RESUMEN
PURPOSE: To investigate the impact of the Chinese medicine compound Ento-PB on oxazolone (OXZ)-induced ulcerative colitis (UC) in rats. METHODS: UC rats induced by OXZ were treated with Ento-PB. The damage to the colon was assessed using several measures, including the disease activity index (DAI), colon length, colon weight/length ratio, colonic mucosal damage index, and histological score. The levels of interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13), epidermal growth factor (EGF), inducible nitric oxide synthase, and total nitric oxide synthase (tNOS) in rat serum, as well as the levels of tumor necrosis factor-α (TNF-α) and myeloperoxidase (MPO) in rat colon tissue, were determined using enzyme-linked immunosorbent assay and conventional kits. RESULTS: After being treated with Ento-PB, the DAI score and macroscopic lesion score of OXZ-induced UC rats were significantly reduced. Ento-PB prevented the shortening of rat colons, reduced the ratio of colon weight to length, and improved colon tissue lesions. Meanwhile, Ento-PB could significantly inhibit the activities of proinflammatory cytokines TNF-α, IL-13, and MPO, as well as tNOS and iNOS, while upregulating the expression of anti-inflammatory cytokines IL-4 and IL-10. Moreover, a significant increase in the expression level of EGF was observed in UC rats treated with Ento-PB, indicating that Ento-PB could enhance the repair of damaged intestinal epithelial tissue. CONCLUSIONS: Ento-PB demonstrates significant anti-UC activities in OXZ-induced UC rats by regulating the expression levels of inflammatory factors and promoting the repair of colon tissue. This study provides scientific evidence to support the further development of Ento-PB.
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Colitis Ulcerosa , Colon , Oxazolona , Peroxidasa , Animales , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/patología , Masculino , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Peroxidasa/análisis , Peroxidasa/metabolismo , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Modelos Animales de Enfermedad , Factor de Necrosis Tumoral alfa/análisis , Factor de Necrosis Tumoral alfa/metabolismo , Ratas Sprague-Dawley , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Ratas , Ensayo de Inmunoadsorción Enzimática , Factor de Crecimiento Epidérmico/análisis , Citocinas/metabolismo , Interleucina-13/análisis , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo II/análisis , Reproducibilidad de los Resultados , Resultado del TratamientoRESUMEN
Glioblastoma multiforme (GBM) is one of the most aggressive and deadly forms of brain cancer, which has a very complex tumor microenvironment (TME) promoting tumor growth, immune evasion, and resistance to therapy. The main players within this environment are represented by cytokines such as Interleukin-4, Interleukin-6, and Interleukin-13, along with the costimulatory molecule CD40. The paper draws back the curtain on the complex interactions played out by these molecules in contributing to the formation of a TME within GBM. IL-4 and IL-13 induce an immunosuppressive environment through the polarization of tumor-associated macrophages (TAMs) into a pro-tumoral M2 phenotype. In contrast, IL-6 takes part in the activation of the JAK-STAT3 pathway, enhancing survival and proliferation of tumor cells. In this context, CD40 either induces anti-tumor immunity through APC activation or facilitates tumors by angiogenesis and survival pathways. The synergistic actions of these molecules create feedback loops that keep up the malignancy of GBM and present a big problem for therapy. Knowledge of these interactions opens new ways for the development of multi-targeted therapeutic strategies at the other end. This may result in the interruption of the tumor-supportive environment in GBM, reducing tumor growth and improving patient outcomes by targeting IL-4, IL-6, IL-13, and CD40 simultaneously.
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Neoplasias Encefálicas , Antígenos CD40 , Glioblastoma , Interleucina-13 , Interleucina-4 , Interleucina-6 , Microambiente Tumoral , Humanos , Antígenos CD40/metabolismo , Ensayos Clínicos como Asunto , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismoRESUMEN
Immune memory has been expanded to group 2 innate lymphoid cells (ILC2s), but the cellular and molecular bases remain incompletely understood. Based on house dust mite (HDM)-induced mice asthma models and human samples, we applied flow cytometry, parabiosis, in vivo imaging and adoptive transplantation to confirm the persistence, migration and function of CD45+lineage-CD90.2+NK1.1-NKp46-ST2-KLRG1+IL-17RB+ memory-like ILC2s (ml-ILC2s). Regulated by CCR9/CCL25 and S1P signaling, ml-ILC2s reside in the lamina propria of small intestines (siLP) in asthma remission, and subsequently move to airway upon re-encountering antigens or alarmins. Furthermore, ml-ILC2s possess properties of longevity, potential of rapid proliferation and producing IL-13, and display transcriptional characteristics with up-regulation of Tox and Tcf-7. ml-ILC2s transplantation restore the asthmatic changes abrogated by Tox and Tcf7 knockdown. Our data identify siLP ml-ILC2s as a memory-like subset, which promotes asthma relapse. Targeting TCF-1 and TOX might be promising for preventing asthma recurrence.
