RESUMEN
Although aberrant activation of the KRAS and PI3K pathway alongside TP53 mutations account for frequent aberrations in human gastric cancers, neither the sequence nor the individual contributions of these mutations have been clarified. Here, we establish an allelic series of mice to afford conditional expression in the glandular epithelium of KrasG12D;Pik3caH1047R or Trp53R172H and/or ablation of Pten or Trp53. We find that KrasG12D;Pik3caH1047R is sufficient to induce adenomas and that lesions progress to carcinoma when also harboring Pten deletions. An additional challenge with either Trp53 loss- or gain-of-function alleles further accelerated tumor progression and triggered metastatic disease. While tumor-intrinsic STAT3 signaling in response to gp130 family cytokines remained as a gatekeeper for all stages of tumor development, metastatic progression required a mutant Trp53-induced interleukin (IL)-11 to IL-6 dependency switch. Consistent with the poorer survival of patients with high IL-6 expression, we identify IL-6/STAT3 signaling as a therapeutic vulnerability for TP53-mutant gastric cancer.
Asunto(s)
Progresión de la Enfermedad , Interleucina-6 , Factor de Transcripción STAT3 , Neoplasias Gástricas , Proteína p53 Supresora de Tumor , Animales , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Interleucina-6/metabolismo , Interleucina-6/genética , Ratones , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Mutación/genética , Fosfohidrolasa PTEN/metabolismo , Fosfohidrolasa PTEN/genética , Humanos , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Interleucina-11/metabolismo , Interleucina-11/genéticaRESUMEN
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
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Envejecimiento , Interleucina-11 , Longevidad , Transducción de Señal , Animales , Femenino , Masculino , Ratones , Envejecimiento/efectos de los fármacos , Envejecimiento/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Proteínas Quinasas Activadas por AMP/metabolismo , Fragilidad/genética , Fragilidad/metabolismo , Fragilidad/prevención & control , Inflamación/metabolismo , Inflamación/tratamiento farmacológico , Interleucina-11/antagonistas & inhibidores , Interleucina-11/deficiencia , Interleucina-11/genética , Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/metabolismo , Subunidad alfa del Receptor de Interleucina-11/deficiencia , Longevidad/efectos de los fármacos , Longevidad/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Humanos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiologíaRESUMEN
BACKGROUND: The roles of IL-10, IL-11, COX-2, BCL6, ZEB1, and ZEB2 genes in the potential correlation between polycystic ovary syndrome (PCOS), inflammation, and cancer remain controversial. AIMS: This study aimed to compare serum levels of IL-10 and IL-11 and gene expression of IL-10, IL-11, COX-2, BCL6, ZEB1, and ZEB2 in PBMCs of women with PCOS and healthy controls. METHODS: A case-control study included 40 women with PCOS as the case group and 40 healthy women as controls. Group matching for age and BMI was performed. Serum levels of IL-10 and IL-11 were assessed using ELISA, while gene expression was measured using real-time PCR. Parameters were compared between groups, and correlations among gene expression and serum levels were explored. RESULTS: In comparison to healthy women, women with PCOS exhibited a significant decrease in the expression of COX-2 and IL-10 genes (p<0.001), alongside a significant increase in ZEB2 gene expression (p<0.001). There were no significant differences observed in the expression of IL-11, BCL6, and ZEB1 genes. Furthermore, the serum level of IL-10 was significantly lower in women with PCOS compared to the control group (p<0.001), while no significant difference was found in IL-11 levels. Additionally, no significant correlations were identified between gene expression and serum levels. CONCLUSION: In women with PCOS, reduced IL-10 gene expression may indicate inflammation and serve as a diagnostic biomarker. However, conflicting findings on COX-2 expression complicate understanding. Elevated ZEB2 expression in PCOS women may lead to infertility, epithelial-mesenchymal transition, and aggressive phenotypes.
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Ciclooxigenasa 2 , Interleucina-10 , Interleucina-11 , Leucocitos Mononucleares , Síndrome del Ovario Poliquístico , Proteínas Proto-Oncogénicas c-bcl-6 , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , Humanos , Femenino , Síndrome del Ovario Poliquístico/sangre , Síndrome del Ovario Poliquístico/inmunología , Síndrome del Ovario Poliquístico/genética , Síndrome del Ovario Poliquístico/diagnóstico , Interleucina-10/sangre , Interleucina-10/genética , Adulto , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/sangre , Interleucina-11/sangre , Interleucina-11/genética , Estudios de Casos y Controles , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/sangre , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/sangre , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/sangre , Adulto Joven , ARN Mensajero/sangre , Regulación de la Expresión Génica/inmunologíaRESUMEN
Patients who have non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations are more prone to brain metastasis (BM) and poor prognosis. Previous studies showed that the tumor microenvironment of BM in these patients is immunosuppressed, as indicated by reduced T-cell abundance and activity, although the mechanism of this immunosuppression requires further study. This study shows that reactive astrocytes play a critical role in promoting the immune escape of BM from EGFR-mutated NSCLC by increasing the apoptosis of CD8+ T lymphocytes. The increased secretion of interleukin 11(IL11) by astrocytes promotes the expression of PDL1 in BM, and this is responsible for the increased apoptosis of T lymphocytes. IL11 functions as a ligand of EGFR, and this binding activates EGFR and downstream signaling to increase the expression of PDL1, culminating in the immune escape of tumor cells. IL11 also promotes immune escape by binding to its intrinsic receptor (IL11Rα/glycoprotein 130 [gp130]). Additional in vivo studies show that the targeted inhibition of gp130 and EGFR suppresses the growth of BM and prolongs the survival time of mice. These results suggest a novel therapeutic strategy for treatment of NSCLC patients with EGFR mutations.
