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INTERLEUKIN 9
LATEST LITERATURE
1: Journal of immunology (Baltimore, Md. : 1950), 2010 Aug 30,
Neutralization of IL-9 Ameliorates Experimental Autoimmune Encephalomyelitis by Decreasing the Effector T Cell Population.
[Abstract]Multiple sclerosis is a CD4(+) T cell-mediated autoimmune disease affecting the CNS. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), have been thought to be Th1-mediated diseases. However, recent studies provide strong evidence that the major pathogenic T cell subsets in EAE are Th17 cells. IL-9, a hematopoietic growth factor, is considered to be a mediator of Th17 cells, but the precise mechanisms of its action are largely unknown. The present study was designed to investigate the role of IL-9 in autoimmune demyelination. IL-9 blockade with anti-IL-9 mAb inhibited the development of EAE, reduced the serum levels of IL-17, the CNS mRNA expression of IL-17, IL-6, IFN-gamma, and TNF-alpha, and the myelin oligodendrocyte glycoprotein (MOG)-induced IL-17, IFN-gamma secretion of lymphocytes. Furthermore, anti-IL-9 mAb in culture suppressed IL-17 production of MOG-reactive T cells and their potency in adoptive transfer EAE. These findings indicate that the protective effect of IL-9 blockade in EAE was likely mediated via inhibition of the development of MOG peptide-specific T cells, which in turn led to reduced infiltration of T cells into the CNS. Thus, anti-IL-9 mAb treatment may provide an effective therapeutic strategy against autoimmune diseases.
2: Immunology, 2010 Jul 28, 62(8)
Interleukin-9 as a T helper type 17 cytokine.
[Abstract]Summary The production of interleukin-9 (IL-9) by CD4 T cells has gathered renewed interest as the result of the observation that its expression is broader than originally thought. This includes the production of IL-9 by a recently characterized subset of CD4 helper T (Th) cells that are termed Th9 as well as production by additional T-cell subsets including Th17 cells. There is an incomplete understanding as to which IL-9-producing T-cell subsets develop under physiological conditions. We describe the conditions used to generate IL-9 in Th17 cells in vitro. We also summarize conditions where both IL-9 and IL-17 are found in vivo and propose that Th17 cells producing IL-9 may co-exist and interact with Th9 cells during conditions of autoimmunity, allergy and infection.
3: Journal of immunology (Baltimore, Md. : 1950), 2010 May 24, 11(6)
TGF-{beta} Induces IL-9 Production from Human Th17 Cells.
[Abstract]The secretion of IL-9, initially recognized as a Th2 cytokine, was recently attributed to a novel CD4 T cell subset termed Th9 in the murine system. However, IL-9 can also be secreted by mouse Th17 cells and may mediate aspects of the proinflammatory activities of Th17 cells. Here we report that IL-9 is secreted by human naive CD4 T cells in response to differentiation by Th9 (TGF-beta and IL-4) or Th17 polarizing conditions. Yet, these differentiated naive cells did not coexpress IL-17 and IL-9, unless they were repeatedly stimulated under Th17 differentiation-inducing conditions. In contrast to the naive cells, memory CD4 T cells were induced to secrete IL-9 by simply providing TGF-beta during stimulation, as neither IL-4 nor proinflammatory cytokines were required. Furthermore, the addition of TGF-beta to the Th17-inducing cytokines (IL-1beta, IL-6, IL-21, IL-23) that induce memory cells to secrete IL-17, resulted in the marked coexpression of IL-9 in IL-17 producing memory cells. The proinflammatory cytokine mediating TGF-beta-dependent coexpression of IL-9 and IL-17 was identified to be IL-1beta. Moreover, circulating monocytes were potent costimulators of IL-9 production by Th17 cells via their capacity to secrete IL-1beta. Finally, to determine whether IL-9/IL-17 coproducing CD4 cells were altered in an inflammatory condition, we examined patients with autoimmune diabetes and demonstrated that these subjects exhibit a higher frequency of memory CD4 cells with the capacity to transition into IL-9(+)IL-17(+) cells. These data demonstrate the presence of IL-17(+)IL-9(+) CD4 cells induced by IL-1beta that may play a role in human autoimmune disease.
4: Journal of biomedicine & biotechnology, 2010, 2010(1)
Increasing a robust antigen-specific cytotoxic T lymphocyte response by FMDV DNA vaccination with IL-9 expressing construct.