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Asma , Factor Nuclear 1-alfa del Hepatocito , Proteínas de Homeodominio , Inmunidad Innata , Memoria Inmunológica , Linfocitos , Animales , Femenino , Humanos , Masculino , Ratones , Traslado Adoptivo , Asma/inmunología , Modelos Animales de Enfermedad , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Interleucina-13/metabolismo , Interleucina-13/genética , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/metabolismo , Intestinos/inmunología , Intestinos/patología , Linfocitos/inmunología , Ratones Endogámicos C57BL , Pyroglyphidae/inmunología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismoRESUMEN
Atopic dermatitis (AD) is a prevalent dermatologic condition affecting both children and adults, and the debate surrounding its association as either a risk or protective factor for malignancies has garnered significant attention. Proposed mechanisms suggest that AD may act protectively against cancer formation through chronic immune system activation or create an inflammatory state conducive to cancer development. This review discusses the relationship between AD and various skin cancers, solid tumors, and hematologic malignancies. Additionally, the authors explore the impact of AD treatments, particularly novel biologic drugs targeting molecular pathways such as JAK-STAT, IL-4, and IL-13 in association with malignancies.
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Dermatitis Atópica , Neoplasias Cutáneas , Dermatitis Atópica/tratamiento farmacológico , Humanos , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias/complicaciones , Carcinoma Basocelular/terapia , Carcinoma de Células Escamosas , Anticuerpos Monoclonales Humanizados/uso terapéutico , Interleucina-4/antagonistas & inhibidores , Interleucina-13/antagonistas & inhibidoresRESUMEN
Integrin activation resulting in enhanced adhesion to the extracellular matrix plays a key role in fundamental cellular processes. Although integrin activation has been extensively studied in circulating cells such as leukocytes and platelets, much less is known about the regulation and functional impact of integrin activation in adherent cells such as smooth muscle. Here, we show that two different asthmagenic cytokines, IL-13 and IL-17A, activate type I and IL-17 cytokine receptor families, respectively, to enhance adhesion of airway smooth muscle. These cytokines also induce activation of ß1 integrins detected by the conformation-specific antibody HUTS-4. Moreover, HUTS-4 binding is increased in the smooth muscle of patients with asthma compared to nonsmokers without lung disease, suggesting a disease-relevant role for integrin activation in smooth muscle. Indeed, integrin activation induced by the ß1-activating antibody TS2/16, the divalent cation manganese, or the synthetic peptide ß1-CHAMP that forces an extended-open integrin conformation dramatically enhances force transmission in smooth muscle cells and airway rings even in the absence of cytokines. We demonstrate that cytokine-induced activation of ß1 integrins is regulated by a common pathway of NF-κB-mediated induction of RhoA and its effector Rho kinase, which in turn stimulates PIP5K1γ-mediated synthesis of PIP2 at focal adhesions, resulting in ß1 integrin activation. Taken together, these data identify a pathway by which type I and IL-17 cytokine receptor family stimulation induces functionally relevant ß1 integrin activation in adherent smooth muscle and help to explain the exaggerated force transmission that characterizes chronic airway diseases such as asthma.
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Asma , Integrina beta1 , Interleucina-13 , Interleucina-17 , Músculo Liso , FN-kappa B , Quinasas Asociadas a rho , Humanos , Integrina beta1/metabolismo , Interleucina-17/metabolismo , Músculo Liso/metabolismo , FN-kappa B/metabolismo , Quinasas Asociadas a rho/metabolismo , Interleucina-13/metabolismo , Asma/metabolismo , Transducción de Señal , Adhesión Celular , Miocitos del Músculo Liso/metabolismo , AnimalesRESUMEN
Keloids, characterized by excessive scar formation following dermal inflammation, pose a therapeutic challenge due to high recurrence rates. Radiation therapy, contraindicated in children, can minimize recurrence post-surgical removal. Dupilumab, which inhibits the pro-fibrotic interleukin-4/interleukin-13 axis, may effectively manage keloids when intralesional corticosteroid injections are unsuccessful. It may also prevent recurrence post-surgery in pediatric patients. This systematic review assesses the efficacy and safety of dupilumab for the treatment of keloids. Through a systematic search adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we identified and analyzed outcomes from three case reports and three case series studies, totaling 15 patients. Results indicate variable responses to treatment, including significant improvements, no clinical change, and worsening of keloid symptoms. Additional research is needed to recommend using dupilumab to treat keloids (Grade D). Treatment response variability may be linked to differences in interleukin-4/interleukin-13 activity between active and inactive keloids. Additionally, the unintended promotion of T helper 17 cell differentiation by dupilumab may worsen keloids.
