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Jean-christophe Renauld - One of the best experts on this subject based on the ideXlab platform.
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acute lymphoblastic leukemia associated jak1 mutants activate the janus kinase stat pathway via Interleukin 9 receptor α homodimers
Journal of Biological Chemistry, 2009Co-Authors: Tekla Hornakova, Judith Staerk, Yohan Royer, Elisabetta Flex, Marco Tartaglia, Stefan N Constantinescu, Laurent Knoops, Jean-christophe RenauldAbstract: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.
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chapter 14 Interleukin 9
The Cytokine Handbook (Fourth Edition), 2003Co-Authors: Jean-christophe Renauld, Jacques Van SnickAbstract:Identified as a T cell and mast cell growth factor with a narrow specificity, IL-9 has proved to be a broadly active cytokine with various targets including B cells, macrophages, eosinophils, hematopoietic precursors, and epithelial cells. Its aggravating role in asthma is probably because of its action on the different cells involved in this disease. Another potential use of IL-9 in vivo stems from its ability to dampen excessive production of inflammatory cytokines by monocytes and macrophages, as shown in septic shock following infection with Pseudomonas aeruginosa are discussed in the chapter. In the view of the induction of IL-10 and TGF, it will also be of interest to evaluate the ability of IL-9 to modulate auto-immune reactions, a field that has not been carefully investigated, but which may create further interesting perspectives for the use, and study of this molecule. The activities of this cytokine on peritoneal B1 lymphocytes or on neurones, for instance, deserve further investigation, and may unravel unexepected links with various pathophysiological situations.
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Interleukin 9 promotes influx and local maturation of eosinophils
Blood, 2001Co-Authors: Jamila Louahed, Jean-christophe Renauld, Anne Vink, Jacques Van Snick, Yuhong Zhou, Lee W Maloy, Pyapalli U Rani, Christine Weiss, Yaniv Tomer, Nicholas C NicolaidesAbstract:The Interleukin 9 (IL-9) pathway has recently been associated with the asthmatic phenotype including an eosinophilic tissue inflammation. The mechanism by which IL-9 affects eosinophils (eos) is not known. To investigate whether this cytokine has a direct activity on the development of eos and eosinophilic inflammation, a model of thioglycolate-induced peritoneal inflammation was used in IL-9 transgenic (TG5) and background strain (FVB) mice. In this model, a transient eosinophilic infiltration in the peritoneal cavity was observed in FVB mice 12 to 24 hours after thioglycolate injection that coincided with peak IL-5 and IL-9 release. In contrast, TG5 mice developed a massive eosinophilia that persisted at high levels (81% of total cells) even 72 hours after thioglycolate injection. Release of eosinophilic major basic protein (MBP), IL-4, and IL-5 to the peritoneal cavity of these mice was significantly increased when compared with the control FVB strain. To study the mechanism by which IL-9 exerts its effect on eos, bone marrow or peritoneal cells were cultured in the presence of IL-5, IL-9, or their combination in vitro. IL-5 alone was able to generate significant numbers of eos in TG5 but not FVB mice, whereas a combination of IL-5 and IL-9 induced marked eosinophilia in both strains indicating a synergism between these 2 cytokines. These data suggest that IL-9 may promote and sustain eosinophilic inflammation via IL-5-driven eos maturation of precursors.
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Interleukin 9 upregulates mucus expression in the airways
American Journal of Respiratory Cell and Molecular Biology, 2000Co-Authors: Jamila Louahed, Jean-christophe Renauld, Roy C. Levitt, Qutayba Hamid, Masao Toda, Jin Jen, Nicholas C NicolaidesAbstract:Interleukin (IL)-9 has recently been shown to play an important role in allergic disease because its expression is strongly associated with the degree of airway responsiveness and the asthmatic-like phenotype. IL-9 is a pleiotropic cytokine that is active on many cell types involved in the allergic immune response. Mucus hypersecretion is a clinical feature of chronic airway diseases; however, the mechanisms underlying the induction of mucin are poorly understood. In this report, we show that IL-9 regulates the expression of a subset of mucin genes in lung cells both in vivo and in vitro. In vivo, the constitutive expression of IL-9 in transgenic mice results in elevated MUC2 and MUC5AC gene expression in airway epithelial cells and periodic acid-Schiff–positive staining (reflecting mucous glycogenates). Similar results were observed in C57BL/6J mice after IL-9 intratracheal instillation. In contrast, instillation of the T helper 1–associated cytokine interferon γ failed to induce mucin production. In vit...
