MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation.

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene ß-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target ß-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. STATEMENT OF SIGNIFICANCE: MEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

Identification and characterisation of anti-IL-13 inhibitory single domain antibodies provides new insights into receptor selectivity and attractive opportunities for drug discovery.

Interleukin-13 (IL-13) is a cytokine involved in T-cell immune responses and is a well validated therapeutic target for the treatment of asthma, along with other allergic and inflammatory diseases. IL-13 signals through a ternary signalling complex formed with the receptors IL-13Rα1 and IL-4Rα. This complex is assembled by IL-13 initially binding IL-13Rα1, followed by association of the binary IL-13:IL-13Rα1 complex with IL-4Rα. The receptors are shared with IL-4, but IL-4 initially binds IL-4Rα. Here we report the identification and characterisation of a diverse panel of single-domain antibodies (VHHs) that bind to IL-13 (KD 40 nM-5.5 µM) and inhibit downstream IL-13 signalling (IC50 0.2-53.8 µM). NMR mapping showed that the VHHs recognise a number of epitopes on IL-13, including previously unknown allosteric sites. Further NMR investigation of VHH204 bound to IL-13 revealed a novel allosteric mechanism of inhibition, with the antibody stabilising IL-13 in a conformation incompatible with receptor binding. This also led to the identification of a conformational equilibrium for free IL-13, providing insights into differing receptor signalling complex assembly seen for IL-13 compared to IL-4, with formation of the IL-13:IL-13Rα1 complex required to stabilise IL-13 in a conformation with high affinity for IL-4Rα. These findings highlight new opportunities for therapeutic targeting of IL-13 and we report a successful 19F fragment screen of the IL-13:VHH204 complex, including binding sites identified for several hits. To our knowledge, these 19F containing fragments represent the first small-molecules shown to bind to IL-13 and could provide starting points for a small-molecule drug discovery programme.

Eblasakimab, a novel IL-13 receptor alpha 1 monoclonal antibody, blocks STAT6 phosphorylation with low dose in human volunteers.

Eblasakimab is a first-in-class monoclonal antibody under investigation for the treatment of atopic dermatitis (AD), which targets IL-13Rα1, a subunit of the Type 2 receptor complex. IL-13Rα1 stimulates phosphorylation of signal transducer and activator of transcription 6 (STAT6) to drive inflammation. This brief report investigates the mechanistic basis of eblasakimab and its effects on IL-13Rα1 signaling as part of a phase 1a, open-label, single ascending dose study. Single ascending doses of eblasakimab were administered by intravenous or subcutaneous injection to healthy male volunteers. The impact of eblasakimab on IL-13Rα1 receptor occupancy and STAT6 phosphorylation was assessed in participant blood monocytes. No serious treatment emergent adverse events were reported. Eblasakimab effectively blocked the IL-13Rα1 receptor and inhibited STAT6 phosphorylation with single doses of 3 mg/kg intravenously and 300 mg subcutaneously. Results support further clinical development of eblasakimab as a novel biologic for AD, with potential for 2- to 4-week dosing regimens.

Low IL-13Rα1 expression on mast cells tunes them unresponsive to IL-13.

Cytokine-mediated mast cell regulation enables precise optimization of their own proinflammatory cytokine production. During allergic inflammation, interleukin (IL)-4 regulates mast cell functions, tissue homing, and proliferation, but the direct role of closely related IL-13 for mast cell activation remains unclear. Previous work has shown that mast cells are potent IL-13 producers, but here we show that mouse mast cells do not directly respond to IL-13 by Stat6 activation, as they do not express measurable amount of IL-13 receptor α1 (IL-4Rα1) messenger RNA. Consequently, IL-4 responses are mediated via type I IL-4R (IL-4/IL4Rα/γC), and IL-4-induced Stat6 activation is abolished in γC-deficient mast cells. Type II IL-4R deficiency (IL-13Rα1 knockout) has no effect on IL-4-induced Stat6 activation. In basophils, both IL-4 and IL-13 induce Stat6 activation in wild-type and γC-deficient cells, while in type II IL-4R-deficient basophils, IL-4 signaling is impaired at low ligand concentration. Thus, mast cell and basophil sensitivity to IL-4/IL-13 is different, and in mast cells, lack of IL-13Rα1 expression likely explains their unresponsiveness to IL-13.