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Anticuerpos Monoclonales Humanizados , Queloide , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Interleucina-13 , Interleucina-4/metabolismo , Queloide/tratamiento farmacológico , Queloide/terapia , Resultado del TratamientoRESUMEN
The clinical manifestations of atopic dermatitis (AD) and chronic nodular prurigo (CNPG) include pruritus and eczema/lesions, posing significant challenges for patients. Th2 cells and ILC2, marked by cytokine production-particularly IL-4/13-are crucial therapeutic targets. Despite displaying a dose-dependent lack of pruritus induction post-injection, IL-13 acts through the IL-13Rα1 and IL-13Rα2 receptor system. Our study focused on investigating ex vivo skin biopsies in AD (n = 17), CNPG (n = 14) and healthy controls (HC; n = 10), examining the gene expression landscape of interleukins linked with pruritus (IL-13, IL-4, IL-31) and their corresponding receptors. Compared to HC, results revealed a significant upregulation of IL-4, IL-13, and IL-13RA1 in AD, whereas CNPG did not show increased IL13 expression. Notably, the decoy receptor IL-13RA2 displayed intriguing patterns, with AD showing a marked increase compared to both HC and CNPG. Positive correlations between receptor expression and itch intensity and hyperkinesis sensation underscore clinical relevance, potentially serving as biomarkers. The findings suggest a pivotal role of IL-4 and IL-13, along with IL-13RA1, in pruritus pathogenesis in both entities, while IL-13 upregulation in AD is countered by IL-13RA2. The comparable expression of IL-13RA2 to HC in CNPG suggests the absence of this regulatory mechanism, potentially worsening the disease and leading to prolonged scratching behavior. These insights illuminate the intricate interplay of interleukins and receptors in different pruritus phenotypes, laying the groundwork for understanding underlying mechanisms and offering avenues for therapeutic intervention.
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Dermatitis Atópica , Interleucina-13 , Interleucinas , Prurigo , Prurito , Humanos , Dermatitis Atópica/metabolismo , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Dermatitis Atópica/inmunología , Prurigo/metabolismo , Prurigo/patología , Prurigo/genética , Femenino , Adulto , Masculino , Interleucina-13/metabolismo , Interleucina-13/genética , Interleucinas/metabolismo , Interleucinas/genética , Prurito/metabolismo , Prurito/genética , Persona de Mediana Edad , Interleucina-4/metabolismo , Interleucina-4/genética , Enfermedad Crónica , Piel/metabolismo , Piel/patología , Adulto Joven , Subunidad alfa1 del Receptor de Interleucina-13/metabolismo , Subunidad alfa1 del Receptor de Interleucina-13/genética , Subunidad alfa2 del Receptor de Interleucina-13/metabolismo , Subunidad alfa2 del Receptor de Interleucina-13/genéticaRESUMEN
Background and Objectives: Atopic dermatitis is a chronic inflammatory skin disorder with a significant burden on patients' quality of life. This systematic review aims to evaluate the restoration of skin barrier abnormalities with interleukin-4/interleukin-13 (IL-4/IL-13) inhibitors and Janus kinase (JAK) inhibitors in atopic dermatitis. Materials and Methods: A comprehensive review of the literature was conducted, focusing on studies that assess the use of IL-4/IL-13 inhibitors and JAK inhibitors for atopic dermatitis. We identified eligible studies by searching Medline via PubMed with a special focus on their effect on the restoration of the epidermal barrier. Included studies evaluated the transepidermal water loss (TEWL), the reduction in epidermal thickness (ET), the improvement in ceramide synthesis, and the increase in stratum corneum hydration (SCH) with IL-4/IL-13 inhibitors and JAK inhibitors. The quality of included studies was assessed using the ROBINS-I and the RoB 2.0 tool for assessing the risk of bias. Results: Ten of the included studies concern dupilumab, while two concern JAK inhibitors. Ten were observational studies and two were randomized controlled trials (RCTs). The total number of included participants was 378 concerning dupilumab and 38 concerning JAK inhibitors. Five studies did not include any comparison group, three included healthy volunteers, two were conducted versus placebo, and two compared dupilumab with other treatments. The follow-up period ranged between 29 days and 32 weeks. The results demonstrated a significant decrease in transepidermal water loss (TEWL) and an increase in SCH on eczematous lesions for patients with sustained response to dupilumab treatment and observed improvements in ET and filaggrin (FLG) staining, which further support the efficacy of JAK inhibitors in enhancing skin barrier function. Conclusions: This review underscores the efficacy of IL-4/IL-13 inhibitors in improving skin barrier function. However, the limited number of studies focusing on JAK inhibitors and the overall lack of RCTs highlight the need for further research to establish the definitive role of IL-4/IL-13 inhibitors and JAK inhibitors in the restoration of the skin barrier.
