nicolaides NC. Interleukin-9 upregulates mucus expression in the airways. Am J Respir Cell Mol Biol. 2000;22:649–656. doi: 10.1165/ajrcmb.22.6.3927. [DOI] [PubMed] [Google Scholar]
  • 69.Reader JR, Hyde DM, Schelegle ES, Aldrich MC, Stoddard AM, McLane MP, Levitt RC, Tepper JS. Interleukin-9 induces mucous cell metaplasia independent of inflammation. Am J Respir Cell Mol Biol. 2003;28:664–672. doi: 10.1165/rcmb.2002-0207OC. [DOI] [PubMed] [Google Scholar]
  • 70.Vermeer PD, Harson R, Einwalter LA, Moninger T, Zabner J. Interleukin-9 induces goblet cell hyperplasia during repair of human airway epithelia. Am J Respir Cell Mol Biol. 2003;28:286–295. doi: 10.1165/rcmb.4887. [DOI] [PubMed] [Google Scholar]
  • 71.Gounni AS, Hamid Q, Rahman SM, Hoeck J, Yang J, Shan L. IL-9-mediated induction of eotaxin1/CCL11 in human airway smooth muscle cells. J Immunol. 2004;173:2771–2779. doi: 10.4049/jimmunol.173.4.2771. [DOI] [PubMed] [Google Scholar]
  • 72.Baraldo S, Faffe DS, Moore PE, Whitehead T, McKenna M, Silverman ES, Panettieri RA, Jr, Shore SA. Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. Am J Physiol Lung Cell Mol Physiol. 2003;284:L1093–1102. doi: 10.1152/ajplung.00300.2002. [DOI] [PubMed] [Google Scholar]
  • 73.Yamasaki A, Saleh A, Koussih L, Muro S, Halayko AJ, Gounni AS. IL-9 induces CCL11 expression via STAT3 signalling in human airway smooth muscle cells. PLoS One. 2010;5:e9178. doi: 10.1371/journal.pone.0009178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.McMillan SJ, Bishop B, Townsend MJ, McKenzie AN, Lloyd CM. The absence of interleukin 9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity. J Exp Med. 2002;195:51–57. doi: 10.1084/jem.20011732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Cheng G, Arima M, Honda K, Hirata H, Eda F, Yoshida N, Fukushima F, Ishii Y, Fukuda T. Anti-interleukin-9 antibody treatment inhibits airwayinflammation and hyperreactivity in mouse asthma model. Am J Respir Crit Care Med. 2002;166:409–416. doi: 10.1164/rccm.2105079. [DOI] [PubMed] [Google Scholar]
  • 76.Kung TT, Luo B, Crawley Y, Garlisi CG, Devito K, Minnicozzi M, Egan RW, Kreutner W, Chapman RW. Effect of anti-mIL-9 antibody onthe development of pulmonary inflammation and airway hyperresponsiveness in allergic mice. Am J Respir Cell Mol Biol. 2001;25:600–605. doi: 10.1165/ajrcmb.25.5.4533. [DOI] [PubMed] [Google Scholar]
  • 77.Knoops L, Louahed J, Van Snick J, Renauld JC. IL-9 promotes but is not necessary for systemic anaphylaxis. J Immunol. 2005;175:335–341. doi: 10.4049/jimmunol.175.1.335. [DOI] [PubMed] [Google Scholar]
  • 78.Osterfeld H, Ahrens R, Strait R, Finkelman FD, Renauld JC, Hogan SP. Differential roles for the IL-9/IL-9 receptor alpha-chain pathway in systemic and oral antigen-induced anaphylaxis. J Allergy Clin Immunol. 2010;125:469–476. e462. doi: 10.1016/j.jaci.2009.09.054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Forbes EE, Groschwitz K, Abonia JP, Brandt EB, Cohen E, Blanchard C, Ahrens R, Seidu L, McKenzie A, Strait R, Finkelman FD, Foster PS, Matthaei KI, Rothenberg ME, Hogan SP. IL-9-and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J Exp Med. 2008;205:897–913. doi: 10.1084/jem.20071046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Faulkner H, Humphreys N, Renauld JC, Van Snick J, Grencis R. Interleukin-9 is involved in host protective immunity to intestinal nematode infection. Eur J Immunol. 1997;27:2536–2540. doi: 10.1002/eji.1830271011. [DOI] [PubMed] [Google Scholar]
  • 81.Faulkner H, Renauld JC, Van Snick J, Grencis RK. Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris. Infect Immun. 1998;66:3832–3840. doi: 10.1128/iai.66.8.3832-3840.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Leech MD, Grencis RK. Induction of enhanced immunity to intestinal nematodes using IL-9-producing dendritic cells. J Immunol. 2006;176:2505–2511. doi: 10.4049/jimmunol.176.4.2505. [DOI] [PubMed] [Google Scholar]
  • 83.Richard M, Grencis RK, Humphreys NE, Renauld JC, Van Snick J. Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice. Proc Natl Acad Sci U S A. 2000;97:767–772. doi: 10.1073/pnas.97.2.767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Arendse B, Van Snick J, Brombacher F. IL-9 is a susceptibility factor in Leishmania major infection by promoting detrimental Th2/type 2 responses. J Immunol. 2005;174:2205–2211. doi: 10.4049/jimmunol.174.4.2205. [DOI] [PubMed] [Google Scholar]