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proinflammatory cytokines and Interleukin 9 exacerbate excitotoxic lesions of the newborn murine neopallium
Annals of Neurology, 2000Co-Authors: Mariealiette Dommergues, Jean-christophe Renauld, Juliana Patkai, Philippe Evrard, Pierre GressensAbstract:Many prenatal and perinatal factors are hypothesized to play a role in the cause of cerebral palsy (CP). Epidemiological data implicate maternal-fetal infection and associated increase in circulating cytokines. Murine model data suggest that excitotoxic damage can produce pathological change in brain tissue consistent with lesions observed in CP. Specifically, on day 5 after birth, mouse pups injected with ibotenate, a glutamatergic analogue, develop transcortical necrosis and white matter cysts mimicking some human perinatal lesions associated with CP. The present study builds on this murine model to assess the modulating role of several cytokines on the development of excitotoxic lesions. Pups pretreated with Interleukin (IL)-1beta, IL-6, IL-9, or tumor necrosis factor-alpha developed significantly larger ibotenate-induced cortical and white matter damage than controls; IL-4 did not produce such an effect. In a similar manner, IL-9-overexpressing transgenic pups developed ibotenate-induced brain lesions, which were significantly larger than those induced in nontransgenic control pups. Pretreatment with proinflammatory cytokines significantly increased neopallial microglial density without affecting astrocytic density; IL-9 or IL-4 did not produce a similar effect. To our knowledge, this is the first in vivo study to demonstrate that systemically administered proinflammatory cytokines and IL-9 exacerbate brain lesions that are similar to those found in human infants with CP.
Y C Yang - One of the best experts on this subject based on the ideXlab platform.
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14 3 3zeta interacts with the alpha chain of human Interleukin 9 receptor
Biochemical Journal, 2000Co-Authors: Daniel Sliva, Y X Zhu, J Chen, S Tsai, Y C YangAbstract:Interleukin 9 (IL-9) exerts its pleiotropic effects through the IL-9 receptor (IL-9R) complex, which consists of the IL-9R alpha-chain, which determines the cytokine specificity, and the IL-2 receptor gamma-chain. In the present study we used a modified yeast two-hybrid system to isolate cDNA species encoding proteins that interacted with the intracellular domain of the human IL-9R alpha-chain (hIL-9Ralpha). We have identified 14-3-3zeta as an hIL-9Ralpha-interacting protein. We also mapped residues 518-522 (Arg-Ser(519)-Trp-Thr(521)-Phe) in hIL-9Ralpha and helix I of 14-3-3zeta as being important for interaction. Moreover, peptide competition experi-ments suggested that interaction between hIL-9Ralpha and 14-3-3zeta requires the phosphorylation of Ser(519) or Thr(521). This is the first demonstration that 14-3-3 can interact with a non-tyrosine kinase receptor. The interaction between 14-3-3 and IL-9Ralpha but not IL-4Ralpha also suggests a potential role for 14-3-3 in determining cytokine specificity.