[Abstract]Various chemokines and cytokines as adjuvants can be used to improve efficacy of DNA vaccination. In this study, we sought to investigate if a DNA construct expressing IL-9 (designed as proV-IL9) as a molecular adjuvant enhance antigen specific immune responses elicited by the pcD-VP1 DNA vaccination. Mice immunized with pcD-VP1 combined with proV-IL9 developed a strong humoral response. In addition, the coinoculation induced significant higher level of antigen-specific cell proliferation and cytotoxic response. This agreed well with higher expression level of IFN-gamma and perforin in CD8+ T cells, but not with IL-17 in these T cells. The results indicate that IL-9 induces the development of IFN-gamma-producing CD8+ T cells (Tc1), but not the IL-17-producing CD8+ T cells (Tc17). Up-regulated expressions of BCL-2 and BCL-XL were exhibited in these Tc1 cells, suggesting that IL-9 may trigger antiapoptosis mechanism in these cells. Together, these results demonstrated that IL-9 used as molecular adjuvant could enhance the immunogenicity of DNA vaccination, in augmenting humoral and cellular responses and particularly promoting Tc1 activations. Thus, the IL-9 may be utilized as a potent Tc1 adjuvant for DNA vaccines.
5: Nature immunology, 2010 May 2,
The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation.
[Abstract]CD4(+) helper T cells acquire effector phenotypes that promote specialized inflammatory responses. We show that the ETS-family transcription factor PU.1 was required for the development of an interleukin 9 (IL-9)-secreting subset of helper T cells. Decreasing PU.1 expression either by conditional deletion in mouse T cells or the use of small interfering RNA in human T cells impaired IL-9 production, whereas ectopic PU.1 expression promoted IL-9 production. Mice with PU.1-deficient T cells developed normal T helper type 2 (T(H)2) responses in vivo but showed attenuated allergic pulmonary inflammation that corresponded to lower expression of Il9 and chemokines in peripheral T cells and in lungs than that of wild-type mice. Together our data suggest a critical role for PU.1 in generating the IL-9-producing (T(H)9) phenotype and in the development of allergic inflammation.
6: Current opinion in molecular therapeutics, 2010 Apr, 12(2)
MEDI-528, an anti-IL-9 humanized antibody for the treatment of asthma.
[Abstract]In development by MedImmune LLC, under license from Genaera Corp, MEDI-528 is an injectable, humanized mAb against IL-9 for the potential treatment of asthma. In asthma, airway inflammation is usually adequately minimized with standard-of-care treatments, such as inhaled corticosteroids and leukotriene modifiers, but it is sometimes less responsive to such therapies and other anti-inflammatory approaches are required. Several T-helper cell type 2-derived cytokines, such as IL-4, -5, -9 and -13, play a major role in the development of disease pathogenic features in asthma, including airway eosinophilia, increased IgE production, mucus hypersecretion and airway hyperreactivity. As an IL-9 antagonist, MEDI-528 appears to inhibit a range of asthma pathogenic features in antigen-exposed mice. To date, clinical data are modest, although insufficient to judge the efficacy of the drug in humans, and larger and longer-term clinical trials are required. MEDI-528, along with other anticytokine therapies targeting different ILs, remains under investigation in early-phase trials for asthma. Time will tell if this form of therapy can be used as an add-on to less efficacious anti-inflammatory therapy or can replace the existing anti-inflammatory therapies in the treatment of asthma.
7: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology, 2010 Feb, 104(2)
Serum interleukin 9 in allergic rhinitis.
[Abstract]BACKGROUND: Previous findings support the concept that IL-9 may play a significant role in mediating both pro-inflammatory and changes in airway responsiveness that characterizes the atopic asthmatic state. We previously demonstrated that human airway smooth muscle (ASM) cells express a functional IL-9R that mediate CCL11 expression. However, the signaling pathway governing this effect is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we showed that IL-9 mediated CCL11 expression in ASM cells does not rely on STAT6 or STAT5 but on STAT3 pathway. IL-9 induced rapid STAT3 activation in primary ASM cells that was not observed in case of STAT6 or STAT5. STAT3 binding to CCL11 promoter was also observed in vivo upon IL-9 stimulation of ASM cells. Disruption of STAT3 activity with SH2 domain binding inhibitory peptide results in significant reduction of IL-9 mediated CCL11 promoter activity. DN STAT3beta over-expression in ASM cells, but not Ser 727 STAT3 or STAT6 DN, abolishes IL-9 mediated CCL11 promoter activity. Finally, STAT3 but not STAT6 silenced ASM cells showed significant reduction in IL-9 mediated CCL11 promoter activity and mRNA expression. CONCLUSION/SIGNIFICANCE: Taken together, our results indicate that IL-9 mediated CCL11 via STAT3 signalling pathway may play a crucial role in airway inflammatory responses.
