STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation

Hoshino, Akihiko; Tsuji, Takemasa; Matsuzaki, Junko; Jinushi, Takafumi; Ashino, Shigeru; Teramura, Takashi; Chamoto, Kenji; Tanaka, Yoshitaka; Asakura, Yumiko; Sakurai, Takanobu; Mita, Yasuo; Takaoka, Akiko; Nakaike, Shiro; Takeshima, Tsuguhide; Ikeda, Hiroaki; Nishimura, Takashi

doi:10.1093/intimm/dxh151

Cited by 69 publications

(67 citation statements)

References 43 publications

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“…Upregulation of P-selectin and VCAM-1 has been documented following OSM (71,72) or IL-4 and IL-13 (73-75) stimulation of vascular endothelial cells. Because STAT6 is necessary for P-selectin (73,74), but not VCAM-1 (15,32,76) expression, this suggests that abrogation of eosinophil accumulation into STAT6 2/2 mouse lungs following AdmOSM administration could be attributed to the inhibition of P-selectin upregulation in concert with abolished eotaxin-1/2 expression. Neutrophils also use P-selectin glycoprotein ligand 1-P-selectin interactions during cell trafficking (68), and their chemotaxis is mediated by the neutrophil-selective CXC chemokine KC (77).…”

Section: Discussionmentioning

confidence: 99%

A Mouse Model of Airway Disease: Oncostatin M-Induced Pulmonary Eosinophilia, Goblet Cell Hyperplasia, and Airway Hyperresponsiveness Are STAT6 Dependent, and Interstitial Pulmonary Fibrosis Is STAT6 Independent

Fritz

Kerr

Fattouh

et al. 2011

The Journal of Immunology

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Oncostatin M (OSM), a pleiotropic cytokine of the gp130 cytokine family, has been implicated in chronic allergic inflammatory and fibrotic disease states associated with tissue eosinophilia. Mouse (m)OSM induces airway eosinophilic inflammation and interstitial pulmonary fibrosis in vivo and regulates STAT6 activation in vitro. To determine the requirement of STAT6 in OSM-induced effects in vivo, we examined wild-type (WT) and STAT6-knockout (STAT6−/−) C57BL/6 mouse lung responses to transient ectopic overexpression of mOSM using an adenoviral vector (AdmOSM). Intratracheal AdmOSM elicited persistent eosinophilic lung inflammation that was abolished in STAT6−/− mice. AdmOSM also induced pronounced pulmonary remodeling characterized by goblet cell hyperplasia and parenchymal interstitial fibrosis. Goblet cell hyperplasia was STAT6 dependent; however, parenchymal interstitial fibrosis was not. OSM also induced airway hyperresponsiveness in WT mice that was abolished in STAT6−/− mice. OSM stimulated an inflammatory signature in the lungs of WT mice that demonstrated STAT6-dependent regulation of Th2 cytokines (IL-4, IL-13), chemokines (eotaxin-1/2, MCP-1, keratinocyte chemoattractant), and extracellular matrix modulators (tissue inhibitor of matrix metalloproteinase-1, matrix metalloproteinase-13), but STAT6-independent regulation of IL-4Rα, total lung collagen, collagen-1A1, -1A2 mRNA, and parenchymal collagen and α smooth muscle actin accumulation. Thus, overexpression of mOSM induces STAT6-dependent pulmonary eosinophilia, mucous/goblet cell hyperplasia, and airway hyperresponsiveness but STAT6-independent mechanisms of lung tissue extracellular matrix accumulation. These results also suggest that eosinophil or neutrophil accumulation in mouse lungs is not required for OSM-induced lung parenchymal collagen deposition and that OSM may have unique roles in the pathogenesis of allergic and fibrotic lung disease.

