Genomes and Genes
Summary: A multifunctional cytokine secreted by primarily by activated TH2 CELLS that may play a role as a regulator of allergic INFLAMMATION. It has been shown to enhance the growth and CELL DIFFERENTIATION of MAST CELLS, and can act on a variety of other immune cells.
- Kung T, Luo B, Crawley Y, Garlisi C, DeVito K, Minnicozzi M, et al. Effect of anti-mIL-9 antibody on the development of pulmonary inflammation and airway hyperresponsiveness in allergic mice. Am J Respir Cell Mol Biol. 2001;25:600-5 pubmed..A single dose of the antibody was ineffective on all measures. These results indicate that an antibody to mIL-9 inhibits the development of allergic pulmonary inflammation and AHR in mice. ..
- Ying S, Meng Q, Kay A, Robinson D. Elevated expression of interleukin-9 mRNA in the bronchial mucosa of atopic asthmatics and allergen-induced cutaneous late-phase reaction: relationships to eosinophils, mast cells and T lymphocytes. Clin Exp Allergy. 2002;32:866-71 pubmed..707, P = 0.015). Elevated expression of IL-9 in allergic inflammation may contribute to local eosinophil infiltration and survival in asthma and other allergic atopic diseases. ..
- Baraldo S, Faffe D, Moore P, Whitehead T, McKenna M, Silverman E, et al. Interleukin-9 influences chemokine release in airway smooth muscle: role of ERK. Am J Physiol Lung Cell Mol Physiol. 2003;284:L1093-102 pubmed..Our results indicate that airway smooth muscle is a target for IL-9 and that IL-9 amplifies the potential for these cells to recruit eosinophils and neutrophils into the airways by a mechanism involving ERK. ..
- 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;170:3461-7 pubmed..Taken together, IL-9 appears to act as a potent enhancer for the SCF-dependent growth of mast cell progenitors in humans, particularly asthmatic patients. ..
- Erpenbeck V, Hohlfeld J, Volkmann B, Hagenberg A, Geldmacher H, Braun A, et al. Segmental allergen challenge in patients with atopic asthma leads to increased IL-9 expression in bronchoalveolar lavage fluid lymphocytes. J Allergy Clin Immunol. 2003;111:1319-27 pubmed..Lymphocytes are the major cellular source of IL-9. The increased expression and its correlation with eosinophil numbers suggest a potential role for IL-9 in the late phase of the allergic response. ..
- Forbes E, Groschwitz K, Abonia J, Brandt E, Cohen E, Blanchard C, et al. IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. J Exp Med. 2008;205:897-913 pubmed publisher..These observations demonstrate a central role for IL-9 and mast cells in experimental intestinal permeability in oral antigen sensitization and suggest that IL-9-mediated mast cell responses have an important role in food allergy. ..
- Elyaman W, Bradshaw E, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A. 2009;106:12885-90 pubmed publisher..The mechanism of IL-9 effects on T(H)17 and T(regs) is through activation of STAT3 and STAT5 signaling. Our findings highlight a role of IL-9 as a regulator of pathogenic versus protective mechanisms of immune responses. ..
- Demoulin J, Louahed J, Dumoutier L, Stevens M, Renauld J. MAP kinase activation by interleukin-9 in lymphoid and mast cell lines. Oncogene. 2003;22:1763-70 pubmed..In summary, these results indicate that IL-9 can transiently activate the mitogen-activated protein kinase pathway, which contributes to growth stimulation of hematopoietic cell lines. ..
- Reader J, Hyde D, Schelegle E, Aldrich M, Stoddard A, McLane M, et al. Interleukin-9 induces mucous cell metaplasia independent of inflammation. Am J Respir Cell Mol Biol. 2003;28:664-72 pubmed..IL-9 seems to directly stimulate mucous cell metaplasia without the requirement of inflammatory cell influx. ..
- McDermott J, Bartram R, Knight P, Miller H, Garrod D, Grencis R. Mast cells disrupt epithelial barrier function during enteric nematode infection. Proc Natl Acad Sci U S A. 2003;100:7761-6 pubmed..These results provide the mechanism whereby mucosal mast cells mediate parasite expulsion from the intestine. ..
- Ikeda R, Miller M, Nayar J, Walker L, Cho J, McElwain K, et al. Accumulation of peribronchial mast cells in a mouse model of ovalbumin allergen induced chronic airway inflammation: modulation by immunostimulatory DNA sequences. J Immunol. 2003;171:4860-7 pubmed
- Glimelius I, Edström A, Amini R, Fischer M, Nilsson G, Sundstrom C, et al. IL-9 expression contributes to the cellular composition in Hodgkin lymphoma. Eur J Haematol. 2006;76:278-83 pubmed..IL-9 expression is related to the histology, clinical picture and the presence of eosinophils and mast cells in HL. These results indicate that IL-9 is an important part of the cytokine network and inflammatory infiltrate in HL. ..