8: Cell cycle (Georgetown, Tex.), 2009 Dec 14, 8(23)
Interleukin-9 and T cell subsets.
[Abstract]
9: Journal of immunology (Baltimore, Md. : 1950), 2009 Oct 15, 183(8)
Antigen-induced increases in pulmonary mast cell progenitor numbers depend on IL-9 and CD1d-restricted NKT cells.
[Abstract]Pulmonary mast cell progenitor (MCp) numbers increase dramatically in sensitized and aerosolized Ag-challenged mice. This increase depends on CD4(+) T cells, as no MCp increase occurs in the lungs of sensitized wild-type (WT) mice after mAb depletion of CD4(+) but not CD8(+) cells before aerosol Ag challenge. Neither the genetic absence of IL-4, IL-4Ralpha chain, STAT-6, IFN-gamma, or IL-12p40 nor mAb blockade of IFN-gamma, IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17A, IL-12p40, or IL-12p40Rbeta1 before Ag challenge in WT mice reduces the pulmonary MCp increase. However, sensitized and Ag-challenged IL-9-deficient mice and sensitized WT mice given mAb to IL-9 just before Ag challenge show significant reductions in elicited lung MCp/10(6) mononuclear cells of 47 and 66%, respectively. CD1d-deficient mice and WT mice receiving anti-CD1d before Ag challenge also show significant reductions of 65 and 59%, respectively, in elicited lung MCp/10(6) mononuclear cells, revealing an additional requirement for MCp recruitment. However, in Jalpha18-deficient mice, which lack only type 1 or invariant NKT cells, the increase in the numbers of lung MCp with Ag challenge was intact, indicating that their recruitment must be mediated by type 2 NKT cells. Furthermore, anti-CD1d treatment of IL-9-deficient mice or anti-IL-9 treatment of CD1d-deficient mice does not further reduce the significant partial impairment of MCp recruitment occurring with a single deficiency. 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.
10: The Journal of experimental medicine, 2009 Aug 3, 206(8)
IL-9 as a mediator of Th17-driven inflammatory disease.
[Abstract]We report that like other T cells cultured in the presence of transforming growth factor (TGF) beta, Th17 cells also produce interleukin (IL) 9. Th17 cells generated in vitro with IL-6 and TGF-beta as well as purified ex vivo Th17 cells both produced IL-9. To determine if IL-9 has functional consequences in Th17-mediated inflammatory disease, we evaluated the role of IL-9 in the development and progression of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. The data show that IL-9 neutralization and IL-9 receptor deficiency attenuates disease, and this correlates with decreases in Th17 cells and IL-6-producing macrophages in the central nervous system, as well as mast cell numbers in the regional lymph nodes. Collectively, these data implicate IL-9 as a Th17-derived cytokine that can contribute to inflammatory disease.
11: Clinical therapeutics, 2009 Apr, 31(4)
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.
[Abstract]BACKGROUND: Interleukin-9 (IL-9) is involved in pathogenic aspects of the asthmatic response, including induction of the proliferation of T-helper type 2 lymphocytes, mucus production, and mast-cell differentiation, proliferation, and recruitment to the lung. In preclinical studies in mice, inhibition of IL-9 through neutralizing monoclonal antibody (mAb) treatment partially reduced airway hyperresponsiveness and mast-cell progenitor migration to the lung. OBJECTIVE: The goal of the present studies was to determine the safety and pharmacokinetic profiles and immunogenicity of MEDI-528, a humanized immunoglobulin G1k anti-IL-9 mAb, in healthy adult volunteers. METHODS: In separate open-label, Phase I dose-escalation studies, single doses of MEDI-528 0.3, 1.0, 3.0, or 9.0 mg/kg were administered as an intravenous infusion (20 mg/min administered over 1-40 minutes, depending on dose) and by subcutaneous injection. All subjects were followed for 84 days. Any laboratory test value outside the normal reference range was considered an adverse event (AE). RESULTS: Twenty-four subjects were enrolled in the intravenous study, and 29 subjects were enrolled in the subcutaneous study. No deaths or serious or severe AEs occurred in either study. The most frequently reported AEs in the intravenous study were laboratory test abnormalities; the most frequently reported AEs in the subcutaneous study were pharyngolaryngeal pain, palpable lymph nodes, and laboratory test abnormalities. The single-dose pharmacokinetics of MEDI-528 were linear and dose proportional over the dose range studied with both routes of administration. The mean t((1/2)) after intravenous administration was approximately 26 days (range, 25-28 days); the mean t((1/2)) after subcutaneous administration ranged from 33 to 87 days across doses. A low titer (1:80) of antibodies to MEDI-528 was detected on day 84 in a single volunteer receiving intravenous MEDI-528 3.0 mg/kg. No antibody titers were detected in any of the volunteers receiving subcutaneous MEDI-528. CONCLUSIONS: Administered intravenously or subcutaneously, MEDI-528 had an acceptable safety profile and exhibited linear pharmacokinetics over the dose range studied in healthy adults in these Phase I studies. 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).