Interleukin-3 stabilizes CD124/IL-4α surface expression in mast cells via Tyk2 and STAT6.

Interleukin (IL)-4 signals can modulate mast cells, which express the IL-4Rα chain. The IL-4Rα can heterodimerise with the common γ-chain and utilizes JAK1 and JAK2 for signal transduction, while complexes of IL-4Rα with IL-13Rα1 subunit mediates signals via JAK2 and Tyk2. Here, we report that IL-3 is an essential factor for the continuous expression of the IL-4Rα chain on mast cells, which did not express the IL-13Rα1 chain. We demonstrate that the signals induced by IL-3 important for IL-4Rα expression are mediated by Tyk2 and STAT6 activation and the subsequent maintenance of HSP90 levels. In line with that, inhibition of either Tyk2, STAT6 or HSP90 impaired the IL-3-induced IL-4Rα upregulation. Consequently, the IL-3 maintained IL-4Rα surface expression via Tyk2 is essential for the costimulatory effect of IL-4 on the IL-33-induced production of IL-6 and IL-13.

Epithelial cell-expressed type II IL-4 receptor mediates eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, food-driven allergic disease, characterized by eosinophil-rich inflammation in the esophagus. The histopathological and clinical features of EoE have been attributed to overproduction of the type 2 cytokines IL-4 and IL-13, which mediate profound alterations in the esophageal epithelium and neutralizing of their shared receptor component (IL-4Rα) with a human antibody drug (dupilumab) demonstrates clinical efficacy. Yet, the relative contribution of IL-4 and IL-13 and whether the type II IL-4 receptor (comprised of the IL-4Rα chain in association with IL-13Rα1) mediates this effect has not been determined. METHODS: Experimental EoE was induced in WT, Il13ra1-/- , and Krt14Cre /Il13ra1fl/fl mice by skin-sensitized using 4-ethoxymethylene-2-phenyl-2-oxazolin (OXA) followed by intraesophageal challenges. Esophageal histopathology was determined histologically. RNA was extracted and sequenced for transcriptome analysis and compared with human EoE RNAseq data. RESULTS: Induction of experimental EoE in mice lacking Il13ra1 and in vivo IL-13 antibody-based neutralization experiments blocked antigen-induced esophageal epithelial and lamina propria thickening, basal cell proliferation, eosinophilia, and tissue remodeling. In vivo targeted deletion of Il13ra1 in esophageal epithelial cells rendered mice protected from experimental EoE. Single-cell RNA sequencing analysis of human EoE biopsies revealed predominant expression of IL-13Rα1 in epithelial cells and that EoE signature genes correlated with IL-13 expression compared with IL-4. CONCLUSIONS: We demonstrate a definitive role for IL-13 signaling via IL-13Rα1 in EoE. These data provide mechanistic insights into the mode of action of current therapies in EoE and highlight the type II IL-4R as a future therapeutic target.

The IL-4/IL-13 signaling axis promotes prostatic fibrosis.

BACKGROUND: Lower urinary tract symptoms (LUTS) are a costly and pervasive medical problem for millions of aging men. Recent studies have showed that peri-urethral tissue fibrosis is an untreated pathobiology contributing to LUTS. Fibrosis results from excessive extracellular matrix deposition which increases transition zone and peri-urethral tissue stiffness and compromises prostatic urethral flexibility and compliance, producing urinary obstructive symptoms. Inflammatory cells, including neutrophils, macrophages, and T-lymphocytes, secrete a medley of pro-fibrotic proteins into the prostatic microenvironment, including IFNγ, TNFα, CXC-type chemokines, and interleukins, all of which have been implicated in inflammation-mediated fibrosis. Among these, IL-4 and IL-13 are of particular interest because they share a common signaling axis that, as shown here for the first time, promotes the expression and maintenance of IL-4, IL-13, their cognate receptors, and ECM components by prostate fibroblasts, even in the absence of immune cells. Based on studies presented here, we hypothesize that the IL-4/IL-13 axis promotes prostate fibroblast activation to ECM-secreting cells. METHODS: N1 or SFT1 immortalized prostate stromal fibroblasts were cultured and treated, short- or long-term, with pro-fibrotic proteins including IL-4, IL-13, TGF-ß, TNF-α, IFNγ, with or without prior pre-treatment with antagonists or inhibitors. Protein expression was assessed by immunohistochemistry, immunofluorescence, ELISA, immunoblot, or Sircoll assays. Transcript expression levels were determined by qRT-PCR. Intact cells were counted using WST assays. RESULTS: IL-4Rα, IL-13Rα1, and collagen are concurrently up-regulated in human peri-urethral prostate tissues from men with LUTS. IL-4 and IL-13 induce their own expression as well as that of their cognate receptors, IL-4Rα and IL-13Rα1. Low concentrations of IL-4 or IL-13 act as cytokines to promote prostate fibroblast proliferation, but higher (>40ng/ml) concentrations repress cellular proliferation. Both IL-4 and IL-13 robustly and specifically promote collagen transcript and protein expression by prostate stromal fibroblasts in a JAK/STAT-dependent manner. Moreover, IL-4 and IL-13-mediated JAK/STAT signaling is coupled to activation of the IL-4Rα receptor. CONCLUSIONS: Taken together, these studies show that IL-4 and IL-13 signal through the IL-4Rα receptor to activate JAK/STAT signaling, thereby promoting their own expression, that of their cognate receptors, and collagens. These finding suggest that the IL-4/IL-13 signaling axis is a powerful, but therapeutically targetable, pro-fibrotic mechanism in the lower urinary tract.