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Dermatitis Atópica , Interleucina-13 , Interleucina-4 , Inhibidores de las Cinasas Janus , Dermatitis Atópica/tratamiento farmacológico , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Inhibidores de las Cinasas Janus/farmacología , Interleucina-4/análisis , Anticuerpos Monoclonales Humanizados/uso terapéutico , Pérdida Insensible de Agua/efectos de los fármacos , Proteínas FilagrinaRESUMEN
Interleukin (IL)-13 has emerged as one of the recently identified cytokine. Since IL-13 causes the severity of COVID-19 and alters crucial biological processes, it is urgent to explore novel molecules or peptides capable of including IL-13. Computational prediction has received attention as a complementary method to in-vivo and in-vitro experimental identification of IL-13 inducing peptides, because experimental identification is time-consuming, laborious, and expensive. A few computational tools have been presented, including the IL13Pred and iIL13Pred. To increase prediction capability, we have developed PredIL13, a cutting-edge ensemble learning method with the latest ESM-2 protein language model. This method stacked the probability scores outputted by 168 single-feature machine/deep learning models, and then trained a logistic regression-based meta-classifier with the stacked probability score vectors. The key technology was to implement ESM-2 and to select the optimal single-feature models according to their absolute weight coefficient for logistic regression (AWCLR), an indicator of the importance of each single-feature model. Especially, the sequential deletion of single-feature models based on the iterative AWCLR ranking (SDIWC) method constructed the meta-classifier consisting of the top 16 single-feature models, named PredIL13, while considering the model's accuracy. The PredIL13 greatly outperformed the-state-of-the-art predictors, thus is an invaluable tool for accelerating the detection of IL13-inducing peptide within the human genome.
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Aprendizaje Profundo , Interleucina-13 , Péptidos , Humanos , Biología Computacional/métodos , COVID-19/inmunología , Interleucina-13/metabolismo , Modelos Logísticos , Aprendizaje Automático , Programas InformáticosRESUMEN
BACKGROUND: Inflammatory cytokines play a major role in the pathogenesis of myocardial infarction (MI). Although information on the importance of interleukin 13 (IL13) in human MI is limited, it has been well documented in the mouse model. Genetic variation in the IL13 gene has been associated with the structure and expression of the IL13. In the present study, we hypothesized that IL13 common genetic variants would be associated with a predisposition to the development of MI. MATERIALS AND METHODS: The present study enrolled 305 MI patients and 310 matched healthy controls. Common genetic polymorphisms in the IL13 gene (rs20541, rs1881457, and rs1800925) were genotyped using the TaqMan SNP genotyping method. Plasma levels of IL13 were measured using an enzyme-linked immunosorbent assay (ELISA). RESULTS: In MI patients, minor alleles of the IL13 rs1881457 and rs1800925 polymorphisms were less common than in healthy controls [rs1881457: AC (P = 0.004, OR = 0.61), C (P = 0.001, OR = 0.66); rs1800925: CT (P = 0.006, OR = 0.59)]. Further haplotype analysis of three studied SNPs revealed a significant association with predisposition to MI. Interestingly, IL13 rs1881457 and rs1800925 were linked to plasma levels of IL13: the reference genotype had higher levels, heterozygotes were intermediate, and the alternate genotype had the lowest levels. CONCLUSIONS: In the Chinese population, IL13 (rs1881457 and rs180092) variants are associated with different plasma IL13 levels and offer protection against MI development. However, additional research is required to validate our findings in different populations, including descent samples.
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Pueblo Asiatico , Predisposición Genética a la Enfermedad , Haplotipos , Interleucina-13 , Infarto del Miocardio , Polimorfismo de Nucleótido Simple , Humanos , Infarto del Miocardio/genética , Masculino , Femenino , Estudios de Casos y Controles , Interleucina-13/genética , Interleucina-13/sangre , Persona de Mediana Edad , Pueblo Asiatico/genética , Anciano , China/epidemiología , Alelos , Genotipo , Pueblos del Este de AsiaRESUMEN
Objective:The purpose of this study is to explore the expression of prostacyclin receptorï¼IPï¼ in patients with chronic rhinosinusitisï¼CRSï¼ and its possible association with type 2 inflammation. Methods:HE staining was used to observe the morphological changes of nasal mucosa, qRT-PCR was used to detect the expression of IP in polyps and nasal mucosa, and IHC was used to detect the expression of IP, IL-4, IL-5 and IL-13 in polyps and nasal mucosa. Results:Compared with the control group, the nasal mucosa of patients with various types of CRS was obviously thickened, accompanied by inflammatory cell infiltration and gland hyperplasia. The statistical results of IHC showed that the expression levels of IL-4, IL-5 and IL-13 in CRS group were significantly higher than those in control groupï¼P<0.05ï¼, and the IP expression in control group was significantly higher than that in ECRS group and non-ECRS groupï¼P<0.05ï¼. The IP expression in ECRS group was negatively correlated with IL-4, IL-5 and IL-13. The results of qRT-PCR showed that the expression of IP mRNA in control group was significantly higher than that in ECRS group and non-ECRS groupï¼P<0.05ï¼. Conclusion:IL-4, IL-5 and IL-13 are highly expressed in the nasal mucosa of CRS patients, while IP is poorly expressed in the nasal mucosa of CRS patients, and IP is negatively correlated with IL-4, IL-5 and IL-13, suggesting that IP is related to the occurrence and development of type 2 inflammation and may be a potential therapeutic target for CRS patients.
