RESUMO
A comprehensive understanding of the intricate cellular and molecular changes governing the complex interactions between cells within acne lesions is currently lacking. Herein, we analyzed early papules from six subjects with active acne vulgaris, utilizing single-cell and high-resolution spatial RNA sequencing. We observed significant changes in signaling pathways across seven different cell types when comparing lesional skin samples (LSS) to healthy skin samples (HSS). Using CellChat, we constructed an atlas of signaling pathways for the HSS, identifying key signal distributions and cell-specific genes within individual clusters. Further, our comparative analysis revealed changes in 49 signaling pathways across all cell clusters in the LSS- 4 exhibited decreased activity, whereas 45 were upregulated, suggesting that acne significantly alters cellular dynamics. We identified ten molecules, including GRN, IL-13RA1 and SDC1 that were consistently altered in all donors. Subsequently, we focused on the function of GRN and IL-13RA1 in TREM2 macrophages and keratinocytes as these cells participate in inflammation and hyperkeratinization in the early stages of acne development. We evaluated their function in TREM2 macrophages and the HaCaT cell line. We found that GRN increased the expression of proinflammatory cytokines and chemokines, including IL-18, CCL5, and CXCL2 in TREM2 macrophages. Additionally, the activation of IL-13RA1 by IL-13 in HaCaT cells promoted the dysregulation of genes associated with hyperkeratinization, including KRT17, KRT16, and FLG. These findings suggest that modulating the GRN-SORT1 and IL-13-IL-13RA1 signaling pathways could be a promising approach for developing new acne treatments.
Assuntos
Acne Vulgar , Pele , Humanos , Acne Vulgar/genética , Acne Vulgar/patologia , Acne Vulgar/metabolismo , Pele/patologia , Pele/metabolismo , Transdução de Sinais/genética , Masculino , Macrófagos/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , FemininoRESUMO
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.
Assuntos
Regulação Neoplásica da Expressão Gênica , Interleucina-13 , Neoplasias Hepáticas , Fatores de Transcrição MEF2 , Neoplasias Gástricas , Animais , Feminino , Humanos , Masculino , Camundongos , beta Catenina/metabolismo , beta Catenina/genética , Linhagem Celular Tumoral , Interleucina-13/metabolismo , Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Regiões Promotoras Genéticas , Transdução de Sinais , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Regulação para Cima , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
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.
Assuntos
Esofagite Eosinofílica , Humanos , Camundongos , Animais , Esofagite Eosinofílica/patologia , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-13/metabolismo , Células Epiteliais/metabolismoRESUMO
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.
Assuntos
Sintomas do Trato Urinário Inferior , Próstata , Quimiocinas CXC/metabolismo , Colágeno/metabolismo , Fibrose , Humanos , Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucinas/metabolismo , Sintomas do Trato Urinário Inferior/patologia , Masculino , Próstata/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In search of new therapies for pancreatic cancer, cytokine pathways have attracted increasing interest in recent years. Cytokines play a vital role in the crosstalk between tumour cells and the tumour microenvironment. The related inflammatory cytokines IL-4 and IL-13 can regularly be detected at increased levels in the microenvironment of pancreatic cancer. They share a receptor heterodimer consisting of IL-4Rα and IL-13Rα1. While IL-4Rα induces a more oncogenic phenotype, the role of IL-13Rα1 was yet to be determined. ShRNA-based knockdown of IL-13Rα1 was performed in Capan-1 and MIA PaCa-2. We assessed cell growth and migratory capacities under the influence of IL-13Rα1. Pathway alterations were detected by immunoblot analysis. We now have demonstrated that the loss of IL-13Rα1 induces apoptosis in pancreatic cancer cells. This was associated with an epithelial-to-mesenchymal transition. Loss of IL-13Rα1 also abolished the effects of exogenous IL-4 and IL-13 stimulation. Interestingly, in wild type cells, cytokine stimulation caused a similar increase in migratory capacities as after IL-13Rα1 knockdown. Overall, our results indicate the vital role of IL-13Rα1 in the progression of pancreatic cancer. The differential expression of IL-4Rα and IL-13Rα1 has to be taken into account when considering a cytokine-targeted therapy in pancreatic cancer.