12: Proceedings of the National Academy of Sciences of the United States of America, 2009 Aug 4, 106(31)
IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells.
[Abstract]The development of T helper (T(H))17 and regulatory T (T(reg)) cells is reciprocally regulated by cytokines. Transforming growth factor (TGF)-beta alone induces FoxP3(+) T(reg) cells, but together with IL-6 or IL-21 induces T(H)17 cells. Here we demonstrate that IL-9 is a key molecule that affects differentiation of T(H)17 cells and T(reg) function. IL-9 predominantly produced by T(H)17 cells, synergizes with TGF-beta1 to differentiate na?ve CD4(+) T cells into T(H)17 cells, while IL-9 secretion by T(H)17 cells is regulated by IL-23. Interestingly, IL-9 enhances the suppressive functions of FoxP3(+) CD4(+) T(reg) cells in vitro, and absence of IL-9 signaling weakens the suppressive activity of nT(regs) in vivo, leading to an increase in effector cells and worsening of experimental autoimmune encephalomyelitis. 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.
13: Genes and immunity, 2009 Jun, 10(4)
Functional analysis of -351 interleukin-9 promoter polymorphism reveals an activator controlled by NF-kappaB.
[Abstract]Genetic studies have shown linkages for asthma to the chromosomal region 5q31-q33 in humans that includes the IL-9 gene. An A-to-G base substitution has been identified at bp -351 in the IL-9 promoter. The role of this polymorphism in IL-9 promoter function was assessed utilizing CD4+ T cells purified from individuals with one or two of the G alleles in comparison to those homozygous for the wild-type A. The presence of an A at -351 (A allele) increased mitogen-stimulated IL-9 transcription twofold in comparison to subjects with one or two G alleles at this position. Binding of nuclear extract proteins from IL-9-producing human cell lines to DNA sequences including this base exchange demonstrated specific binding of the transcription factor NF-kappaB. Binding of NF-kappaB to the IL-9 promoter was confirmed in vivo using the chromatin immunoprecipitation assay. Recombinant NF-kappaB bound to a promoter fragment with the A allele with fivefold higher affinity than it did to a promoter with the G allele. Individuals carrying the A allele of the IL-9 promoter display increased synthesis of IL-9, which may result in strong Th2 immune responses and a modulation of their susceptibility to infectious, neoplastic, parasitic or atopic disease.
14: Journal of immunology (Baltimore, Md. : 1950), 2009 Apr 15, 182(8)
IL-9 promotes IL-13-dependent paneth cell hyperplasia and up-regulation of innate immunity mediators in intestinal mucosa.
[Abstract]IL-9 contributes to lung inflammatory processes such as asthma, by promoting mast cell differentiation, B cell activation, eosinophilia, and mucus production by lung epithelial cells. The observation that IL-9 overexpressing mice show increased mast cell numbers in the intestinal mucosa suggests that this cytokine might also play a role in intestinal inflammation. In colons from IL-9 transgenic mice, the expression of Muc2, a major intestinal mucin gene, was up-regulated, together with that of CLCA3 chloride channel and resistin like alpha, which are goblet cell-associated genes. Additional IL-9 up-regulated genes were identified and included innate immunity genes such as angiogenin 4 and the PLA2g2a phospholipase A(2), which are typical Paneth cell markers. Histochemical staining of Paneth cells by phloxine/tartrazine showed that IL-9 induces Paneth cell hyperplasia in Lieberk¨¹hn glands of the small intestine, and in the colonic mucosa, where this cell type is normally absent. Expression of Paneth cell markers, including angiogenin 4, PLA2g2a, and cryptdins, was induced in the colon of wild-type mice after two to four daily administrations of IL-9. By crossing IL-9 transgenic mice with IL-13(-/-) mice, or by injecting IL-9 into IL-4R(-/-) mice, we showed that IL-13 was required for the up-regulation of these Paneth cell-specific genes by IL-9. 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.