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Inflamación , Mucosa Nasal , Pólipos Nasales , Receptores de Epoprostenol , Rinosinusitis , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Crónica , Inflamación/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Mucosa Nasal/metabolismo , Pólipos Nasales/metabolismo , Receptores de Epoprostenol/metabolismo , Rinosinusitis/metabolismoRESUMEN
Surfactant Protein A (SP-A) is an innate immune modulator produced by the lung with known protective effects against bacteria and viruses. Its role in asthma, an inflammatory lung disease that affects 10% of the world's population, is not entirely known. In this review, we demonstrate that SP-A confers protection against exposure to interleukin-13, a type 2 cytokine integral to eosinophilic asthma, in a mouse model of SP-A deficiency, a house dust mite model of asthma, and in human bronchial epithelial cells from participants with asthma. We also show that small peptides derived from SP-A, such as the major allele of single nucleotide polymorphism (SNP) rs1965708, which includes the carbohydrate recognition domain of SP-A2 at position 223, reduce airway hyperresponsiveness, airway eosinophils, and mucus in a mouse model of asthma. These data suggest that SP-A has beneficial effects relevant to asthma and that an SP-A peptide may have a new therapeutic use in asthma.
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Asma , Modelos Animales de Enfermedad , Inmunidad Innata , Proteína A Asociada a Surfactante Pulmonar , Asma/inmunología , Asma/tratamiento farmacológico , Animales , Proteína A Asociada a Surfactante Pulmonar/genética , Proteína A Asociada a Surfactante Pulmonar/metabolismo , Proteína A Asociada a Surfactante Pulmonar/inmunología , Humanos , Ratones , Polimorfismo de Nucleótido Simple , Interleucina-13/metabolismo , Interleucina-13/inmunología , Interleucina-13/genética , Pulmón/inmunología , Pulmón/metabolismo , Antiasmáticos/farmacología , Antiasmáticos/uso terapéutico , Pyroglyphidae/inmunologíaRESUMEN
Intestinal tuft cells are critical for anti-helminth parasite immunity because they produce IL-25, which triggers IL-13 secretion by activated group 2 innate lymphoid cells (ILC2s) to expand both goblet and tuft cells. We show that epithelial Elp3, a tRNA-modifying enzyme, promotes tuft cell differentiation and is consequently critical for IL-25 production, ILC2 activation, goblet cell expansion and control of Nippostrongylus brasiliensis helminth infection in mice. Elp3 is essential for the generation of intestinal immature tuft cells and for the IL-13-dependent induction of glycolytic enzymes such as Hexokinase 1 and Aldolase A. Importantly, loss of epithelial Elp3 in the intestine blocks the codon-dependent translation of the Gator1 subunit Nprl2, an mTORC1 inhibitor, which consequently enhances mTORC1 activation and stabilizes Atf4 in progenitor cells. Likewise, Atf4 overexpression in mouse intestinal epithelium blocks tuft cell differentiation in response to intestinal helminth infection. Collectively, our data define Atf4 as a negative regulator of tuft cells and provide insights into promotion of intestinal type 2 immune response to parasites through tRNA modifications.