Assuntos
Interleucina-13 , Neoplasias Pancreáticas , Apoptose , Citocinas/metabolismo , Humanos , Interleucina-13/farmacologia , Subunidade alfa1 de Receptor de Interleucina-13/genética , Interleucina-4/metabolismo , Interleucina-4/farmacologia , Neoplasias Pancreáticas/genética , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Type 2 inflammationârelated cytokine IL-13 plays a protective role in experimental papilloma induction in mice. To understand the mechanisms by which IL-13 contributes to papilloma formation, we utilized Il13rα1-knockout (KO) mice in a widely used 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoyl phorbol-13-acetate two-stage skin carcinogenesis protocol that mimics the development of squamous cell carcinoma. KO mice developed more papillomas and significantly faster than wild-type mice. Papilloma development reduced regulatory T cells in wild-type mice but substantially less in KO mice. In line with this, IL-2 and IL-10 levels decreased in wild-type mice but not in KO mice. Furthermore, systemic IL-5 and TSLP levels were elevated, whereas IL-22 was decreased during papilloma formation in the skin of KO mice. Polymorphonuclear myeloidâderived suppressor cells were decreased in the KO mice at the early phase of papilloma induction. We show that IL-13Rα1 protects from papilloma development in chemically induced skin carcinogenesis, and our results provide further insights into the protective role of functional IL-4 and IL-13 signaling through type II IL-4 receptor in tumor development.
Assuntos
Papiloma , Neoplasias Cutâneas , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Carcinogênese/genética , Carcinogênese/patologia , Carcinógenos/toxicidade , Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13 , Camundongos , Camundongos Knockout , Papiloma/induzido quimicamente , Papiloma/genética , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Linfócitos T Reguladores/metabolismo , Acetato de Tetradecanoilforbol/toxicidadeRESUMO
Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally accepted that IL-4 and IL-13 can exert effects on epithelial tumor cells through corresponding receptors. Type II IL-4 receptor (IL-4Rα/IL-13Rα1), predominantly expressed in non-hematopoietic cells, is identified to be the main target for both IL-4 and IL-13 in tumors. Moreover, IL-13 can also signal by binding to the IL-13Rα2 receptor. Structural similarity due to the use of the same receptor complex generated in response to IL-4/IL-13 results in overlapping but also distinct signaling pathways and functions. The aim of this review was to summarize knowledge about IL-4 and IL-13 and their receptors in pancreatic cancer in order understand the implication of IL-4 and IL-13 and their receptors for pancreatic tumorigenesis and progression and for developing possible new diagnostic and therapeutic targets.
Assuntos
Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa2 de Receptor de Interleucina-13/genética , Interleucina-13/genética , Interleucina-4/genética , Neoplasias Pancreáticas/genética , Carcinogênese/genética , Humanos , Subunidade alfa de Receptor de Interleucina-4/genética , Neoplasias Pancreáticas/patologia , Receptores de Interleucina/genética , Transdução de Sinais/genéticaRESUMO
One of the most frequently identified tumors and a contributing cause of death in women is breast cancer (BC). Many biomarkers associated with survival and prognosis were identified in previous studies through database mining. Nevertheless, the predictive capabilities of single-gene biomarkers are not accurate enough. Genetic signatures can be an enhanced prediction method. This research analyzed data from The Cancer Genome Atlas (TCGA) for the detection of a new genetic signature to predict BC prognosis. Profiling of mRNA expression was carried out in samples of patients with TCGA BC (n = 1222). Gene set enrichment research has been undertaken to classify gene sets that vary greatly between BC tissues and normal tissues. Cox models for additive hazards regression were used to classify genes that were strongly linked to overall survival. A subsequent Cox regression multivariate analysis was used to construct a predictive risk parameter model. Kaplan-Meier survival predictions and log-rank validation have been used to verify the value of risk prediction parameters. Seven genes (PGK1, CACNA1H, IL13RA1, SDC1, AK3, NUP43, SDC3) correlated with glycolysis were shown to be strongly linked to overall survival. Depending on the 7-gene-signature, 1222 BC patients were classified into subgroups of high/low-risk. Certain variables have not impaired the prognostic potential of the seven-gene signature. A seven-gene signature correlated with cellular glycolysis was developed to predict the survival of BC patients. The results include insight into cellular glycolysis mechanisms and the detection of patients with poor BC prognosis.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Glicólise/genética , RNA Mensageiro/genética , Adenilato Quinase/genética , Neoplasias da Mama/metabolismo , Canais de Cálcio Tipo T/genética , Biologia Computacional , Gerenciamento de Dados , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa1 de Receptor de Interleucina-13/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Fosfoglicerato Quinase/genética , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida , Sindecana-1/genética , Sindecana-3/genéticaRESUMO
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.