Protein and miRNA profile of circulating extracellular vesicles in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is an idiopathic and heterogenous cholestatic liver disease characterized by chronic inflammation and fibrosis of the biliary tree. Currently, no effective therapies are available for this condition, whose incidence is rising. At present, specificity and sensitivity of current serum markers used to diagnose PSC are limited and often unreliable. In this study, we characterize circulating extracellular vesicles and provide supporting data on their potential use as novel surrogate biomarkers for PSC. EVs are membrane surrounded structures, 100-1000 nm in size, released by cells under various conditions and which carry a variety of bioactive molecules, including small non-coding RNAs, lipids and proteins. In recent years, a large body of evidence has pointed to diagnostic implications of EVs and relative cargo in various human diseases. We isolated EVs from serum of well-characterized patients with PSC or control subjects by differential centrifugation and size-exclusion chromatography. A complete characterization identified elevated levels of circulating EVs in PSC patients compared to healthy control subjects (2000 vs. 500 Calcein-FITC + EVs/µL). Tissue and cell specificity of circulating EVs was assessed by identification of liver-specific markers and cholangiocyte marker CK-19. Further molecular characterization identified 282 proteins that were differentially regulated in PSC-derived compared to healthy control-EVs. Among those, IL-13Ra1 was the most significantly and differentially expressed protein in PSC-derived EVs and correlated with the degree of liver fibrosis. In addition to protein profiling, we performed a miRNA-sequencing analysis which identified 11 among established, liver-specific (e.g., miR-122 and miR-192) and novel miRNAs. One of the newly identified miRNAs, miR-4645-3p, was significantly up-regulated fourfold in PSC-derived EVs compared to circulating EVs isolated from healthy controls. This study provides supporting evidence of the potential role of circulating EVs and associated protein and miRNA cargo as surrogate noninvasive and reliable biomarker for PSC.

Early-life inflammation primes a T helper 2 cell-fibroblast niche in skin.

Inflammation early in life can prime the local immune milieu of peripheral tissues, which can cause lasting changes in immunological tone that confer disease protection or susceptibility1. The cellular and molecular mechanisms that prompt changes in immune tone in many nonlymphoid tissues remain largely unknown. Here we find that time-limited neonatal inflammation induced by a transient reduction in neonatal regulatory T cells causes a dysregulation of subcutaneous tissue in mouse skin. This is accompanied by the selective accumulation of type 2 helper T (TH2) cells within a distinct microanatomical niche. TH2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as TH2-interacting fascial fibroblasts (TIFFs), which expand in response to TH2 cytokines to form subcutaneous fibrous bands. Activation of the TH2-TIFF niche due to neonatal inflammation primes the skin for altered reparative responses to wounding. Furthermore, we identify fibroblasts in healthy human skin that express the TIFF transcriptional signature and detect these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a previously unidentified TH2 cell niche in skin and functionally characterize a disease-associated fibroblast population. The results also suggest a mechanism of immunological priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells to establish an immunological set-point in tissues that is maintained throughout life.

Expression of IL4Rα and IL13Rα1 are associated with poor prognosis of soft-tissue sarcoma of the extremities, superficial trunk, and retroperitoneum.

