Strategies targeting the IL-4/IL-13 axes in disease

May, Richard; Fung, Michael

doi:10.1016/j.cyto.2015.05.018

Cited by 144 publications

(116 citation statements)

References 529 publications

(431 reference statements)

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“…Pendrin knockout is also associated with reduced lung inflammation in a murine model of Bordetella pertussis lung infection (26). IL-13, the cytokine used commonly in in vitro and animal models of airway inflammation, is elevated in CF, asthma, chronic rhinosinusitis, viral and certain bacterial infections, and chronic obstructive pulmonary disease, and in response to cigarette smoke (27)(28)(29)(30)(31)(32)(33)(34). In murine models of asthma, pendrin knockout reduces pulmonary pathology, airway hyperreactivity, and immune cell infiltration, while pendrin overexpression increases airway hyperreactivity (10,11).…”

mentioning

confidence: 99%

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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Pendrin (SLC26A4) is a Cl 2 /anion exchanger expressed in the epithelium of inflamed airways where it is thought to facilitate Cl 2 absorption and HCO 3 2 secretion. Studies using pendrin knockout mice and airway epithelial cells from hearing-impaired subjects with pendrin loss of function suggest involvement of pendrin in inflammatory lung diseases, including cystic fibrosis (CF), perhaps by regulation of airway surface liquid (ASL) volume. Here we identified small-molecule pendrin inhibitors and demonstrated their efficacy in increasing ASL volume. A cell-based, functional high-throughput screen of ∼36,000 synthetic small molecules produced 3 chemical classes of inhibitors of human pendrin. After structure-activity studies, tetrahydropyrazolopyridine and pyrazolothiophenesulfonamide compounds reversibly inhibited pendrin-facilitated Cl 2 exchange with SCN 2 , I 2 , NO 3 2 , and HCO 3 2 with drug concentration causing 50% inhibition down to ∼2.5 mM. In well-differentiated primary cultures of human airway epithelial cells from non-CF and CF subjects, treatment with IL-13, which causes inflammation with strong pendrin up-regulation, strongly increased Cl 2 /HCO 3 2 exchange and the increase was blocked by pendrin inhibition. Pendrin inhibition significantly increased ASL depth (by ∼8 mm) in IL-13-treated non-CF and CF cells but not in untreated cells. These studies implicate the involvement of pendrin-facilitated Cl 2 / HCO 3 2 in the regulation of ASL volume and suggest the utility of pendrin inhibitors in inflammatory lung diseases, including CF

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mentioning

confidence: 99%

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Haggie

Phuan²,

Tan³

et al. 2016

FASEB j.

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“…Th2-induced fibrogenesis can lead to a deleterious consequence by augmenting mucosal and transmural fibrotic process, a prototypic manifestation of IBDs (15, 33). It is well known that IL-4, the core signature of Th2 responses, is highly expressed in certain types of inflammation and also exerts pleiotropic functions due to extremely broad distribution of IL-4 receptors (10). Enormous reports have also provided evidences that IL-4 participates in the pathogenesis of IBDs (34, 35).…”

Section: Discussionmentioning

confidence: 99%

“…In the meantime, the function of IL-4 is not yet fully known as the extremely broad distribution of IL-4 receptors (10). Previous studies have shown that IL-4 is the key pro-inflammatory cytokine in the pathological progression of atopic dermatitis, allergic rhinitis, COPD, and cancer (11).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-4 Inhibits Regulatory T Cell Differentiation through Regulating CD103+ Dendritic Cells

Chen

Zhang

et al. 2017

Front. Immunol.

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CD103+ dendritic cells (DCs) have been shown to play a crucial role in the pathogenesis of inflammatory bowel diseases (IBDs) through educating regulatory T (Treg) cells differentiation. However, the mechanism of CD103+ DCs subsets differentiation remains elusive. Interleukin (IL)-4 is a pleiotropic cytokine that is upregulated in certain types of inflammation, including IBDs and especially ulcerative colitis. However, the precise role of IL-4 in the differentiation of CD103+ DCs subpopulation remains unknown. In this study, we observed a repressive role of IL-4 on the CD103+ DCs differentiation in both mouse and human. High-dose IL-4 inhibited the CD103+ DC differentiation. In comparison to CD103− DCs, CD103+ DCs expressed high levels of the co-stimulatory molecules and indoleamine 2,3-dioxygenase (IDO). Interestingly, IL-4 diminished IDO expression on DCs in a dose-dependent manner. Besides, high-dose IL-4-induced bone marrow-derived DCs, and monocyte-derived DCs revealed mature DCs profiles, characterized by increased co-stimulatory molecules and decreased pinocytotic function. Furthermore, DCs generated under low concentrations of IL-4 favored Treg cells differentiation, which depend on IDO produced by CD103+ DCs. Consistently, IL-4 also reduced the frequency of CD103+ DC in vivo. Thus, we here demonstrated that the cytokine IL-4 involved in certain types of inflammatory diseases by orchestrating the functional phenotype of CD103+ DCs subsets.

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“…Therapeutic biologics that target the key mediators of type 2 immune responses, IL-4 and IL-13, are in clinical development [36]. The combined targeting of the IL-13 and IL-33 pathways, therefore, represents a promising strategy for treating type 2 inflammationassociated immune disorders.…”

Section: Pulmonary Diseasesmentioning

confidence: 99%

Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

Chen

Tsai

Yang

et al. 2018

Cell Physiol Biochem

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Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in innate and adaptive immune responses via interaction with its receptor, ST2. Activation of ST2 signalling by IL-33 triggers pleiotropic immune functions in multiple ST2-expressing immune cells, including macrophages, neutrophils, eosinophils, basophils, mast cells, type 2 helper T cells, regulatory T cells, and group 2 innate lymphoid cells. IL-33-mediated effector functions contribute to the tissue inflammatory and reparative responses in various organs including lung, skin, kidney, central nerve system, cardiovascular system, and gastrointestinal system. Endogenous IL-33/ ST2 signaling exhibits diverse immune regulatory functions during progression of different diseases. IL-33 likely functions as a disease sensitizer and plays pathological roles in inflamed tissues in allergic disorders that involve hyperreactive immune responses in the context of skin and pulmonary allergy. However, IL-33 also mediates tissue-protective functions during the recovery phase following tissue injury in the central nerve system and gastrointestinal system. Modulation of the IL-33/ST2 axis, therefore, represents a promising strategy for treating immune disorders that involve dysregulation of the cytokine signalling. In the past two decades, therapeutic strategies blocking IL-33/ST2 have been extensively studied for the treatment of diseases in animal models. In this review, the current progress on the development of therapeutic biologics for targeting IL-33/ST2 signalling in inflammatory diseases is summarized.

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Strategies targeting the IL-4/IL-13 axes in disease

Cited by 144 publications

References 529 publications

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

Interleukin-4 Inhibits Regulatory T Cell Differentiation through Regulating CD103+ Dendritic Cells

Therapeutic Strategies for Targeting IL-33/ST2 Signalling for the Treatment of Inflammatory Diseases

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