15: In vivo (Athens, Greece), 2008 Nov-Dec, 22(6)
Aberrant activation of interleukin-9 receptor and downstream Stat3/5 in primary T-cell lymphomas in vivo in susceptible B6 and resistant C3H mice.
[Abstract]BACKGROUND: Interleukin (IL)-2 family cytokine-mediated signal transduction plays important roles not only in normal development but also in the malignant transformation of lymphoid cells. However, little is known about the status of receptor activation and downstream signal transduction in primary lymphomas in vivo. MATERIALS AND METHODS: Primary T-cell lymphomas (TL) of mice were induced by X-ray irradiation. Expression and activation of IL-2 family cytokine receptors and downstream Janus kinase (Jak)-signal transducers and activators of transcription (Stat) pathway were determined. RESULTS: IL-9Ra was exceptionally highly expressed and phosphorylated in primary TL. IL-9Ralpha proteins in TL were heterogeneous due to different glycosylation. Downstream Stat3 and 5, but not Stat1, were also phosphorylated. There was a clear strain difference between susceptible C57BL/6 and resistant C3H mice in Stat3 and 5 activation and expression of Cyclin D1. CONCLUSION: Aberrant expression, modification and activation of IL-9Ralpha and Stat proteins contribute to in vivo growth of TL in a manner linking to the genetic susceptibility to TL induction.
16: The Journal of biological chemistry, 2009 Mar 13, 284(11)
Acute lymphoblastic leukemia-associated JAK1 mutants activate the Janus kinase/STAT pathway via interleukin-9 receptor alpha homodimers.
[Abstract]Activating mutations in JAK1 have been reported in acute lymphoblastic leukemias, but little is known about the mechanisms involved in their constitutive activation. Here, we studied the ability of JAK1 V658F and A634D to activate the Janus kinase (JAK)/STAT pathway upon ectopic expression in HEK293 cells alone or together with the other components of the interleukin-9 receptor complex (IL-9Ralpha, gammac, and JAK3). Expression of JAK1 mutants alone failed to trigger STAT activation, but co-expression of the IL-9Ralpha chain promoted JAK1 mutant phosphorylation and STAT activation. Mutation of the FERM domain of JAK1, which is critical for cytokine receptor association, or of the single tyrosine of IL-9Ralpha involved in STAT recruitment abolished this activity, indicating that JAK1 mutants need to associate with a functional IL-9Ralpha to activate STAT factors. Several lines of evidence indicated that IL-9Ralpha homodimerization was involved in this process. IL-9Ralpha variants with mutations of the JAK-interacting BOX1 region not only failed to promote JAK1 activation but also acted as dominant negative forms reverting the effect of wild-type IL-9Ralpha. Coimmunoprecipitation experiments also showed the formation of IL-9Ralpha homodimers. Interestingly, STAT activation was partially inhibited by expression of gammac, suggesting that overlapping residues are involved in IL-9Ralpha homodimerization and IL-9Ralpha/gammac heterodimerization. Co-expression of wild-type JAK3 partially reverted the inhibition by gammac, indicating that JAK3 cooperates with JAK1 mutants within the IL-9 receptor complex. Similar results were observed with IL-2Rbeta. Taken together, our results show that IL-9Ralpha and IL-2Rbeta homodimers efficiently mediate constitutive activation of ALL-associated JAK1 mutants.
17: Experimental lung research, 2008 Nov, 34(9)
Interleukin-9 and -13 inhibit spontaneous and corticosteroid induced apoptosis of normal airway epithelial cells.