BACKGROUND: IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited. METHODS: This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test. RESULTS: In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001). CONCLUSIONS: This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.

CYT387, a Novel JAK2 Inhibitor, Suppresses IL-13-Induced Epidermal Barrier Dysfunction Via miR-143 Targeting IL-13Rα1 and STAT3.

Atopic dermatitis (AD) is a chronic inflammatory skin disease influencing not only children but also adults. It is well-known that AD has a complex pathogenesis without effective therapy. Herein, we explored the function and mechanism of CYT387, a novel JAK2 inhibitor, on epidermal barrier damage. HaCaT cells exposed with high-concentration Ca2+ (1.8 mM) for 14 days were recruited for the model of keratinocytes (KC). The cell model of skin barrier damage was induced by IL-13, and KC markers such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL) were detected to judge the success of the model. In this study, we found that miR-143 was lowly expressed whereas IL-13Rα1 was highly expressed in blood cells of patients with AD, indicating their negative correlation. Moreover, IL-13 treatment down-regulated miR-143 and up-regulated activated JAK2 and STAT3 phosphorylation, which was reversed by CYT387 administration. The dual-luciferase reporter assay verified that miR-143 could directly bind to 3'-UTR of IL-13Rα1, as well as STAT3. Furthermore, the function of CYT387 in the skin barrier damage induced by IL-13 was abolished by miR-143 inhibitor. Thus, CYT387 might alleviate IL-13-induced epidermal barrier damage via targeting IL-13Rα1 and STAT3 by miR-143 to repress inflammation. These findings revealed that the protective effects and the underlying mechanisms of CYT387 in AD, which provided evidence that miR-143 may be a novel therapeutic target for AD.

Rapamycin blocks the IL-13-induced deficiency of Epidermal Barrier Related Proteins via upregulation of miR-143 in HaCaT Keratinocytes.

Interleukin (IL)-13 plays a key role in the pathogenesis of atopic dermatitis (AD). Our preliminary study demonstrated that forced expression of miR-143 could block IL-13-induced down-regulation of epidermal barrier related proteins in epidermal keratinocytes. As previous studies suggested that miR-143 expression was regulated by mammalian target of rapamycin (mTOR) signaling pathway, we investigated the mechanism of mTOR signaling pathway in the epidermal barrier dysfunction of AD. The HaCaT cells were stimulated by IL-13 and subsequently treated with rapamycin. The expression levels of miR-143, IL-13 receptor α1 (IL-13Rα1), p-mTOR, p-S6K1, p-Akt, and epidermal barrier related proteins were analyzed through RT-qPCR and/or western blotting. The current study showed that IL-13 increased the expression levels of p-mTOR, p-S6K1, and p-Akt, and that rapamycin blocked IL-13-induced down-regulation of miR-143, suppressed the IL-13Rα1 expression and up-regulated the expressions of filaggrin, loricrin, and involucrin in HaCaT cells. This study proposed that IL-13 could activate the mTOR signaling pathway, and confirmed the vital role of mTOR-miR-143 signaling axis in the pathogenesis of AD. It provided solid evidences regarding rapamycin as a potential effective therapeutic option in the management of AD.

Interleukin-13 drives metabolic conditioning of muscle to endurance exercise.

Repeated bouts of exercise condition muscle mitochondria to meet increased energy demand-an adaptive response associated with improved metabolic fitness. We found that the type 2 cytokine interleukin-13 (IL-13) is induced in exercising muscle, where it orchestrates metabolic reprogramming that preserves glycogen in favor of fatty acid oxidation and mitochondrial respiration. Exercise training-mediated mitochondrial biogenesis, running endurance, and beneficial glycemic effects were lost in Il13-/- mice. By contrast, enhanced muscle IL-13 signaling was sufficient to increase running distance, glucose tolerance, and mitochondrial activity similar to the effects of exercise training. In muscle, IL-13 acts through both its receptor IL-13Rα1 and the transcription factor Stat3. The genetic ablation of either of these downstream effectors reduced running capacity in mice. Thus, coordinated immunological and physiological responses mediate exercise-elicited metabolic adaptations that maximize muscle fuel economy.

Implications of IL-13Rα2 in atopic skin inflammation.