Assuntos
Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Neoplasias Retroperitoneais/diagnóstico , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Extremidades/patologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Retroperitoneais/metabolismo , Neoplasias Retroperitoneais/patologia , Espaço Retroperitoneal/patologia , Sarcoma/metabolismo , Sarcoma/patologia , Neoplasias de Tecidos Moles/metabolismo , Neoplasias de Tecidos Moles/patologia , Análise de Sobrevida , Adulto JovemRESUMO
Mucosal-associated invariant T (MAIT) cells are unconventional T cells that recognize antigens derived from riboflavin biosynthesis. In addition to anti-microbial functions, human MAIT cells are associated with cancers, autoimmunity, allergies and inflammatory disorders, although their role is poorly understood. Activated MAIT cells are well known for their rapid release of Th1 and Th17 cytokines, but we have discovered that chronic stimulation can also lead to potent interleukin (IL)-13 expression. We used RNA-seq and qRT-PCR to demonstrate high expression of the IL-13 gene in chronically stimulated MAIT cells, and directly identify IL-13 using intracellular flow cytometry and multiplex bead analysis of MAIT cell cultures. This unexpected finding has important implications for IL-13-dependent diseases, such as colorectal cancer (CRC), that occur in mucosal areas where MAIT cells are abundant. We identify MAIT cells near CRC tumors and show that these areas and precancerous polyps express high levels of the IL-13 receptor, which promotes tumor progression and metastasis. Our data suggest that MAIT cells have a more complicated role in CRC than currently realized and that they represent a promising new target for immunotherapies where IL-13 can be a critical factor.
Assuntos
Neoplasias Colorretais/imunologia , Interleucina-13/metabolismo , Células T Invariantes Associadas à Mucosa/imunologia , Lesões Pré-Cancerosas/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Colo/citologia , Colo/imunologia , Colo/patologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Humanos , Imunoterapia/métodos , Interleucina-13/imunologia , Subunidade alfa1 de Receptor de Interleucina-13 , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/metabolismo , Lesões Pré-Cancerosas/patologia , Lesões Pré-Cancerosas/terapia , RNA-Seq , Receptores de Interleucina-13/metabolismo , Reto/citologia , Reto/imunologia , Reto/patologiaRESUMO
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.