[Abstract]The airway epithelium is the target of physical and allergic insults. The resulting inflammatory signals from Th2 cytokines including interleukin (IL)-9 and IL-13 have pleiotropic activities and have been implicated in airway remodeling in asthmatics. The objective of this study was to determine the role of IL-9 and IL-13 in the regulation of normal airway epithelial cell death and epithelial repair. In a cell culture model, a normal human airway epithelial cell line and primary airway epithelial cells were treated with IL-9 or IL-13 alone and in combination. Apoptosis was determined by multiple techniques, including enrichment of nucleosomes released into the cytoplasm, mitochondrial membrane polarity perturbation, cytosolic cytochrome c released and the detection of cleaved p85-poly(ADP-ribose)polymerase (PARP). Proliferation was quantified by BrdU incorporation. IL-9 and IL-13 treatment, alone and in combination, resulted in a significant reduction in spontaneous airway epithelial cell apoptosis when compared to controls. The cytoprotective effect of IL-9 was associated with up-regulation of the antiapoptotic molecule Bcl-2. IL-13 also demonstrated coordinate pro-proliferative activity .Dexamethasone induces apoptosis in airway epithelial cells. Coincubation with IL-9 or IL-13 was protective against this corticosteroid-induced apoptosis by up-regulation of Bcl-2. These data demonstrate that IL-9 and IL-13 may be critical to normal cellular homeostasis in the setting of airway epithelial injury. A dysregulated response to these cytokines may contribute to airway remodeling in asthma.
18: Nature immunology, 2008 Dec, 9(12)
IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells.
[Abstract]Transcription factor Foxp3 is critical for generating regulatory T cells (T(reg) cells). Transforming growth factor-beta (TGF-beta) induces Foxp3 and suppressive T(reg) cells from naive T cells, whereas interleukin 6 (IL-6) inhibits the generation of inducible T(reg) cells. Here we show that IL-4 blocked the generation of TGF-beta-induced Foxp3(+) T(reg) cells and instead induced a population of T helper cells that produced IL-9 and IL-10. The IL-9(+)IL-10(+) T cells demonstrated no regulatory properties despite producing abundant IL-10. Adoptive transfer of IL-9(+)IL-10(+) T cells into recombination-activating gene 1-deficient mice induced colitis and peripheral neuritis, the severity of which was aggravated if the IL-9(+)IL-10(+) T cells were transferred with CD45RB(hi) CD4(+) effector T cells. Thus IL-9(+)IL-10(+) T cells lack suppressive function and constitute a distinct population of helper-effector T cells that promote tissue inflammation.
19: Cell death and differentiation, 2008 Oct, 15(10)
IL-9/IL-9 receptor signaling selectively protects cortical neurons against developmental apoptosis.
[Abstract]In mammals, programmed cell death (PCD) is a central event during brain development. Trophic factors have been shown to prevent PCD in postmitotic neurons. Similarly, cytokines have neurotrophic effects involving regulation of neuronal survival. Nevertheless, neuronal PCD is only partially understood and host determinants are incompletely defined. The present study provides evidence that the cytokine interleukin-9 (IL-9) and its receptor specifically control PCD of neurons in the murine newborn neocortex. IL-9 antiapoptotic action appeared to be time-restricted to early postnatal stages as both ligand and receptor transcripts were mostly expressed in neocortex between postnatal days 0 and 10. This period corresponds to the physiological peak of apoptosis for postmitotic neurons in mouse neocortex. In vivo studies showed that IL-9/IL-9 receptor pathway inhibits apoptosis in the newborn neocortex. Furthermore, in vitro studies demonstrated that IL-9 and its receptor are mainly expressed in neurons. IL-9 effects were mediated by the activation of the JAK/STAT (janus kinase/signal transducer and activator of transcription) pathway, whereas nuclear factor-kappaB (NF-kappaB) or Erk pathways were not involved in mediating IL-9-induced inhibition of cell death. Finally, IL-9 reduced the expression of the mitochondrial pro-apoptotic factor Bax whereas Bcl-2 level was not significantly affected. Together, these data suggest that IL-9/IL-9 receptor signaling pathway represents a novel endogenous antiapoptotic mechanism for cortical neurons by controlling JAK/STAT and Bax levels.
20: Current protocols in immunology / edited by John E. Coligan ... [et al.], 2002 Nov, Chapter 6(10)
Measurement of mouse and human interleukin 9.
[Abstract]This unit describes two proliferation assays to detect or quantitate human and murine interleukin 9 (IL-9). The first is based on the ability of IL-9 to stimulate the proliferation of the TS1h9RA3 cell line, a murine IL-9-dependent cell line transfected with the human IL-9 receptor. An alternate protocol is based on the ability of IL-9 to stimulate the proliferation of the human megakaryoblastic leukemia cell line, M-O7e. M-O7e cells depend on either human IL-3 or granulocyte/macrophage colony-stimulating factor (GM-CSF) for growth, although other cytokines including IL-2, -4, -6, and -9 and steel factor are also weakly mitogenic (relative to IL-3 and GM-CSF). Thus, although M-O7e cells can readily be used to quantitate levels of IL-9 in the absence of other cytokines, analysis in the presence of complex mixtures of cytokines (e.g., natural sources) requires the use of specific antibodies against IL-9 and the other cytokines, as described in this unit.