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14 3 3ζ interacts with the α chain of human Interleukin 9 receptor
Biochemical Journal, 2000Co-Authors: Daniel Sliva, Y X Zhu, J Chen, S Tsai, Y C YangAbstract:important for interaction. Moreover, peptide competition experiments suggested that interaction between hIL-9Ra and 14-3-3f requires the phosphorylation of Ser&"* or Thr&#". This is the first demonstration that 14-3-3 can interact with a non-tyrosine kinase receptor. The interaction between 14-3-3 and IL-9Ra but not IL-4Ra also suggests a potential role for 14-3-3 in determining cytokine specificity. proteins interact with a number of signalling proteins, including Raf, Bcr and Bcr}Abl, polyomavirus middle T antigen, phosphoinositide 3-kinase, cdc25 phosphatase, PTPH1 phosphatase, the proto-oncogene product Cbl, tryptophan hydroxylase, protein kinase C and IRS-1 [21‐28]. In addition, insulin-like growth factor I receptor, adhesion receptor platelet glycoprotein Iba and glucocorticoid receptor have been shown to interact with 14-3-3 proteins [29,30]. To identify molecules involved in IL-9R signalling, we performed yeast two-hybrid screening to identify proteins binding to the intracellular domain of hIL-9Ra. Several interacting clones encoding 14-3-3 isoforms with the highest sequence similarity to 14-3-3f were identified. The interaction between full-length 14-3-3f and hIL-9Ra was confirmed by coimmunoprecipitation, and the interacting domain of hIL-9Ra was identified through a yeast two-hybrid assay. We also showed that serine or threonine phosphorylation is necessary for the binding of 14-3-3f to hIL-9Ra and identified a novel motif in hIL-9Ra for binding 14-3-3f.
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Interleukin 9 induces tyrosine phosphorylation of insulin receptor substrate 1 via jak tyrosine kinases
Journal of Biological Chemistry, 1995Co-Authors: Tinggui Yin, Susanne R Keller, Frederick W Quelle, Bruce A Witthuhn, Monica Likshing Tsang, Gustav E Lienhard, James N Ihle, Y C YangAbstract:Interleukin (IL)-9 stimulates the proliferation of a variety of hematopoietic lineages through its interaction with a receptor of the cytokine receptor superfamily. In the studies presented here, we have begun to characterize the downstream signaling pathways activated by IL-9. In addition to the activation of JAK1 and JAK3 tyrosine kinases, IL-9, unlike most hematopoietic cytokines but similar to IL-4, induces the tyrosine phosphorylation of a 170-kDa protein that is related to the insulin receptor substrate-1 (IRS-1). We further demonstrate for the first time that IRS-1 is not only associated with JAK1 but also tyrosine phosphorylated and functionally involved in IL-9 signaling in TS1 lymphocytes transfected with the murine IRS-1 cDNA. Cotransfection studies and in vitro experiments directly demonstrate that JAK1, JAK2, or JAK3 is capable of tyrosine phosphorylating IRS-1, suggesting a functional role for these kinases in vivo. Lastly, we demonstrate that IL-9 induces the tyrosine phosphorylation of Stat3 and in this regard differs from IL-4, which triggers tyrosine phosphorylation of Stat6. Taken together, these results strongly suggest that IL-9 and IL-4 utilize common and unique signaling pathways via inducing the similar and distinct tyrosine-phosphorylated proteins.
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jak1 kinase forms complexes with Interleukin 4 receptor and 4ps insulin receptor substrate 1 like protein and is activated by Interleukin 4 and Interleukin 9 in t lymphocytes
Journal of Biological Chemistry, 1994Co-Authors: Tinggui Yin, Monica Likshing Tsang, Y C YangAbstract:Interleukin (IL)-4 and IL-9 regulate the proliferation of T lymphocytes through interactions with their receptors. Previous studies have shown that unknown tyrosine kinases are involved in the proliferative signaling triggered by IL-4 and IL-9. Here we show that IL-4 and IL-9 induce overlapping (170, 130, and 125 kilodalton (kDa)) and distinct (45 and 88/90 kDa, respectively) protein tyrosine phosphorylation in T lymphocytes. We further identify the 170-kDa tyrosine-phosphorylated protein as 4PS/insulin receptor substrate-1-like (IRS-1L) protein and 130-kDa protein as JAK1 kinase. Furthermore, we demonstrate for the first time that JAK1 forms complexes with the IL-4 receptor and 4PS/IRS-1L protein following ligand-receptor interaction. In addition, we demonstrate that IL-9, but not IL-4, induced tyrosine phosphorylation of Stat 91 transcriptional factor. The overlapping and distinct protein tyrosine phosphorylation and activation of the same JAK1 kinase in T lymphocytes strongly suggests that IL-4 and IL-9 share the common signal transduction pathways and that the specificity for each cytokine could be achieved through the unique tyrosine-phosphorylated proteins triggered by individual cytokines.