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Section: Discussionmentioning

confidence: 99%

A Mouse Model of Airway Disease: Oncostatin M-Induced Pulmonary Eosinophilia, Goblet Cell Hyperplasia, and Airway Hyperresponsiveness Are STAT6 Dependent, and Interstitial Pulmonary Fibrosis Is STAT6 Independent

Fritz

Kerr

Fattouh

et al. 2011

The Journal of Immunology

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“…STAT-6 is required for the development of airway inflammation, mucus production and AHR in animal models of acute allergic airways disease [21,53,54]. MCCUSKER et al [55] generated a cell-penetrating STAT-6 inhibitory peptide (STAT-6-IP) consisting of the protein transduction domain 4 fused to a phosphotyrosine-containing sequence predicted to bind with high affinity to the SH2 domain of STAT-6; thus, acting as a dominant negative inhibitor of the wild-type STAT-6 protein.…”

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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“…In addition, ROS has been implicated in mucous hypersecretion in asthma and has been reported to be activated by IL-13 [13-15]. We also examined the level of ROS in vivo and in vitro .…”

Section: Resultsmentioning

confidence: 99%

LPS Exposure in Early Life Protects Against Mucus Hypersecretion in Ovalbumin-Induced Asthma by Down-Regulation of the IL-13 and JAK-STAT6 Pathways

Ding¹,

Liu²,

Zou³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Previous studies have shown that lipopolysaccharide (LPS) exposure may have a protective effect on asthma by reducing airway hyper-responsiveness, airway inflammation and serum IgE levels. However, there are few studies investigating the effect of LPS on mucous secretion in asthma. In this study, we evaluate the relationship between LPS pre-treatment in infant mice and airway mucus hypersecretion in an OVA (ovalbumin)-induced asthma model, and further explore the mechanisms behind this effect. Methods: Mice were pre-treated with LPS by intranasal instillation (i.n.) from the 3^rd day of life for 10 consecutive days before the OVA-induced asthma model was established. In order to detect mucus secretion, periodic acid-Schiff (PAS) staining was carried out, and the expression of Muc5ac was detected. The IL-13 levels in Bronchoalveolar lavage fluid (BALF) and lung tissue were also detected. In vitro, the expression of Muc5ac mRNA and protein was quantified in IL-13-stimulated 16HBE cells with or without LPS pre-treatment. In addition, proteins in the JAK2/STAT6 pathway, transcription factors (forkhead box transcription factor A2 (FOXA2), activation protein-1(AP-1), NF-κB), and the levels of reactive oxygen species (ROS) were also measured in vivo and in vitro. Results: LPS pre-treatment reduced mucus secretion, as demonstrated by decreased PAS staining and muc5ac expression. Further exploration of the underlying mechanisms of this phenomenon revealed that LPS pre-treatment decreased the production of IL-13, IL-13 induced ROS synthesis was reduced, and the JAK2/STAT6 pathway was inhibited. Decreased stat6 increased transcription factor FOXA2, and the relatively increased FOXA2 further decreased the level of Muc5ac and mucous hypersecretion in OVA-induced asthma. Conclusions: LPS pre-treatment ameliorated mucus hypersecretion in an OVA-induced asthma model by inhibition of IL-13 production and by further inhibiting the JAK2/STAT6 pathway and ROS activity, and up-regulating expression of FOXA2.

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STAT6-mediated signaling in Th2-dependent allergic asthma: critical role for the development of eosinophilia, airway hyper-responsiveness and mucus hypersecretion, distinct from its role in Th2 differentiation

Cited by 69 publications

References 43 publications

A Mouse Model of Airway Disease: Oncostatin M-Induced Pulmonary Eosinophilia, Goblet Cell Hyperplasia, and Airway Hyperresponsiveness Are STAT6 Dependent, and Interstitial Pulmonary Fibrosis Is STAT6 Independent

A Mouse Model of Airway Disease: Oncostatin M-Induced Pulmonary Eosinophilia, Goblet Cell Hyperplasia, and Airway Hyperresponsiveness Are STAT6 Dependent, and Interstitial Pulmonary Fibrosis Is STAT6 Independent

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

LPS Exposure in Early Life Protects Against Mucus Hypersecretion in Ovalbumin-Induced Asthma by Down-Regulation of the IL-13 and JAK-STAT6 Pathways

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