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Factor de Transcripción Activador 4 , Diferenciación Celular , Mucosa Intestinal , Diana Mecanicista del Complejo 1 de la Rapamicina , Animales , Ratones , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitología , Mucosa Intestinal/inmunología , Mucosa Intestinal/citología , Nippostrongylus/inmunología , Células Caliciformes/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Interleucina-13/metabolismo , Interleucina-13/genéticaRESUMEN
Calcitriol, the bioactive form of vitamin D, exerts its biological functions by binding to its cognate receptor, the vitamin D receptor (VDR). The indicators of the severity of allergies and asthma have been linked to low vitamin D levels. However, the role of calcitriol in regulating IL-4 and IL-13, two cytokines pivotal to allergic inflammation, remained unclear. Our study observed diminished IL-4 and IL-13 secretion in murine and human Th2 cells treated with calcitriol. In murine Th2 cells, Gata3 expression was attenuated by calcitriol. However, the expression of the transcriptional repressor Gfi1, too, was attenuated in the presence of calcitriol. Ectopic expression of either Gfi1 or VDR impaired the secretion of IL-13 in Th2 cells. In murine Th2 cells, VDR interacted with Gata3 but not Gfi1. Gfi1 significantly impaired Il13 promoter activation, which calcitriol failed to restore. Conversely, calcitriol augmented Gfi1 recruitment to the Il13 promoter. Ecr, a conserved region between these two genes, which enhanced the transactivation of Il4 and Il13 promoters, is essential for calcitriol-mediated suppression of both the genes. Calcitriol augmented the recruitment of VDR to the Il13 promoter and Ecr regions. Gata3 recruitment was significantly impaired at the Il13 and Ecr loci in the presence of calcitriol but increased at the Il4 promoter. Furthermore, the recruitment of the histone deacetylase HDAC1 was universally increased at the promoters of Il4, Il13, and Ecr when calcitriol was present. Together, our data clearly elucidate that calcitriol modulates VDR, Gata3, and Gfi1 to suppress IL-4 and IL-13 production in Th2 cells.
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Calcitriol , Factor de Transcripción GATA3 , Interleucina-13 , Interleucina-4 , Receptores de Calcitriol , Células Th2 , Factor de Transcripción GATA3/metabolismo , Factor de Transcripción GATA3/genética , Receptores de Calcitriol/metabolismo , Receptores de Calcitriol/genética , Calcitriol/farmacología , Animales , Interleucina-4/metabolismo , Interleucina-4/inmunología , Interleucina-13/metabolismo , Interleucina-13/inmunología , Ratones , Células Th2/inmunología , Humanos , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genéticaRESUMEN
Importance: Cendakimab selectively targets interleukin (IL)-13, a type 2 cytokine implicated in atopic dermatitis (AD) pathogenesis, by inhibiting binding to its receptors (IL13R-α1 and IL13R-α2). Proof-of-concept work in AD supports using cendakimab for type 2 inflammatory diseases. Objective: To evaluate the efficacy and safety of cendakimab compared with placebo in patients with moderate to severe AD. Design, Setting, and Participants: This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging clinical trial was conducted from May 2021 to November 2022. Adult patients with moderate to severe AD and inadequate response to topical medications were enrolled at 69 sites in 5 countries (US [n = 26], Japan [n = 17], Canada [n = 9], Poland [n = 9], and Czech Republic [n = 8]). Data were analyzed between April 25, 2023, and October 16, 2023. Interventions: Patients were randomized (1:1:1:1) to receive subcutaneous cendakimab, 360 mg, every 2 weeks; 720 mg, every 2 weeks; 720 mg, once weekly; or placebo. Main Outcome and Measure: Mean percentage change in Eczema Area and Severity Index scores from baseline to week 16. Hierarchical testing with multiplicity adjustment was performed for 720 mg, once weekly vs placebo, then 720 mg, every 2 weeks vs placebo, and then 360 mg, every 2 weeks vs placebo. Results: Overall, 221 patients were randomized, and 220 received study drug (95 women [43%]; mean [SD] age, 37.7 [13.9] years; 720 mg, once weekly [54 (24%)]; 720 mg, every 2 weeks [55 (25%)]; 360 mg, every 2 weeks [55 (25%)]; placebo [56 (26%)]). The primary efficacy end point was met for cendakimab, 720 mg, once weekly vs placebo (-84.4 vs -62.7; P = .003) but missed statistical significance for 720 mg, every 2 weeks (-76.0 vs -62.7; P = .06). The treatment effect for 360 mg, every 2 weeks (-16.3; nominal P = .03 vs placebo) was comparable with 720 mg, once weekly (-21.8); however, significance was not claimed because the hierarchical testing sequence was interrupted. Of patients with treatment-emergent adverse events leading to discontinuation, 4 (7.4%) received 720 mg, once weekly; 2 (3.6%) 720 mg, every 2 weeks; 1 (1.8%) 360 mg, every 2 weeks; and 2 (3.6%) placebo. Conclusions and Relevance: The results of this randomized clinical trial indicated that cendakimab was effective, generally safe, and well-tolerated in patients with moderate to severe AD. The primary end point was met with a significant reduction in Eczema Area and Severity Index scores with 720 mg, once weekly at week 16. Cendakimab demonstrated progressive AD improvement at all doses during 16 weeks of treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04800315.