- Temann U, Ray P, Flavell R. Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology. J Clin Invest. 2002;109:29-39 pubmed..These findings suggest that pathologic changes in the lung require additional signals beyond IL-9, provided by IL-4, IL-5, and IL-13, to develop fully. ..
- Steenwinckel V, Louahed J, Lemaire M, Sommereyns C, Warnier G, McKenzie A, et al. IL-9 promotes IL-13-dependent paneth cell hyperplasia and up-regulation of innate immunity mediators in intestinal mucosa. J Immunol. 2009;182:4737-43 pubmed publisher..Taken together, our data indicate that Paneth cell hyperplasia and expression of their various antimicrobial products contribute to the immune response driven by TH2 cytokines, such as IL-9 and IL-13 in the intestinal mucosa...
- Merz H, Houssiau F, Orscheschek K, Renauld J, Fliedner A, Herin M, et al. Interleukin-9 expression in human malignant lymphomas: unique association with Hodgkin's disease and large cell anaplastic lymphoma. Blood. 1991;78:1311-7 pubmed..These results suggest that IL-9 is not involved as an autocrine growth factor in the pathogenesis of most B- and T-cell lymphomas, but that it may play a role in HD and LCAL. ..
- Jones T, Hallgren J, Humbles A, Burwell T, Finkelman F, Alcaide P, et al. Antigen-induced increases in pulmonary mast cell progenitor numbers depend on IL-9 and CD1d-restricted NKT cells. J Immunol. 2009;183:5251-60 pubmed publisher..These findings implicate type 2 NKT cells and IL-9 as central regulators that function in the same pathway mediating the Ag-induced increase in numbers of pulmonary MCp. ..
- Abdelilah S, Latifa K, Esra N, Cameron L, Bouchaib L, Nicolaides N, et al. Functional expression of IL-9 receptor by human neutrophils from asthmatic donors: role in IL-8 release. J Immunol. 2001;166:2768-74 pubmed..Taken together, these findings suggest a novel role for PMNs in allergic disease through the expression and activation of the IL-9R. ..
- Uyttenhove C, Simpson R, 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;85:6934-8 pubmed..Of a number of cell lines, only helper T cells responded to P40, and this response was not mediated by either interleukin 2 or interleukin 4. ..
- Renauld J, van der Lugt N, Vink A, van Roon M, Godfraind C, Warnier G, et al. Thymic lymphomas in interleukin 9 transgenic mice. Oncogene. 1994;9:1327-32 pubmedTransgenic mice overexpressing the interleukin 9 gene were generated to study the biological activity of this cytokine in vivo...
- Levitt R, McLane M, MacDonald D, Ferrante V, Weiss C, Zhou T, et al. IL-9 pathway in asthma: new therapeutic targets for allergic inflammatory disorders. J Allergy Clin Immunol. 1999;103:S485-91 pubmed..These data support a central role for the IL-9 pathway in the complex pathogenesis of allergic inflammation. ..
- Demoulin J, Uyttenhove C, Lejeune D, Mui A, Groner B, Renauld J. STAT5 activation is required for interleukin-9-dependent growth and transformation of lymphoid cells. Cancer Res. 2000;60:3971-7 pubmed..Our data suggest that STAT5 is an important mediator of IL-9-driven proliferation and that dysregulation of STAT5 activation favors tumorigenesis of lymphoid cells. ..
- Demoulin J, Grasso L, Atkins J, Stevens M, Louahed J, Levitt R, et al. Role of insulin receptor substrate-2 in interleukin-9-dependent proliferation. FEBS Lett. 2000;482:200-4 pubmed..Finally, 32D cells that were transfected with the IL-9 receptor but lack IRS expression survived in the presence of IL-9. Ectopic IRS1 expression allowed for IL-9-induced proliferation, in the absence of significant PKB phosphorylation. ..
- Nicolaides N, Holroyd K, Ewart S, Eleff S, Kiser M, Dragwa C, et al. Interleukin 9: a candidate gene for asthma. Proc Natl Acad Sci U S A. 1997;94:13175-80 pubmed..We assessed bronchial responsiveness as a quantitative trait in mice and found it linked to chromosome 13. Interleukin 9 (IL-9) is located in the linked region and was analyzed as a gene candidate...
- Lu L, Lind E, Gondek D, Bennett K, Gleeson M, Pino Lagos K, et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature. 2006;442:997-1002 pubmed..Finally, immunohistochemical analysis clearly demonstrates the existence of this novel T(Reg)-IL-9-mast cell relationship within tolerant allografts. ..
