YM-341619 suppresses the differentiation of spleen T cells into Th2 cells in vitro, eosinophilia, and airway hyperresponsiveness in rat allergic models

Ohga, Keiko; Kuromitsu, Sadao; Takezawa, Ryuichi; Numazaki, Mako; Ishikawa, Jun; Nagashima, S.; Shimizu, Yoshiyuki

doi:10.1016/j.ejphar.2008.06.035

Cited by 19 publications

(14 citation statements)

References 48 publications

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“…For example, the therapeutic YM-341619 suppressed STAT-6 dependent gene expression. YM-341619 administered orally to rats during OVA-induced allergic inflammation decreased eosinophil recruitment to the lungs, and decreased airway reactivity (17). Antibodies that target IL-13, IL-4, or the IL-4Ra chain of the IL-13R decreased the activation of STAT6, and are currently undergoing human clinical trials to reduce asthma symptoms and mucus production (16,(29)(30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we examined IL-17A mucous cell metaplasia in the absence of STAT6. Understanding this mechanism is important, because therapeutics targeting the STAT6 pathway are being developed for the treatment of asthma (16,17,(29)(30)(31)(32)(33)). These patients demonstrate increased levels of mucus production, but with variable expressions of IL-13 or periostin, an IL-13 marker protein (34), calling into question the absolute IL-13 dependence of airway mucus production in asthma.…”

Section: Discussionmentioning

confidence: 99%

“…IL-13 and STAT6 signaling are currently being targeted for asthma therapy (15)(16)(17), and it remains unknown whether down-regulating STAT6 signaling may modulate IL-17A-driven airway mucous cell metaplasia in patients with asthma. Therefore, understanding whether IL-17A-mediated mucous cell hyperplasia occurs in a STAT6-independent model is important for drug development.…”

Section: Il-17a Secretion From Cd4mentioning

confidence: 99%

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IL-17A Induces Signal Transducers and Activators of Transcription–6–Independent Airway Mucous Cell Metaplasia

Newcomb¹,

Boswell²,

Sherrill³

et al. 2013

Am J Respir Cell Mol Biol

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Mucous cell metaplasia is a hallmark of asthma, and may be mediated by signal transducers and activators of transcription (STAT)-6 signaling. IL-17A is increased in the bronchoalveolar lavage fluid of patients with severe asthma, and IL-17A also increases mucus production in airway epithelial cells. Asthma therapeutics are being developed that inhibit STAT6 signaling, but the role of IL-17A in inducing mucus production in the absence of STAT6 remains unknown. We hypothesized that IL-17A induces mucous cell metaplasia independent of STAT6, and we tested this hypothesis in two murine models in which increased IL-17A protein expression is evident. In the first model, ovalbumin (OVA)-specific D011.10 Th17 cells were adoptively transferred into wild-type (WT) or STAT6 knockout (KO) mice, and the mice were challenged with OVA or PBS. WT-OVA and STAT6 KO-OVA mice demonstrated increased airway IL-17A and IL-13 protein expression and mucous cell metaplasia, compared with WT-PBS or STAT6 KO-PBS mice. In the second model, WT, STAT1 KO, STAT1/STAT6 double KO (DKO), or STAT1/STAT6/IL-17 receptor A (RA) triple KO (TKO) mice were challenged with respiratory syncytial virus (RSV) or mock viral preparation, and the mucous cells were assessed. STAT1 KO-RSV mice demonstrated increased airway mucous cell metaplasia compared with WT-RSV mice. STAT1 KO-RSV and STAT1/STAT6 DKO-RSV mice also demonstrated increased mucous cell metaplasia, compared with STAT1/STAT6/IL17RA TKO-RSV mice. We also treated primary murine tracheal epithelial cells (mTECs) from WT and STAT6 KO mice. STAT6 KO mTECs showed increased periodic acid-Schiff staining with IL-17A but not with IL-13. Thus, asthma therapies targeting STAT6 may increase IL-17A protein expression, without preventing IL-17A-induced mucus production.Keywords: asthma; mucous cell metaplasia; IL-17A; STAT6; Airway mucus is a hallmark of asthma. Airway epithelial cell remodeling in asthma includes mucous cell metaplasia and mucus hypersecretion, which narrows the airway lumen and limits airflow (1). A major component of mucus consists of mucins, which are large glycoproteins that determine the viscoelasticity of mucus (2). Mucin genes are expressed in many tissues, but MUC5AC and MUC5B constitute the primary mucin genes expressed in the airway epithelial cells of the lung (3). Previous studies have shown that IL-13, a Th2 cytokine that is increased during allergic airway inflammation, is required for airway mucous cell metaplasia (4-7).IL-13 is abundant in the sputum of some patients with asthma (8). IL-13 binds to the IL-13 receptor (R), which is comprised of two subunits, IL-4Ra and IL-13Ra1. The binding of IL-13 to the IL-13R results in the phosphorylation and activation of the downstream transcription factor signal transducers and activators of transcription (STAT)-6 and the transcription of IL-13-mediated genes. STAT6 and IL-13 are required for maximal airway mucous cell metaplasia in murine models of allergic airway inflammation (4-6, 9). The airway instillation of recombinant IL-13 or t...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Il-17a Secretion From Cd4mentioning