Atopic dermatitis (AD) is a common eczematous skin disorder characterized by skin inflammation, barrier disruption, chronic pruritus and marked scratching. Th2 cytokines, especially IL-13, play a pathogenic role in AD. IL-13 signals via a heterodimeric receptor composed of IL-4Rα and IL-13 Rα1. A second receptor, IL-13 Rα2, binds to IL-13 with high affinity, but it works as a decoy receptor. IL-13 Rα2 is overexpressed in the lesional skin of AD. Notably, mechanical scratching, as well as IL-13 itself, also upregulates IL-13 Rα2 expression. The scratch-induced IL-13 Rα2 upregulation may attenuate the IL-13-mediated epidermal barrier dysfunction and dermal fibrosis. Recent studies stress an importance of another IL-13 Rα2 ligand, chitinase 3-like 1 or YKL-40 in Th2 differentiation. However, the implications of increased IL-13 Rα2 levels remain elusive in AD. In this review, we summarize the recent topics on IL-13 Rα2 in atopic skin inflammation.

Unique IL-13Rα2/STAT3 mediated IL-13 regulation detected in lung conventional dendritic cells, 24 h post viral vector vaccination.

This study demonstrates that 24 h following viral vector-based vaccination IL-13Rα2 functions as a master sensor on conventional dendritic cells (cDCs), abetted by high protein stability coupled with minimal mRNA expression, to rapidly regulate DC mediated IL-13 responses at the lung mucosae, unlike IL-13Rα1. Under low IL-13, IL-13Rα2 performs as a primary signalling receptor, whilst under high IL-13, acts to sequester IL-13 to maintain homeostasis, both in a STAT3-dependent manner. Likewise, we show that viral vector-derived IL-13 levels at the vaccination site can induce differential STAT3/STAT6 paradigms in lung cDC, that can get regulated collaboratively or independently by TGF-ß1 and IFN-γ. Specifically, low IL-13 responses associated with recombinant Fowlpox virus (rFPV) is regulated by early IL-13Rα2, correlated with STAT3/TGF-ß1 expression. Whilst, high IL-13 responses, associated with recombinant Modified Vaccinia Ankara (rMVA) is regulated in an IL-13Rα1/STAT6 dependent manner associated with IFN-γR expression bias. Different viral vaccine vectors have previously been shown to induce unique adaptive immune outcomes. Taken together current observations suggest that IL-13Rα2-driven STAT3/STAT6 equilibrium at the cDC level may play an important role in governing the efficacy of vector-based vaccines. These new insights have high potential to be exploited to improve recombinant viral vector-based vaccine design, according to the pathogen of interest and/or therapies against IL-13 associated disease conditions.

IL-13 secreted by ILC2s promotes the self-renewal of intestinal stem cells through circular RNA circPan3.

Intestinal stem cells (ISCs) are maintained by stemness signaling for precise modulation of self-renewal and differentiation under homeostasis. However, the way in which intestinal immune cells regulate the self-renewal of ISCs remains elusive. Here we found that mouse and human Lgr5+ ISCs showed high expression of the immune cell-associated circular RNA circPan3 (originating from the Pan3 gene transcript). Deletion of circPan3 in Lgr5+ ISCs impaired their self-renewal capacity and the regeneration of gut epithelium in a manner dependent on immune cells. circPan3 bound mRNA encoding the cytokine IL-13 receptor subunit IL-13Rα1 (Il13ra1) in ISCs to increase its stability, which led to the expression of IL-13Rα1 in ISCs. IL-13 produced by group 2 innate lymphoid cells in the crypt niche engaged IL-13Rα1 on crypt ISCs and activated signaling mediated by IL-13‒IL-13R, which in turn initiated expression of the transcription factor Foxp1. Foxp1 is associated with ß-catenin in rendering its nuclear translocation, which caused activation of the ß-catenin pathway and the maintenance of Lgr5+ ISCs.

IL-13 signaling through IL-13 receptor α2 mediates airway epithelial wound repair.