Assuntos
Remodelação das Vias Aéreas/fisiologia , Células Epiteliais/metabolismo , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Interleucina-13/metabolismo , Pulmão/metabolismo , Transdução de Sinais/fisiologia , Cicatrização/fisiologia , Asma/metabolismo , Asma/patologia , Linhagem Celular , Células Epiteliais/fisiologia , Epitélio/metabolismo , Epitélio/patologia , Receptores ErbB/metabolismo , Humanos , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Pulmão/fisiologiaRESUMO
BACKGROUND: Enzymatically inactive chitinase-like protein CHI3L1 drives inflammatory response and promotes tumor progression. However, its role in gastric cancer (GC) tumorigenesis and metastasis has not yet been fully elucidated. We determined the significance of CHI3L1 expression in patients with GC. We also explored an as-yet unknown receptor of CHI3L1 and investigated the involved signaling in GC metastasis. METHODS: CHI3L1 expression was evaluated by immunoblotting, tissue microarray-based immunohistochemistry analysis (n = 100), and enzyme linked immunosorbent assay (ELISA) (n = 150). The interactions between CD44 and CHI3L1 or Interleukin-13 receptor alpha 2 (IL-13Rα2) were analyzed by co-immunoprecipitation, immunofluorescence co-localization assay, ELISA, and bio-layer interferometry. The roles of CHI3L1/CD44 axis in GC metastasis were investigated in GC cell lines and experimental animal model by gain and loss of function. RESULTS: CHI3L1 upregulation occurred during GC development, and positively correlated with GC invasion depth, lymph node status, and tumor staging. Mechanically, CHI3L1 binding to CD44 activated Erk and Akt, along with ß-catenin signaling by phosphorylating ß-catenin at Ser552 and Ser675. CD44 also interacted with IL-13Rα2 to form a complex. Notably, CD44v3 peptide and protein, but not CD44v6 peptide or CD44s protein, bound to both CHI3L1 and IL-13Rα2. Our in vivo and in vitro data further demonstrated that CHI3L1 promoted GC cell proliferation, migration, and metastasis. CONCLUSIONS: CHI3L1 binding to CD44v3 activates Erk, Akt, and ß-catenin signaling, therefore enhances GC metastasis. CHI3L1 expression is a novel biomarker for the prognosis of GC, and these findings have thus identified CHI3L1/CD44 axis as a vital pathway and potential therapeutic target in GC.
Assuntos
Biomarcadores Tumorais/genética , Proteína 1 Semelhante à Quitinase-3/genética , Receptores de Hialuronatos/genética , Neoplasias Gástricas/genética , Animais , Proliferação de Células/genética , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Subunidade alfa1 de Receptor de Interleucina-13/genética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Metástase Neoplásica , Proteína Oncogênica v-akt/genética , Prognóstico , Transdução de Sinais/genética , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/genéticaRESUMO
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 (pâ¯<â¯0.001) and IL-13Rα1 expression in tumor tissues (36 of 40, pâ¯<â¯0.001) in patients with NKTCL than in control cohort. IL-13 secretion was observed in tumor tissues (30 of 40, pâ¯<â¯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.
Assuntos
Regulação Neoplásica da Expressão Gênica , Subunidade alfa1 de Receptor de Interleucina-13/genética , Interleucina-13/genética , Interleucina-13/farmacologia , Linfoma Extranodal de Células T-NK/genética , Anticorpos/farmacologia , Comunicação Autócrina , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Relação Dose-Resposta a Droga , Humanos , Interleucina-13/antagonistas & inibidores , Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Linfoma Extranodal de Células T-NK/metabolismo , Linfoma Extranodal de Células T-NK/patologia , Fosforilação/efeitos dos fármacos , Prognóstico , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Transdução de SinaisRESUMO
Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naïve CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process.
Assuntos
Hipersensibilidade/imunologia , Interleucina-13/imunologia , Subunidade alfa de Receptor de Interleucina-4/imunologia , Interleucina-4/imunologia , Receptores de Interleucina-13/imunologia , Humanos , Imunidade Celular , Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13 , Interleucina-4/metabolismo , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Receptores de Interleucina-13/metabolismo , Transdução de Sinais/imunologiaRESUMO
OBJECTIVE: At present, there are no clinical or laboratory measures that accurately forecast the progression of skin fibrosis and organ involvement in patients with systemic sclerosis (SSc). The goal of this study was to identify skin biomarkers that could be prognostic for the progression of skin fibrosis in patients with early diffuse cutaneous SSc (dcSSc). METHODS: We analyzed clinical data and gene expression in skin biopsy samples from 38 placebo-treated patients, part of the Roche Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (FASSCINATE) phase II study of tocilizumab in SSc. RNA samples were analyzed using nCounter. A trajectory model based on a modified Rodnan skin thickness score was used to describe 3 skin disease trajectories over time. We examined the association of skin gene expression with skin score trajectory groups, by chi-square test. Logistic regression was used to examine the prognostic power of each gene identified. RESULTS: We found that placebo-treated patients with high expression of messenger RNA for CD14, SERPINE1, IL13RA1, CTGF, and OSMR at baseline were more likely to have progressive skin score trajectories. We also found that those genes were prognostic for the risk of skin progression and that IL13RA1, OSMR, and SERPINE1 performed the best. CONCLUSION: Skin gene expression of biomarkers associated with macrophages (CD14, IL13RA1) and transforming growth factor ß activation (SERPINE1, CTGF, OSMR) are prognostic for progressive skin disease in patients with dcSSc. These biomarkers may provide guidance in decision-making about which patients should be considered for aggressive therapies and/or for clinical trials.