- Knoops L, Louahed J, Van Snick J, Renauld J. IL-9 promotes but is not necessary for systemic anaphylaxis. J Immunol. 2005;175:335-41 pubmed..Taken together, the data reported in this study indicate that IL-9 promotes systemic anaphylaxis reactions, acting at both the sensitization and effector stages, but is not absolutely required for this process. ..
- Steenwinckel V, Louahed J, Orabona C, Huaux F, Warnier G, McKenzie A, et al. IL-13 mediates in vivo IL-9 activities on lung epithelial cells but not on hematopoietic cells. J Immunol. 2007;178:3244-51 pubmed
- Veldhoen M, Uyttenhove C, Van Snick J, Helmby H, Westendorf A, Buer J, et al. Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008;9:1341-6 pubmed publisher..Thus, transforming growth factor-beta constitutes a regulatory 'switch' that in combination with other cytokines can 'reprogram' effector T cell differentiation along different pathways. ..
- Hauber H, Bergeron C, Hamid Q. IL-9 in allergic inflammation. Int Arch Allergy Immunol. 2004;134:79-87 pubmed..Furthermore, the specific role of IL-9 in allergic diseases and the potential therapeutic approach of blocking IL-9 will be discussed. ..
- McNamara P, Flanagan B, Baldwin L, Newland P, Hart C, Smyth R. Interleukin 9 production in the lungs of infants with severe respiratory syncytial virus bronchiolitis. Lancet. 2004;363:1031-7 pubmed..b>Interleukin 9, a type 2 cytokine has been proposed as a key cytokine in susceptibility to asthma...
- Tsicopoulos A, Shimbara A, de Nadai P, Aldewachi O, Lamblin C, Lassalle P, et al. Involvement of IL-9 in the bronchial phenotype of patients with nasal polyposis. J Allergy Clin Immunol. 2004;113:462-9 pubmed..These results suggest an important role for IL-9 in the pathogenesis of BHR and a causal relation between IL-9 and the development of bronchial eosinophilia in asthma. ..
- Godfraind C, Louahed J, Faulkner H, Vink A, Warnier G, Grencis R, et al. Intraepithelial infiltration by mast cells with both connective tissue-type and mucosal-type characteristics in gut, trachea, and kidneys of IL-9 transgenic mice. J Immunol. 1998;160:3989-96 pubmed
- Eklund K, Ghildyal N, Austen K, Stevens R. 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;151:4266-73 pubmed
- Faulkner H, Renauld J, Van Snick J, Grencis R. Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris. Infect Immun. 1998;66:3832-40 pubmed..muris. ..
- Zhou Y, McLane M, Levitt R. Th2 cytokines and asthma. Interleukin-9 as a therapeutic target for asthma. Respir Res. 2001;2:80-4 pubmed..We also discuss these results in comparison with the experiments supporting the involvement of other T H2 cytokines such as IL-4, IL-5 and IL-13. ..
- Demoulin J, Van Roost E, Stevens M, Groner B, Renauld J. Distinct roles for STAT1, STAT3, and STAT5 in differentiation gene induction and apoptosis inhibition by interleukin-9. J Biol Chem. 1999;274:25855-61 pubmed..These results suggest that survival and cell growth are redundantly controlled by multiple STAT factors, whereas differentiation gene induction is more specifically correlated with individual STAT activation by IL-9. ..
- Hültner L, Kölsch S, Stassen M, Kaspers U, Kremer J, Mailhammer R, et al. In activated mast cells, IL-1 up-regulates the production of several Th2-related cytokines including IL-9. J Immunol. 2000;164:5556-63 pubmed..These results are of particular importance in the light of recent reports that strongly support a central role of IL-9 in allergic lung inflammation and in host defense against worm infections. ..
- Stassen M, Muller C, Arnold M, Hültner L, Klein Hessling S, Neudörfl C, et al. 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;166:4391-8 pubmed
- Gounni A, Hamid Q, Rahman S, Hoeck J, Yang J, Shan L. IL-9-mediated induction of eotaxin1/CCL11 in human airway smooth muscle cells. J Immunol. 2004;173:2771-9 pubmed..Taken together, these data provide new evidence demonstrating that IL-9-dependent activation of ASM cells contributes to eosinophilic inflammation observed in asthma. ..
- Louahed J, Kermouni A, Van Snick J, Renauld J. IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones. J Immunol. 1995;154:5061-70 pubmedb>Interleukin 9 (IL-9) is a TH2 cytokine that has been shown to promote the antigen-independent growth of some mouse T helper clones...
