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

Oh, Chad K.; Geba, Gregory P.; Molfino, Néstor A.

doi:10.1183/09059180.00007609

Cited by 237 publications

(171 citation statements)

References 74 publications

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“…IL-4Ra/IL-2Rg expression is restricted to hematopoietically derived cells, including lymphocytes and myeloid cells. IL-13Ra1/ IL-4Ra is expressed on hematopoietic cells and stromal cells, which in the lung include epithelial cells and fibroblasts (38). We assessed the relative expression levels of each receptor component on myeloid cells (monocytes and monocyte-derived macrophages) and lung fibroblasts, including IMR90 cells, which are derived from primary fetal human lung fibroblasts ( Fig.…”

Section: Il-4 and Il-13 Protein Quantificationmentioning

confidence: 99%

Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

Chandriani¹,

DePianto²,

N'Diaye³

et al. 2014

The Journal of Immunology

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IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Rα and IL-13Rα2. Whereas IL-13Rα1/IL-4Rα engagement by IL-13 leads to the activation of STAT6, the molecular events triggered by IL-13 binding to IL-13Rα2 remain incompletely understood. IL-4 can bind to and signal through the IL-13Rα1/IL-4Rα complex but does not interact with IL-13Rα2. Idiopathic pulmonary fibrosis is a progressive and generally fatal parenchymal lung disease of unknown etiology with no current pharmacologic treatment options that substantially prolong survival. Preclinical models of fibrotic diseases have implicated IL-13 activity on multiple cell types, including macrophages and fibroblasts, in initiating and perpetuating pathological fibrosis. In this study, we show that IL-13, IL-4, IL-13Rα2, and IL-13–inducible target genes are expressed at significantly elevated levels in lung tissue from patients with idiopathic pulmonary fibrosis compared with control lung tissue. IL-4 and IL-13 induce virtually identical transcriptional responses in human monocytes, macrophages, and lung fibroblasts. IL-13Rα2 expression can be induced in lung fibroblasts by IL-4 or IL-13 via a STAT6-dependent mechanism, or by TNF-α via a STAT6-independent mechanism. Endogenously expressed IL-13Rα2 decreases, but does not abolish, sensitivity of lung fibroblasts to IL-13 and does not affect sensitivity to IL-4. Genome-wide transcriptional analyses of lung fibroblasts stimulated with IL-13 in the presence of Abs that selectively block interactions of IL-13 with IL-13Rα1/IL-4Rα or IL-13Rα2 show that endogenously expressed IL-13Rα2 does not activate any unique IL-13–mediated gene expression patterns, confirming its role as a decoy receptor for IL-13 signaling.

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Section: Il-4 and Il-13 Protein Quantificationmentioning

confidence: 99%

Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

Chandriani¹,

DePianto²,

N'Diaye³

et al. 2014

The Journal of Immunology

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“…IL-4 signals through the type I receptor that is made up of the IL-4Ra chain and the common g chain (gc), whereas both IL-4 and IL-13 signal through the type II IL-4 receptor, which consists of the IL-4Ra chain and the IL-13Ra1chain (Mitchell et al 2010;Oh et al 2010). IL-13 can also bind to the IL-13Ra2 chain, which has been well characterized as a decoy receptor in its secreted form.…”

Section: Il-4/il-13 Receptor Engagement and Signal Transductionmentioning

confidence: 99%

Cytokine Pathways in Allergic Disease

et al. 2012

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Cytokines are critical in allergic intercellular communication networks, and they contribute to disease pathology through the recruitment and activation of pro-inflammatory leukocytes and in chronic disease to pro-fibrotic/remodeling events. Th2 cytokines predominate primarily in mild to moderate allergic asthma, although clinical trials with inhibitors of IL-4 and IL-5 have not provided the robust efficacy observed in animal models of allergy. These results not only highlight the complexity of allergic disease, but they also point to the importance of other cytokine networks in driving pathology. The heterogeneous nature of the disease is emphasized by the fact that the Th2/Th1/Th17 cytokine balance can be influenced by the initiating allergic trigger. For example, the house dust mite allergen Der p 2 mimics the activity of MD-2 by presenting lipopolysaccharide to Toll-like receptor-4 for the activation of inflammatory genes including innate-type cytokines. Here we discuss the functions of the novel cytokine players, thymic stromal lymphopoetin (TSLP), IL-33, IL-25, and IL-9 and delineate nonredundant roles for IL-4 and IL-13 in allergic disease. Persistent efforts in the characterization of these and other cytokine networks will be essential for understanding the complex pathogenic mechanisms that underpin allergic disease and for guiding targeted therapeutic interventions.

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“…Антагонисты Th2 цитокинов В последние годы антагонисты Th2 цитокинов (IL4, IL5, IL13) находятся на стадии активного изучения их эффективности при тяжелой, недостаточно контролиру-емой БА, несмотря на применение максимальных доз ингаляционных и системных ГКС [27,28].…”

Section: противовоспалительная терапия бронхиальной астмы глюкокортикunclassified

Potential Role of Serum Periostin in the Early Detection of Bronchial Asthma in Children

Sobotyuk¹,

Gaponenko²,

Бочанцев³

et al. 2016

Vopr. sovr. pediatr.

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АКТУАЛЬНОСТЬНи значительные достижения в диагностике бронхи-альной астмы (БА), ни внедрение в практику современных методов контроля и профилактики бронхиальной обструк-ции так и не привели к снижению заболеваемости, осо-бенно среди детского населения. B наши дни БА -наи-более распространенная хроническая форма патологии дыхательных путей в младшей возрастной группе [1,2].В конце XX -начале XXI века исследователи на экс-периментальных моделях убедительно показали, что Т хел перы второго типа (Th2) играют важнейшую роль в развитии аллергической БА, и с их активацией связаны

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

Cited by 237 publications

References 74 publications

Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

Endogenously Expressed IL-13Rα2 Attenuates IL-13–Mediated Responses but Does Not Activate Signaling in Human Lung Fibroblasts

Cytokine Pathways in Allergic Disease

Potential Role of Serum Periostin in the Early Detection of Bronchial Asthma in Children

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