21: The Journal of experimental medicine, 2008 Apr 14, 205(4)
IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity.
[Abstract]Previous mouse and clinical studies demonstrate a link between Th2 intestinal inflammation and induction of the effector phase of food allergy. However, the mechanism by which sensitization and mast cell responses occurs is largely unknown. We demonstrate that interleukin (IL)-9 has an important role in this process. IL-9-deficient mice fail to develop experimental oral antigen-induced intestinal anaphylaxis, and intestinal IL-9 overexpression induces an intestinal anaphylaxis phenotype (intestinal mastocytosis, intestinal permeability, and intravascular leakage). In addition, intestinal IL-9 overexpression predisposes to oral antigen sensitization, which requires mast cells and increased intestinal permeability. 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.
22: Allergology international : official journal of the Japanese Society of Allergology, 2008 Jun, 57(2)
House dust mite extract induces interleukin-9 expression in human eosinophils.
[Abstract]BACKGROUND: Eosinophils play a pivotal role in allergic inflammation. Recent evidence suggests that they not only function as terminal effector cells but have potential to interact with allergen and initiate immune responses. We investigated cytokine production from eosinophils through direct interaction with a major allergen, house dust mite (HDM) . METHODS: Purified eosinophils from HDM-sensitized or non-sensitized donors were cultured with HDM extract or lipopolysaccharide (LPS) for 18 or 40 h. A panel of cytokine gene expression in eosinophils was examined by means of real-time RT-PCR. Released cytokines in the culture supernatants were assessed with a specific ELISA. In some experiments, HDM was pretreated with protease inhibitors, then added to the culture. Cytokines tested for gene expression were interleukin (IL)-2, 4, 6, 7, 8, 9, 10, 11, 12, 13, 16,17, 18, TGF-beta1 and GM-CSF,. RESULTS: LPS induced small enhancement of GM-CSF gene expression at 18 h. At 40 h, HDM induced about 60-fold enhancement of IL-9 gene expression. IL-9 protein was also detected in the culture supernatants at 60 h. Those reactions were observed regardless of HDM sensitization status of the donors. HDM-induced IL-9 expression was completely inhibited with a serine protease inhibitor, AEBSF, not with a cysteine protease inhibitor, E-64. CONCLUSIONS: Accumulated eosinophils in the airways in asthma may directly react with HDM and produce IL-9 to further promote Th2-type immune responses. Protease-activated receptor 2, a ligand for serine proteases, which contained in HDM, may be involved in the reaction.
23: Blood, 2008 May 15, 111(10)
Induction of the IL-9 gene by HTLV-I Tax stimulates the spontaneous proliferation of primary adult T-cell leukemia cells by a paracrine mechanism.
[Abstract]The etiologic agent of adult T-cell leukemia (ATL) is human T cell lymphotropic virus type I (HTLV-I). The HTLV-I protein Tax alters gene expression, including those of cytokines and their receptors, which plays an important role in early stages of ATL. Here we demonstrate that expression of interleukin-9 (IL-9) is activated by Tax via an NF-kappaB motif in its proximal promoter, whereas IL-9 receptor-alpha (IL-9Ralpha) expression is not induced by Tax. However, supporting a role for IL-9/IL-9Ralpha in ATL, a neutralizing monoclonal antibody directed toward IL-9Ralpha inhibited ex vivo spontaneous proliferation of primary ATL cells from several patients. Fluorescence-activated cell sorter analysis of freshly isolated peripheral blood mononuclear cells from these patients revealed high level expression of IL-9Ralpha on their CD14-expressing monocytes. Furthermore, purified T cells or monocytes alone from these patients did not proliferate ex vivo, whereas mixtures of these cell types manifested significant proliferation through a contact-dependent manner. Taken together, our data suggest that primary ATL cells, via IL-9, support the action of IL-9Ralpha/CD14-expressing monocytes, which subsequently support the ex vivo spontaneous proliferation of malignant T cells. In summary, these data support a role for IL-9 and its receptor in ATL by a paracrine mechanism.
24: Clinical immunology (Orlando, Fla.), 2008 Feb, 126(2)
IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis.