  • 85.Li E, Zhou P, Petrin Z, Singer SM. Mast cell-dependent control of Giardia lamblia infections in mice. Infect Immun. 2004;72:6642–6649. doi: 10.1128/IAI.72.11.6642-6649.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Fallon PG, Jolin HE, Smith P, Emson CL, Townsend MJ, Fallon R, Smith P, McKenzie AN. IL-4 induces characteristic Th2 responses even in the combined absence of IL-5, IL-9, and IL-13. Immunity. 2002;17:7–17. doi: 10.1016/s1074-7613(02)00332-1. [DOI] [PubMed] [Google Scholar]
  • 87.Dodd JS, Lum E, Goulding J, Muir R, Van Snick J, Openshaw PJ. IL-9regulates pathology during primary and memory responses to respiratory syncytial virus infection. J Immunol. 2009;183:7006–7013. doi: 10.4049/jimmunol.0900085. [DOI] [PubMed] [Google Scholar]
  • 88.Grohmann U, Van Snick J, Campanile F, Silla S, Giampietri A, Vacca C, Renauld JC, Fioretti MC, Puccetti P. IL-9 protects mice from Gram-negative bacterial shock: suppression of TNF-alpha, IL-12, and IFN-gamma, and induction of IL-10. J Immunol. 2000;164:4197–4203. doi: 10.4049/jimmunol.164.8.4197. [DOI] [PubMed] [Google Scholar]
  • 89.Pilette C, Ouadrhiri Y, Van Snick J, Renauld JC, Staquet P, Vaerman JP, Sibille Y. IL-9 inhibits oxidative burst and TNF-alpha release in lipopolysaccharide-stimulated human monocytes through TGF-beta. J Immunol. 2002;168:4103–4111. doi: 10.4049/jimmunol.168.8.4103. [DOI] [PubMed] [Google Scholar]
  • 90.Li H, Nourbakhsh B, Ciric B, Zhang GX, Rostami A. Neutralization of IL-9 ameliorates experimental autoimmune encephalomyelitis by decreasing the effector T cell population. J Immunol. 2010;185:4095–4100. doi: 10.4049/jimmunol.1000986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Eller K, Wolf D, Huber JM, Metz M, Mayer G, McKenzie AN, Maurer M, Rosenkranz AR, Wolf AM. IL-9 Production by Regulatory T Cells Recruits Mast Cells That Are Essential for Regulatory T Cell-Induced Immune Suppression. J Immunol. 2010 doi: 10.4049/jimmunol.1001183. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.Erpenbeck VJ, Hohlfeld JM, Discher M, Krentel H, Hagenberg A, Braun A, Krug N. Increased expression of interleukin-9 messenger RNA after segmental allergen challenge in allergic asthmatics. Chest. 2003;123:370S. [PubMed] [Google Scholar]
  • 93.Shimbara A, Christodoulopoulos P, Soussi-Gounni A, Olivenstein R, Nakamura Y, Levitt RC, Nicolaides NC, Holroyd KJ, Tsicopoulos A, Lafitte JJ, Wallaert B, Hamid QA. IL-9 and its receptor in allergic and nonallergic lung disease: increased expression in asthma. J Allergy Clin Immunol. 2000;105:108–115. doi: 10.1016/s0091-6749(00)90185-4. [DOI] [PubMed] [Google Scholar]
  • 94.Bhathena PR, Comhair SA, Holroyd KJ, Erzurum SC. Interleukin-9 receptor expression in asthmatic airways In vivo. Lung. 2000;178:149–160. doi: 10.1007/s004080000018. [DOI] [PubMed] [Google Scholar]
  • 95.Sun J, Wong B, Cundall M, Goncharova S, Conway M, Dalrymple A, Coyle AJ, Waserman S, Jordana M. Immunoreactivity profile of peripheral blood mononuclear cells from patients with ragweed-induced allergic rhinitis. Clin Exp Allergy. 2007;37:901–908. doi: 10.1111/j.1365-2222.2007.02723.x. [DOI] [PubMed] [Google Scholar]
  • 96.White B, Leon F, White W, Robbie G. Two first-in-human, open-label, phase I dose-escalation safety trials of MEDI-528, a monoclonal antibody against interleukin-9, in healthy adult volunteers. Clin Ther. 2009;31:728–740. doi: 10.1016/j.clinthera.2009.04.019. [DOI] [PubMed] [Google Scholar]
  • 97.Melen E, Gullsten H, Zucchelli M, Lindstedt A, Nyberg F, Wickman M, Pershagen G, Kere J. Sex specific protective effects of interleukin-9 receptor haplotypeson childhood wheezing and sensitisation. J Med Genet. 2004;41:e123. doi: 10.1136/jmg.2004.023135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Aschard H, Bouzigon E, Corda E, Ulgen A, Dizier MH, Gormand F, Lathrop M, Kauffmann F, Demenais F. Sex-specific effect of IL9 polymorphisms on lung function and polysensitization. Genes Immun. 2009;10:559–565. doi: 10.1038/gene.2009.46. [DOI] [PubMed] [Google Scholar]
  • 99.Schuurhof A, Bont L, Siezen CL, Hodemaekers H, van Houwelingen HC, Kimman TG, Hoebee B, Kimpen JL, Janssen R. Interleukin-9 polymorphism in infants with respiratory syncytial virus infection: an opposite effect in boys and girls. Pediatr Pulmonol. 2010;45:608–613. doi: 10.1002/ppul.21229. [DOI] [PubMed] [Google Scholar]
  • 100.Burkhardt J, Petit-Teixeira E, Teixeira VH, Kirsten H, Garnier S, Ruehle S, Oeser C, Wolfram G, Scholz M, Migliorini P, Balsa A, Westhovens R, Barrera P, Alves H, Pascual-Salcedo D, Bombardieri S, Dequeker J, Radstake TR, Van Riel P, van de Putte L, Bardin T, Prum B, Buchegger-Podbielski U, Emmrich F, Melchers I, Cornelis F, Ahnert P. Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis. J Rheumatol. 2009;36:2149–2157. doi: 10.3899/jrheum.090059. [DOI] [PubMed] [Google Scholar]

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