confidence: 99%

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IL-17A Induces Signal Transducers and Activators of Transcription–6–Independent Airway Mucous Cell Metaplasia

Newcomb¹,

Boswell²,

Sherrill³

et al. 2013

Am J Respir Cell Mol Biol

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“…A mouse soluble IL-4 mutant has been shown to have antagonist effects against both IL-4 and IL-13 in vitro via the formation of an unproductive complex with IL-4Ra [50]. Treatment of mice with this antagonist completely inhibited the humoral immune response to allergen and subsequent development of disordered lung function upon allergen challenge [50].…”

Section: Pre-clinical Evidence For the Role Of Il-4/il-13/ Stat-6 In mentioning

confidence: 99%

Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma

Oh¹,

Geba²,

Molfino³

2010

European Respiratory Review

234

164

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Asthma is a complex, persistent, inflammatory disease characterised by airway hyperresponsiveness in association with airway inflammation. Studies suggest that regular use of high-dose inhaled corticosteroids and long-acting bronchodilators or omalizumab (a humanised monoclonal antibody that binds to immunoglobulin E and is often used as next-step therapy) may not be sufficient to provide asthma control in all patients, highlighting an important unmet need. Interleukin-4, interleukin-13, and the signal transducer and activator of transcription factor-6 are key components in the development of airway inflammation, mucus production, and airway hyperresponsiveness in asthma. Biological compounds targeting these molecules may provide a new therapeutic modality for patients with uncontrolled severe asthma. The purpose of this review is to summarise current studies of compounds targeting the interleukin-4/interleukin-13 pathway and to provide a rationale for the development of such compounds for this use.

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“…Interleukin-4 (IL-4) and interleukin-13 (IL-13) are the main immunomodulators to induce the autoimmune responses that are excessively secreted by stimulated Th2 cells, moreover, following that the immunoglobulin E (IgE) and histamine produced by nascent mast cells increases their levels around the bronchial epithelial cells, although these events make the symptoms acute (3). Asthma, atopic dermatitis, and rhinitis that are known to go through a similar signaling process on hyper-responsive symptoms around the epithelial tissues have similar molecular events (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Anti-asthmatic activities in mycelial extract and culture filtrate of Cordyceps sphecocephala J201

Heo

Nam²,

Nam³

et al. 2010

Int J Mol Med

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Abstract. This study investigated the effects of mycelial extract and culture filtrate of Cordyceps sphecocephala J201 on airway hyper-responsiveness, pulmonary immune cell infiltration, and Th2 cytokine expression in animal models of asthma. After Concanavalin A (Con A) activation of mouse primary spleen cells, the IL-4 and IL-13 cytokine expression were significantly decreased in the presence of the mycelial extract and culture filtrate of Cordyceps sphecocephala J201. The asthma model was induced by sensitization to ovalbumin by intraperitoneal (i.p.) injection treatment in mice. The Cordyceps sphecocephala J201 mycelial extract was injected in order to assess the effects of anti-asthmatic activity by comparing lung cell infiltration in ovalbumin-induced asthmatic mice. The results revealed that the increased IL-4, IL-13 and IL-25 expression were controlled by the mycelial extract and culture filtrate of Cordyceps sphecocephala J201, indicating that the extracts reduced the undesirable immune responses and/or cytokine expression exhibited in asthma.

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YM-341619 suppresses the differentiation of spleen T cells into Th2 cells in vitro, eosinophilia, and airway hyperresponsiveness in rat allergic models

Cited by 19 publications

References 48 publications

IL-17A Induces Signal Transducers and Activators of Transcription–6–Independent Airway Mucous Cell Metaplasia

IL-17A Induces Signal Transducers and Activators of Transcription–6–Independent Airway Mucous Cell Metaplasia

Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma

Anti-asthmatic activities in mycelial extract and culture filtrate of Cordyceps sphecocephala J201

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