[Abstract]Although a defective Th1 response has been demonstrated in patients infected with Mycobacterium tuberculosis (Mtb), the mechanisms leading to this defect are not well understood. To study the immune response to Mtb infection, we stimulated PBMC from individuals with latent tuberculosis infection (LTBI) or patients with tuberculosis (TB) with the Mtb specific antigen early secretory antigenic target-6 (ESAT-6). mRNAs for a panel of cytokines were measured using quantitative real-time PCR (qPCR). PBMC from TB patients exhibited low levels of IFN-gamma, IL-12alpha, IL-12beta, and IL-23 mRNA but high levels of IL-9 mRNA. Sera from TB patients blocked the differentiation and function of dendritic cells from TST negative (TST-) donors. Exogenous IL-9 reduced IFN-gamma mRNA expression in PBMC from LTBI by 30% (n=4) and neutralization of IL-9 restored the IFN-gamma mRNA expression in PBMC from TB patients by 66% (n=8). Thus, increased expression of IL-9 may contribute to the development of TB.
25: The Journal of allergy and clinical immunology, 2007 Nov, 120(5)
Expression of IL-9 receptor alpha chain on human germinal center B cells modulates IgE secretion.
[Abstract]BACKGROUND: IL-9 has been shown to affect the differentiation pathway of different cell types. However, its potential role in the maturation pathway of antigen-driven B-cell differentiation and its functional effects remain unknown. OBJECTIVE: To characterize IL-9 receptor alpha chain (IL-9R alpha) expression on human tonsillar B cells at different maturational stages, and to assess its effect on IgE production. METHODS: Freshly purified human tonsillar B cells were fractionated into 3 populations: low-density (LD), medium-density, and high-density cells. Expression levels of IL-9R alpha were determined by using immunohistochemistry and flow cytometry. IL-9R alpha(high)-expressing cells were stimulated with IL-9 in the presence or absence of IL-4, and IgE release was measured by ELISA. RESULTS: IL-9R alpha was expressed on human LD tonsillar B cells, with an ability to transduce signals through activation of signal transducer and activator of transcription 3 and 5. Although IL-9 was unable to induce IgE secretion by itself, it potentiated IL-4-mediated IgE production from LD cells. Moreover, increased IgE was paralleled by an upregulation of IL-9R alpha and CD27, with the latter a memory B-cell marker implicated in increased IgE secretion. CONCLUSION: These results highlight a crucial role for IL-9 in modulating T-cell-dependent B-cell differentiation and establish a new paradigm for understanding the synergistic role of T(H)2 cytokines and their modulatory effect on B-cell maturation and IgE production. CLINICAL IMPLICATIONS: IL-9 appears to be involved in memory B-cell differentiation and T(H)2-mediated allergic diseases such as asthma.
26: American journal of respiratory cell and molecular biology, 2008 Mar, 38(3)
IL-9 and IL-13 induce mucous cell metaplasia that is reduced by IFN-gamma in a Bax-mediated pathway.
[Abstract]One of the major aspects of airway remodeling in asthma is the development of mucous cell metaplasia (MCM). The role of cytokines in the generation and resolution of MCM has been studied in mice and in isolated airway epithelial cells in culture. However, studies using organ cultures that keep the tubular structure of the airways intact and allow studies in the absence of inflammatory cells have not been reported. We established an organ culture system that replicates the allergen-induced MCM in mice and analyzed the role of Bax in the IFN-gamma-induced resolution of MCM. IL-9 or IL-13 induced MCM independently, but a combined IL-9/IL-13 treatment enhanced MCM synergistically. Addition of IFN-gamma at 0.1 ng/ml concentration further increased MCM to levels observed in allergen-exposed mice in vivo. However, MCM was reduced when explants were treated with 50 ng/ml IFN-gamma after MCM was established. While IL-9/IL-13 induced MCM in bronchioles microdissected from bax(+/+) and bax(-/-) mice to a similar extent, IFN-gamma treatment reduced MCM only in bronchioles from bax(+/+) but not in bax(-/-) bronchioles. Restoration of Bax expression in bax(-/-) bronchioles using an adenoviral expression system reduced IL-9/IL-13-induced MCM while MCM was similar in noninfected or adenoviral green fluorescent protein-infected bax(-/-) bronchioles. Furthermore, expressing Bax using an adenoviral expression system reduced allergen-induced MCM in mice. These studies show that allergen-induced MCM is a response to a combination of various cytokines at defined concentrations and that IFN-gamma requires Bax for the resolution of MCM.