Assuntos
Expressão Gênica , Macrófagos/metabolismo , RNA Mensageiro/metabolismo , Esclerodermia Difusa/genética , Pele/citologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Fator de Crescimento do Tecido Conjuntivo/genética , Progressão da Doença , Método Duplo-Cego , Feminino , Fibrose , Marcadores Genéticos/genética , Humanos , Subunidade alfa1 de Receptor de Interleucina-13/genética , Receptores de Lipopolissacarídeos/genética , Masculino , Pessoa de Meia-Idade , Subunidade beta de Receptor de Oncostatina M/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Esclerodermia Difusa/tratamento farmacológico , Esclerodermia Difusa/patologia , Índice de Gravidade de Doença , Pele/patologia , Adulto JovemRESUMO
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. A variety of targeted agents are being tested in the clinic including cancer vaccines, immunotoxins, antibodies and T cell immunotherapy for GBM. We have previously reported that IL-13 receptor subunits α1 and α2 of IL-13R complex are overexpressed in GBM. We are investigating the significance of IL-13Rα1 and α2 expression in GBM tumors. In order to elucidate a possible relationship between IL-13Rα1 and α2 expression with severity and prognoses of subjects with GBM, we analyzed gene expression (by microarray) and clinical data available at the public The Cancer Genome Atlas (TCGA) database (Currently known as Global Data Commons). More than 40% of GBM samples were highly positive for IL-13Rα2 mRNA (Log2 ≥ 2) while only less than 16% samples were highly positive for IL-13Rα1 mRNA. Subjects with high IL-13Rα1 and α2 mRNA expressing tumors were associated with a significantly lower survival rate irrespective of their treatment compared to subjects with IL-13Rα1 and α2 mRNA negative tumors. We further observed that IL-13Rα2 gene expression is associated with GBM resistance to temozolomide (TMZ) chemotherapy. The expression of IL-13Rα2 gene did not seem to correlate with the expression of genes for other chains involved in the formation of IL-13R complex (IL-13Rα1 or IL-4Rα) in GBM. However, a positive correlation was observed between IL-4Rα and IL-13Rα1 gene expression. The microarray data of IL-13Rα2 gene expression was verified by RNA-Seq data. In depth analysis of TCGA data revealed that immunosuppressive genes (such as FMOD, CCL2, OSM, etc.) were highly expressed in IL-13Rα2 positive tumors, but not in IL-13Rα2 negative tumors. These results indicate a direct correlation between high level of IL-13R mRNA expression and poor patient prognosis and that immunosuppressive genes associated with IL-13Rα2 may play a role in tumor progression. These findings have important implications in understanding the role of IL-13R in the pathogenesis of GBM and potentially other cancers.
Assuntos
Neoplasias Encefálicas/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Glioblastoma/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Bases de Dados Genéticas , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/metabolismo , Temozolomida/uso terapêuticoRESUMO
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.