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Dermatitis Atópica , Índice de Severidad de la Enfermedad , Humanos , Dermatitis Atópica/tratamiento farmacológico , Masculino , Femenino , Adulto , Método Doble Ciego , Persona de Mediana Edad , Resultado del Tratamiento , Inyecciones Subcutáneas , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Interleucina-13/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Adulto JovenRESUMEN
Bullous pemphigoid (BP) is a type 2 inflammation- and immunity-driven skin disease, yet a comprehensive understanding of the immune landscape, particularly immune-stromal crosstalk in BP, remains elusive. Herein, using single-cell RNA sequencing (scRNA-seq) and in vitro functional analyzes, we pinpoint Th2 cells, dendritic cells (DCs), and fibroblasts as crucial cell populations. The IL13-IL13RA1 ligand-receptor pair is identified as the most significant mediator of immune-stromal crosstalk in BP. Notably, fibroblasts and DCs expressing IL13RA1 respond to IL13-secreting Th2 cells, thereby amplifying Th2 cell-mediated cascade responses, which occurs through the specific upregulation of PLA2G2A in fibroblasts and CCL17 in myeloid cells, creating a positive feedback loop integral to immune-stromal crosstalk. Furthermore, PLA2G2A and CCL17 contribute to an increased titer of pathogenic anti-BP180-NC16A autoantibodies in BP patients. Our work provides a comprehensive insight into BP pathogenesis and shows a mechanism governing immune-stromal interactions, providing potential avenues for future therapeutic research.
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Quimiocina CCL17 , Células Dendríticas , Fibroblastos , Penfigoide Ampolloso , Análisis de la Célula Individual , Células Th2 , Humanos , Penfigoide Ampolloso/inmunología , Penfigoide Ampolloso/genética , Análisis de la Célula Individual/métodos , Fibroblastos/metabolismo , Fibroblastos/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Quimiocina CCL17/genética , Quimiocina CCL17/metabolismo , Células Th2/inmunología , Autoanticuerpos/inmunología , Transcriptoma , Interleucina-13/metabolismo , Interleucina-13/genética , Interleucina-13/inmunología , Colágenos no Fibrilares/inmunología , Colágenos no Fibrilares/genética , Colágenos no Fibrilares/metabolismo , Inflamación/inmunología , Inflamación/genética , Inflamación/metabolismo , Perfilación de la Expresión Génica/métodos , Masculino , Femenino , Autoantígenos/inmunología , Autoantígenos/metabolismo , Autoantígenos/genética , Colágeno Tipo XVII , Células Mieloides/metabolismo , Células Mieloides/inmunología , Células del Estroma/metabolismo , Células del Estroma/inmunologíaRESUMEN
Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)-4 receptor alpha subunit (IL-4Rα) that blocks IL-4 and IL-13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.
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Anticuerpos Monoclonales Humanizados , Dermatitis Atópica , Interleucina-13 , Subunidad alfa del Receptor de Interleucina-4 , Investigación Biomédica Traslacional , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Subunidad alfa del Receptor de Interleucina-4/antagonistas & inhibidores , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/inmunología , Interleucina-13/antagonistas & inhibidores , Interleucina-13/metabolismo , Interleucina-13/inmunología , Interleucina-4/antagonistas & inhibidores , Interleucina-4/metabolismo , Asma/tratamiento farmacológico , Asma/inmunología , Esofagitis Eosinofílica/tratamiento farmacológico , Esofagitis Eosinofílica/inmunología , Transducción de Señal/efectos de los fármacos , Pólipos Nasales/tratamiento farmacológico , Pólipos Nasales/inmunología , Prurigo/tratamiento farmacológico , Ciencia Traslacional Biomédica , Sinusitis/tratamiento farmacológico , Sinusitis/inmunologíaRESUMEN
Patients with recessive dystrophic epidermolysis bullosa (RDEB) experience numerous complications, which are exacerbated by inflammatory dysregulation and infection. Understanding the immunological mechanisms is crucial for selecting medications that balance inflammation control and immunocompetence. In this cross-sectional study, aiming to identify potential immunotherapeutic targets and inflammatory biomarkers, we delved into the interrelationship between clinical severity and systemic inflammatory parameters in a representative RDEB cohort. Encompassing 84 patients aged 1-67 and spanning all three Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI) severity categories, we analysed the interrelationship of infection history, standard inflammatory markers, systemic cytokines and Ig levels to elucidate their roles in RDEB pathophysiology. Our findings identify C-reactive protein as an excellent biomarker for disease severity in RDEB. A type 2 inflammatory profile prevails among moderate and severe RDEB patients, correlating with dysregulated circulating IgA and IgG. These results underscore the IL4/IL13 pathways as potential evidence-based therapeutic targets. Moreover, the complete inflammatory scenario aligns with Staphylococcus aureus virulence mechanisms. Concurrently, abnormalities in IgG, IgE and IgM levels suggest an immunodeficiency state in a substantial number of the cohort's patients. Our results provide new insights into the interplay of infection and immunological factors in the pathogenesis of RDEB.