Nestor A Molfino - One of the best experts on this subject based on the ideXlab platform.
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a randomized controlled trial to evaluate the effect of an anti Interleukin 9 monoclonal antibody in adults with uncontrolled asthma
Respiratory Research, 2013Co-Authors: Richard Leigh, Kimmie K Mclaurin, Keunpyo Kim, Micki Hultquist, Nestor A MolfinoAbstract:Background Preclinical studies suggest that Interleukin-9 may be a central mediator in the development and maintenance of airway inflammation in asthma. The aim of this study was therefore to evaluate the effects of MEDI-528, an anti-Interleukin-9 monoclonal antibody, in adults with confirmed uncontrolled moderate-to-severe asthma.
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safety profile and clinical activity of multiple subcutaneous doses of medi 528 a humanized anti Interleukin 9 monoclonal antibody in two randomized phase 2a studies in subjects with asthma
BMC Pulmonary Medicine, 2011Co-Authors: Joseph M Parker, Barbara White, Wendy I White, Gabriel Robbie, Craig Laforce, David S Miller, David S Pearlman, Nestor A MolfinoAbstract:Interleukin-9 (IL-9)-targeted therapies may offer a novel approach for treating asthmatics. Two randomized placebo-controlled studies were conducted to assess the safety profile and potential efficacy of multiple subcutaneous doses of MEDI-528, a humanized anti-IL-9 monoclonal antibody, in asthmatics. Study 1: adults (18-65 years) with mild asthma received MEDI-528 (0.3, 1, 3 mg/kg) or placebo subcutaneously twice weekly for 4 weeks. Study 2: adults (18-50 years) with stable, mild to moderate asthma and exercise-induced bronchoconstriction received 50 mg MEDI-528 or placebo subcutaneously twice weekly for 4 weeks. Adverse events (AEs), pharmacokinetics (PK), immunogenicity, asthma control (including asthma exacerbations), and exercise challenge test were evaluated in study 1, study 2, or both. In study 1 (N = 36), MEDI-528 showed linear serum PK; no anti-MEDI-528 antibodies were detected. Asthma control: 1/27 MEDI-528-treated subjects had 1 asthma exacerbation, and 2/9 placebo-treated subjects had a total of 4 asthma exacerbations (one considered a serious AE). In study 2, MEDI-528 (n = 7) elicited a trend in the reduction in mean maximum decrease in FEV1 post-exercise compared to placebo (n = 2) (-6.49% MEDI-528 vs -12.60% placebo; -1.40% vs -20.10%; -5.04% vs -15.20% at study days 28, 56, and 150, respectively). Study 2 was halted prematurely due to a serious AE in an asymptomatic MEDI-528-treated subject who had an abnormal brain magnetic resonance imaging that was found to be an artifact on further evaluation. In these studies, MEDI-528 showed an acceptable safety profile and findings suggestive of clinical activity that support continued study in subjects with mild to moderate asthma. ClinicalTrials (NCT): NCT00507130 and ClinicalTrials (NCT): NCT00590720
Randolph J Noelle - One of the best experts on this subject based on the ideXlab platform.
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cellular sources and immune functions of Interleukin 9
Nature Reviews Immunology, 2010Co-Authors: Randolph J Noelle, Elizabeth NowakAbstract:Interleukin-9 (IL-9) has recently entered the limelight owing to the discovery that it can be produced by multiple T helper cell subsets. This Progress article updates us on the cellular sources, targets and immune functions of IL-9.
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Interleukin 9 as a t helper type 17 cytokine
Immunology, 2010Co-Authors: Elizabeth Nowak, Randolph J NoelleAbstract: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.
Jeanbaptiste Demoulin - One of the best experts on this subject based on the ideXlab platform.