- Holgate S, Church M, Howarth P, Morton E, Frew A, Djukanovic R. Genetic and environmental influences on airway inflammation in asthma. Int Arch Allergy Immunol. 1995;107:29-33 pubmed..These latter findings, being more evident in severe chronic disease, suggest that the 'formed' airway elements are also important in mediating the ongoing inflammation characteristic of asthma. ..
- Gessner A, Blum H, Rollinghoff M. Differential regulation of IL-9-expression after infection with Leishmania major in susceptible and resistant mice. Immunobiology. 1993;189:419-35 pubmed..Treatment of BALB/c mice with neutralizing anti-IL-4 mAb, a regimen known to lead to subsequent cure of infected BALB/c mice, suppressed late IL-9 synthesis. ..
- 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;31:728-40 pubmed publisher..The findings support further investigation of MEDI-528 in multiple-dose trials in patients with asthma. ClinicalTrials.gov Identification numbers: NCT00192296 (intravenous study); NCT00116168 (subcutaneous study). ..
- Temann U, Laouar Y, Eynon E, Homer R, Flavell R. IL9 leads to airway inflammation by inducing IL13 expression in airway epithelial cells. Int Immunol. 2007;19:1-10 pubmed..Our results implicate the lung epithelium as a potentially important source of inflammatory cytokines in asthma. ..
- Wang T, Chen W, Huang Y, Shih N, Feng W, Tseng H, et al. The synergistic effects of the IL-9 gene and environmental exposures on asthmatic Taiwanese families as determined by the transmission/disequilibrium test. Int J Immunogenet. 2006;33:105-10 pubmed
- Lejeune D, Demoulin J, Renauld J. 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. Biochem J. 2001;353:109-116 pubmedb>Interleukin 9 (IL-9) is a cytokine preferentially produced by T helper type 2 lymphocytes and active on various cell types such as T- and B-lymphocytes, mast cells and haemopoietic progenitors...
- Renauld J, Houssiau F, Louahed J, Vink A, Van Snick J, Uyttenhove C. Interleukin-9. Adv Immunol. 1993;54:79-97 pubmed
- Knoops L, Renauld J. IL-9 and its receptor: from signal transduction to tumorigenesis. Growth Factors. 2004;22:207-15 pubmed..Moreover, in vitro, dysregulated IL-9 response can lead to autonomous cell growth and malignant transformation of lymphoid cells associated with constitutive activation of the Jak/STAT pathway. ..
- Fallon P, Smith P, Richardson E, Jones F, Faulkner H, Van Snick J, et al. Expression of interleukin-9 leads to Th2 cytokine-dominated responses and fatal enteropathy in mice with chronic Schistosoma mansoni infections. Infect Immun. 2000;68:6005-11 pubmed..This study highlights the pleiotropic in vivo activity of IL-9 and demonstrates that an elevated Th2 cytokine phenotype leads to death during murine schistosome infection. ..
- Demoulin J, Uyttenhove C, Van Roost E, DeLestré B, Donckers D, Van Snick J, et al. 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;16:4710-6 pubmed..Taken together, these data indicate that a single tyrosine of the IL-9 receptor, required for activation of three different STAT proteins, is necessary for distinct activities of this cytokine, including proliferative responses. ..
- Hauber H, Manoukian J, Nguyen L, Sobol S, Levitt R, Holroyd K, et al. Increased expression of interleukin-9, interleukin-9 receptor, and the calcium-activated chloride channel hCLCA1 in the upper airways of patients with cystic fibrosis. Laryngoscope. 2003;113:1037-42 pubmed..These preliminary findings suggest that hCLCA1 might be an interesting new therapeutic target to control mucus overproduction in airway disease in patients with cystic fibrosis. ..
- Vink A, Warnier G, Brombacher F, Renauld J. Interleukin 9-induced in vivo expansion of the B-1 lymphocyte population. J Exp Med. 1999;189:1413-23 pubmed..The increase of antigen-specific antibody concentration in immunized mice suggests that these B-1 cells are directly or indirectly involved in antibody responses in IL-9 transgenic mice. ..
- Longphre M, Li D, Gallup M, Drori E, Ordoñez C, Redman T, et al. Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells. J Clin Invest. 1999;104:1375-82 pubmed..Furthermore, recombinant IL-9, but not IL-5 or IL-13, stimulated mucin synthesis. These results indicate that IL-9 may account for as much as 50-60% of the mucin-stimulating activity of lung fluids in allergic airway disease. ..
- McMillan S, Bishop B, Townsend M, McKenzie A, Lloyd C. The absence of interleukin 9 does not affect the development of allergen-induced pulmonary inflammation nor airway hyperreactivity. J Exp Med. 2002;195:51-7 pubmed..These findings indicate that IL-9 is not obligatory for the development of eosinophilia and AHR, and imply that other Th2 cytokines can act in a compensatory fashion. ..