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Biomarcadores , Proteína C-Reactiva , Epidermólisis Ampollosa Distrófica , Interleucina-13 , Interleucina-4 , Índice de Severidad de la Enfermedad , Humanos , Estudios Transversales , Biomarcadores/sangre , Niño , Preescolar , Interleucina-4/sangre , Adolescente , Proteína C-Reactiva/metabolismo , Adulto , Adulto Joven , Femenino , Masculino , Lactante , Persona de Mediana Edad , Interleucina-13/sangre , Interleucina-13/metabolismo , AncianoRESUMEN
The interleukin 13 (IL-13) gene single nucleotide polymorphisms (SNPs) are frequently linked to increased vulnerability to allergic asthma. Forkhead box protein P3 (FOXP3) is an important molecule in the formation of regulatory T cells (Treg). The genetic variants that alter FOXP3 function may have a role in the development of asthma and other allergic disorders. We aimed to determine the association of IL-13 rs20541, FOXP3 rs3761548 genes SNPs and serum levels of IL-13 with allergic asthma patients. In this case-control study, 41 Egyptian patients with allergic asthma were included. Age and gender matched. 41 normal volunteers were considered the controls. All subjects were examined for IL-13 rs20541 and FOXP3 rs3761548 SNPs by the polymerase chain reaction /restriction fragment length polymorphism technique. The serum level of IL-13 was assessed by the enzyme linked immunosorbent assay (ELISA). AA genotype at IL-13 rs20541 SNP was statistically significantly different between the studied groups (p= 0.042). Also, a statistically significant difference was detected when compared AA genotype to GG genotype as AA genotype was three times at risk for asthma (p1=0.031) (OR=3.95) and A allele increased the risk of asthma by about 3 times (OR=3.2). AA genotype at FOXP3 rs3761548 SNP was statistically significantly different between the studied groups (p=0.013). Also, a statistically significant difference was detected when compared AA genotype to CC genotype as AA genotype was 7 times at risk for asthma (p1=0.003) (OR=7.04) and A allele increased the risk of asthma by about 3 times (p<0.001) (OR=3.07). The serum level of IL-13 was statistically significant different between both groups (p<0.001). We can conclude that IL-13 could be a useful tool for predicting allergic asthma. Patients with AA genotype of IL-13 rs20541 and AA genotype of FOXP3 rs3761548 have a higher risk for developing allergic asthma.
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Asma , Factores de Transcripción Forkhead , Predisposición Genética a la Enfermedad , Genotipo , Interleucina-13 , Polimorfismo de Nucleótido Simple , Humanos , Interleucina-13/genética , Interleucina-13/sangre , Asma/genética , Asma/sangre , Factores de Transcripción Forkhead/genética , Masculino , Femenino , Egipto , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad/genética , Adulto , Alelos , Adolescente , Frecuencia de los Genes , Adulto JovenRESUMEN
The airway epithelium plays a pivotal role in regulating mucosal immunity and inflammation. Epithelial barrier function, homeostasis of luminal fluid, and mucociliary clearance are major components of mucosal defense mechanisms. The epithelial sodium channel (ENaC) is one of the key players in controlling airway fluid volume and composition, and characteristic cytokines cause ENaC and barrier dysfunctions following pulmonary infections or allergic reactions. Given the limited understanding of the requisite duration and magnitude of cytokines to affect ENaC and barrier function, available treatment options for restoring normal ENaC activity are limited. Previous studies have demonstrated that distinct amino acids can modulate epithelial ion channel activities and barrier function in intestines and airways. Here, we have investigated the time- and concentration-dependent effect of representative cytokines for Th1- (IFN-γ and TNF-α), Th2- (IL-4 and IL-13), and Treg-mediated (TGF-ß1) immune responses on ENaC activity and barrier function in human bronchial epithelial cells. When cells were exposed to Th1 and Treg cytokines, ENaC activity decreased gradually while barrier function remained largely unaffected. In contrast, Th2 cytokines had an immediate and profound inhibitory effect on ENaC activity that was subsequently followed by epithelial barrier disruption. These functional changes were associated with decreased membrane protein expression of α-, ß-, and γ-ENaC, and decreased mRNA levels of ß- and γ-ENaC. A proprietary blend of amino acids was developed based on their ability to prevent Th2 cytokine-induced ENaC dysfunction. Exposure to the select amino acids reversed the inhibitory effect of IL-13 on ENaC activity by increasing mRNA levels of ß- and γ-ENaC, and protein expression of γ-ENaC. This study indicates the beneficial effect of select amino acids on ENaC activity in an in vitro setting of Th2-mediated inflammation suggesting these amino acids as a novel therapeutic approach for correcting this condition.