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distinct roles for stat1 stat3 and stat5 in differentiation gene induction and apoptosis inhibition by Interleukin 9
Journal of Biological Chemistry, 1999Co-Authors: Jeanbaptiste Demoulin, Emiel Van Roost, Monique Stevens, Bernd Groner, Jean-christophe RenauldAbstract:Interleukin-9 (IL-9) activates three distinct STAT proteins: STAT1, STAT3, and STAT5. This process depends on one tyrosine of the IL-9 receptor, which is necessary for proliferation, gene induction, and inhibition of apoptosis induced by glucocorticoids. By introduction of point mutations in amino acids surrounding this tyrosine, we obtained receptors that activated either STAT5 alone or both STAT1 and STAT3, thus providing us with the possibility to study the respective roles of these factors in the biological activities of IL-9. Both mutant receptors were able to prevent apoptosis, but only the mutant that activated STAT1 and STAT3 was able to support induction of granzyme A and L-selectin. In line with these results, constitutively activated STAT5 blocked glucocorticoid-induced apoptosis. In Ba/F3 cells, significant proliferation and pim-1 induction were observed with both STAT-restricted mutants, though proliferation was lower than with the wild-type receptor. 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.
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Interleukin 9 and its receptor an overview of structure and function
International Reviews of Immunology, 1998Co-Authors: Jeanbaptiste Demoulin, Jean-christophe RenauldAbstract:Interleukin-9 (IL-9) is a multifunctional cytokine produced by activated TH2 clones in vitro and during TH2-like T cell responses in vivo. Although IL-9 was initially described as a T cell growth factor, its role in T cell responses is still unclear. While freshly isolated normal T cells do not respond to IL-9, this cytokine induces the proliferation of murine T cell lymphomas in vitro, and in vivo overexpression of IL-9 results in the development of thymic lymphomas. In the human, the existence of an IL-9 mediated autocrine loop has been suggested for some malignancies such as Hodgkin's disease. Various observations indicate that IL-9 is actively involved in mast cells responses by inducing the proliferation and differentiation of these cells. Other potential biological targets for IL-9 include B lymphocytes, and hematopoietic progenitors, for which higher responses were observed with foetal or transformed cells as compared to normal adult progenitors. The IL-9 receptor is a member of the hemopoietin receptor superfamily and interacts with the gamma chain of the IL-2 receptor for signaling. Signal transduction studies have stressed the role of the Jak-STAT pathway in various IL-9 bioactivities, whereas the 4PS/IRS2 adaptor protein might also play a significant role in IL-9 signaling.
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a single tyrosine of the Interleukin 9 il 9 receptor is required for stat activation antiapoptotic activity and growth regulation by il 9
Molecular and Cellular Biology, 1996Co-Authors: Jeanbaptiste Demoulin, Emiel Van Roost, Catherine Uyttenhove, B Delestre, D Donckers, J Van Snick, Jean-christophe RenauldAbstract:Interleukin-9 (IL-9), a T-cell-derived cytokine, interacts with a specific receptor associated with the IL-2 receptor gamma chain. In this report, we analyze the functional domains of the human IL-9 receptor transfected into mouse lymphoid cell lines. Three different functions were examined: growth stimulation in factor-dependent pro-B Ba/F3 cells, protection against dexamethasone-induced apoptosis, and Ly-6A2 induction in BW5147 lymphoma cells. The results indicated that a single tyrosine, at position 116 in the cytoplasmic domain, was required for all three activities. In addition, we observed that human IL-9 reduced the proliferation rate of transfected BW5147 cells, an effect also dependent on the same tyrosine. This amino acid was necessary for IL-9-mediated tyrosine phosphorylation of the receptor and for STAT activation but not for IRS-2/4PS activation or for JAK1 phosphorylation, which depended on a domain closer to the plasma membrane. We also showed that JAK1 was constitutively associated with the IL-9 receptor. Activated STAT complexes induced by IL-9 were found to contain STAT1, STAT3, and STAT5 transcription factors. Moreover, sequence homologies between human IL-9 receptor tyrosine 116 and tyrosines (of other receptors activating STAT3 and STAT5 were observed. 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.