Asthma is an airway inflammatory disease characterized by epithelial barrier dysfunction and airway remodeling. Interleukin-13 (IL-13) is a pleiotropic cytokine shown to contribute to features of airway remodeling. We have previously demonstrated that IL-13 is an important mediator of normal airway epithelial repair and health. The role of IL-13 signaling via its receptor subunits (IL-13Rα1/IL-4Rα and IL-13Rα2) in airway epithelial repair and restoration of intact barrier function is not well understood and was investigated in this study using in vitro models. The blocking of IL-13 signaling via IL-13Rα2 significantly reduced airway epithelial repair by 24 h post-mechanical wounding in 1HAEo- cells. Expression and release of repair-mediating growth factor, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and subsequent activation of EGF receptor (EGFR) were also significantly reduced in response to wounding when IL-13Rα2 was blocked. Our data support that IL-13 signals via IL-13Rα2 to mediate normal airway epithelial repair via HB-EGF-dependent activation of EGFR. In human donor lung tissues, we observed that airway epithelium of asthmatics expressed significantly decreased levels of IL-13Rα2 and increased levels of IL-13Rα1 compared with nonasthmatics. Dysregulated expression of IL-13 receptor subunits in the airways of asthmatics may thus contribute to the epithelial barrier dysfunction observed in asthma.-Yang, S. J., Allahverdian, S., Saunders, A. D. R., Liu, E., Dorscheid, D. R. IL-13 signaling through IL-13 receptor α2 mediates airway epithelial wound repair.

IL-13 and IL-13Rα1 are overexpressed in extranodal natural killer/T cell lymphoma and mediate tumor cell proliferation.

Extranodal NK/T cell lymphoma (NKTCL) is a rare but aggressive subtype of non-Hodgkin lymphoma. Multi-agent chemotherapy and involved-field radiotherapy are used to treat this disease, but the prognosis remains poor. Interleukin 13 and its receptors (IL-13Rs) are correlated with the pathogenesis and progression of various malignances. However, their roles in NKTCL have not been evaluated. In this study, we examined the roles of IL-13 and IL-13Rs in NKTCL and the underlying mechanisms. We found significantly higher serum IL-13 levels (p < 0.001) and IL-13Rα1 expression in tumor tissues (36 of 40, p < 0.001) in patients with NKTCL than in control cohort. IL-13 secretion was observed in tumor tissues (30 of 40, p < 0.001) and several cell lines of NKTCL. However, we did not detect significant associations between clinical characteristics and the expression levels of IL-13 or IL-13Rs. In vitro, IL-13 activated Stat6 and promoted cell proliferation in a dose-dependent manner. In addition, blocking IL-13 exerted a negative effect on tumor cell growth. We conclude that IL-13 functions as an autocrine growth factor in NKTCL and contributes to its pathogenesis. Blocking IL-13 is thus a potential therapeutic approach for NKTCL.

A distinct dendritic cell population arises in the thymus of IL-13Rα1-sufficient but not IL-13Rα1-deficient mice.

IL-13 receptor alpha 1 (IL-13Rα1) associates with IL-4Rα to form a functional IL-4Rα/IL-13Rα1 heteroreceptor (HR) through which both IL-4 and IL-13 signal. Recently, HR expression was associated with the development of M2 type macrophages which function as antigen presenting cells (APCs). Herein, we show that a subset of thymic resident dendritic cells (DCs) expressing high CD11b (CD11bhi) and intermediate CD11c (CD11cint) arise in HR-sufficient but not HR-deficient mice. These DCs, which originate from the bone marrow are able to take up Ag from the peritoneum, traffic through the spleen and the lymph nodes and carry it to the thymus. In addition, since the DCs are able to present Ag to T cells, express high levels of the costimulatory molecule CD24, and comprise a CD8α+ subset, it is likely that the cells contribute to T cell development and perhaps negative selection of self-reactive lymphocytes.

Tricellulin is regulated via interleukin-13-receptor α2, affects macromolecule uptake, and is decreased in ulcerative colitis.

In the two inflammatory bowel diseases, ulcerative colitis (UC) and Crohn's disease (CD), altered expression of tight junction (TJ) proteins leads to an impaired epithelial barrier including increased uptake of luminal antigens supporting the inflammation. Here, we focused on regulation of tricellulin (Tric), a protein of the tricellular TJ essential for the barrier against macromolecules, and hypothesized a role in paracellular antigen uptake. We report that Tric is downregulated in UC, but not in CD, and that its reduction increases the passage of macromolecules. Using a novel visualization method, passage sites were identified at TJ regions usually sealed by Tric. We show that interleukin-13 (IL-13), beyond its known effect on claudin-2, downregulates Tric expression. These two effects of IL-13 are regulated by different signaling pathways: The IL-13 receptor α1 upregulates claudin-2, whereas IL-13 receptor α2 downregulates Tric. We suggest to target the α2 receptor in future developments of therapeutical IL-13-based biologicals.