Assuntos
Colite Ulcerativa/imunologia , Inflamação/imunologia , Subunidade alfa2 de Receptor de Interleucina-13/metabolismo , Mucosa Intestinal/fisiologia , Proteína 2 com Domínio MARVEL/metabolismo , Junções Íntimas/metabolismo , Adulto , Idoso , Antígenos/imunologia , Antígenos/metabolismo , Claudina-2/metabolismo , Doença de Crohn/imunologia , Regulação para Baixo , Feminino , Células HT29 , Humanos , Interleucina-13/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Substâncias Macromoleculares/imunologia , Substâncias Macromoleculares/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Transdução de Sinais , Adulto JovemRESUMO
The IL-13Rα1 signaling pathway and M2 macrophages play crucial roles in schistosome egg-induced hepatic fibrosis via the expression of pro-fibrotic molecules. This study aims to investigate the inhibitory effect and mechanism of action of corilagin on schistosome egg-induced hepatic fibrosis via the IL-13Rα1 signaling pathway in M2 macrophages in vitro and in vivo. The mRNA and protein expression of IL-13Rα1, PPARγ, KLF4, SOCS1, STAT6, p-STAT6, and TGF-ß was measured in vitro with corilagin treatment after IL-13 stimulation and in vivo corilagin treatment after effectively killing the adult schistosomes in schistosome-infected mice. Histological analysis of liver tissue was assessed for the degree of hepatic fibrosis. The results revealed that corilagin significantly reduced the expression of PPARγ, KLF4, SOCS1, p-STAT6, and TGF-ß compared with model group and praziquantel administration (p < 0.01 or p < 0.05) in vivo and in vitro, which indicated a strong inhibitory effect of corilagin on IL-13Rα1 signaling pathway. As well, the inhibitory effect of corilagin showed a significant dose-dependence (p < 0.05). The area of fibrosis and distribution of M2 macrophages in mouse liver tissue were reduced significantly and dose-dependently with corilagin treatment compared to model group or praziquantel administration (p < 0.01 or p < 0.05), indicating that corilagin suppressed IL-13Rα1 signaling pathway and M2 macrophage polarization effectively in vivo. Furthermore, the anti-fibrogenic effect persisted even when IL-13Rα1 was up- or down-regulated in vitro. In conclusion, corilagin can suppress schistosome egg-induced hepatic fibrosis via inhibition of M2 macrophage polarization in the IL-13Rα1 signaling pathway.
Assuntos
Glucosídeos/farmacologia , Taninos Hidrolisáveis/farmacologia , Subunidade alfa1 de Receptor de Interleucina-13/antagonistas & inibidores , Cirrose Hepática Experimental/tratamento farmacológico , Cirrose Hepática Experimental/parasitologia , Macrófagos/efeitos dos fármacos , Schistosoma/patogenicidade , Esquistossomose/tratamento farmacológico , Animais , Anti-Helmínticos/uso terapêutico , Biomarcadores/análise , Linhagem Celular , Glucosídeos/uso terapêutico , Taninos Hidrolisáveis/uso terapêutico , Subunidade alfa1 de Receptor de Interleucina-13/genética , Subunidade alfa1 de Receptor de Interleucina-13/metabolismo , Fator 4 Semelhante a Kruppel , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Praziquantel/uso terapêutico , RNA Interferente Pequeno/genéticaRESUMO
Type 1 diabetes (T1D) manifests when the insulin-producing pancreatic ß cells are destroyed as a consequence of an inflammatory process initiated by lymphocytes of the immune system. The NOD mouse develops T1D spontaneously and serves as an animal model for human T1D. The IL-4Rα/IL-13Rα1 heteroreceptor (HR) serves both IL-4 and IL-13 cytokines, which are believed to function as anti-inflammatory cytokines in T1D. However, whether the HR provides a responsive element to environmental (i.e., physiologic) IL-4/IL-13 in the regulation of peripheral tolerance and the development of T1D has yet to be defined. In this study, NOD mice deficient for the HR have been generated by means of IL-13Rα1 gene disruption and used to determine whether such deficiency affects the development of T1D. Surprisingly, the findings indicate that NOD mice lacking the HR (13R-/-) display resistance to T1D as the rise in blood glucose level and islet inflammation were significantly delayed in these HR-deficient relative to HR-sufficient (13R+/+) mice. In fact, the frequency and spleen-to-pancreas dynamics of both Th1 and Th17 cells were affected in 13R-/- mice. This is likely due to an increase in the frequency of mTGFß+Foxp3int regulatory T cells and the persistence of CD206+ macrophages in the pancreas as both types of cells confer resistance to T1D upon transfer to 13R+/+ mice. These findings reveal new insights as to the role environmental IL-4/IL-13 and the HR play in peripheral tolerance and the development of T1D.