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Astrocitos , Antígeno B7-H1 , Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Interleucina-11 , Neoplasias Pulmonares , Regulación hacia Arriba , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ratones , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/inmunología , Receptores ErbB/metabolismo , Receptores ErbB/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Humanos , Astrocitos/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Regulación hacia Arriba/genética , Escape del Tumor/genética , Modelos Animales de Enfermedad , Mutación/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Línea Celular TumoralRESUMEN
BACKGROUND: Docetaxel resistance represents a significant obstacle in the treatment of prostate cancer. The intricate interplay between cytokine signalling pathways and transcriptional control mechanisms in cancer cells contributes to chemotherapeutic resistance, yet the underlying molecular determinants remain only partially understood. This study elucidated a novel resistance mechanism mediated by the autocrine interaction of interleukin-11 (IL-11) and its receptor interleukin-11 receptor subunit alpha(IL-11RA), culminating in activation of the JAK1/STAT4 signalling axis and subsequent transcriptional upregulation of the oncogene c-MYC. METHODS: Single-cell secretion profiling of prostate cancer organoid was analyzed to determine cytokine production profiles associated with docetaxel resistance.Analysis of the expression pattern of downstream receptor IL-11RA and enrichment of signal pathway to clarify the potential autocrine mechanism of IL-11.Next, chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) was performed to detect the nuclear localization and DNA-binding patterns of phosphorylated STAT4 (pSTAT4). Coimmunoprecipitation and reporter assays were utilized to assess interaction between pSTAT4 and the cotranscription factor CREB-binding protein (CBP) as well as their role in c-MYC transcriptional activity. RESULTS: Autocrine secretion of IL-11 was markedly increased in docetaxel-resistant prostate cancer cells. IL-11 stimulation resulted in robust activation of JAK1/STAT4 signalling. Upon activation, pSTAT4 translocated to the nucleus and associated with CBP at the c-MYC promoter region, amplifying its transcriptional activity. Inhibition of the IL-11/IL-11RA interaction or disruption of the JAK1/STAT4 pathway significantly reduced pSTAT4 nuclear entry and its binding to CBP, leading to downregulation of c-MYC expression and restoration of docetaxel sensitivity. CONCLUSION: Our findings identify an autocrine loop of IL-11/IL-11RA that confers docetaxel resistance through the JAK1/STAT4 pathway. The pSTAT4-CBP interaction serves as a critical enhancer of c-MYC transcriptional activity in prostate cancer cells. Targeting this signalling axis presents a potential therapeutic strategy to overcome docetaxel resistance in advanced prostate cancer.
Asunto(s)
Resistencia a Antineoplásicos , Interleucina-11 , Neoplasias de la Próstata , Humanos , Masculino , Docetaxel/farmacología , Regulación de la Expresión Génica , Interleucina-11/genética , Interleucina-11/metabolismo , Janus Quinasa 1/genética , Janus Quinasa 1/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Transducción de Señal , Factor de Transcripción STAT4/metabolismo , Resistencia a Antineoplásicos/genéticaRESUMEN
IL-11 and IL-6 activate signalling via assembly of the cell surface receptor gp130; however, it is unclear how signals are transmitted across the membrane to instruct cellular responses. Here we solve the cryoEM structure of the IL-11 receptor recognition complex to discover how differences in gp130-binding interfaces may drive signalling outcomes. We explore how mutations in the IL6ST gene encoding for gp130, which cause severe immune deficiencies in humans, impair signalling without blocking cytokine binding. We use cryoEM to solve structures of both IL-11 and IL-6 complexes with a mutant form of gp130 associated with human disease. Together with molecular dynamics simulations, we show that the disease-associated variant led to an increase in flexibility including motion within the cytokine-binding core and increased distance between extracellular domains. However, these distances are minimized as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signalling and dimmer switch mode of action.
Asunto(s)
Interleucina-11 , Interleucina-6 , Humanos , Interleucina-11/genética , Interleucina-6/metabolismo , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Transducción de Señal , Receptores de Interleucina-6/genéticaRESUMEN
BACKGROUND: The Interleukin (IL)-11 gene, which is one of the members of the cytokine family, has an oncogenic role in some cancers. The main goal of this study is to analyze IL-11 expression level in 14 prevalent cancers and highlights its role in patients' survival, drug resistance, and sensitivities. Also, an association of this gene with metastasis and inflammation pathways has been investigated. METHODS AND RESULTS: Using the cancer genome atlas (TCGA) data, the level of IL-11 expression and its role in prognosis and survival rate were evaluated in 13 common cancers. Then, confirming the obtained in-silico outcomes, the relative expression level of this gene in colorectal cancer (CRC) samples and their adjusted tissues were assayed by the RT-qPCR method. Furthermore, to examine the association between IL-11 expression and drug resistance and sensitivity, PharmacoGX data was applied. The co-expression network was used to recognize the pathways in which IL-11 was involved. The results from the TCGA dataset indicated that the expression level of IL-11 increased significantly in 13 prevalence cancers compared to the control groups. Interestingly, this enhanced expression level is associated with a high rate of mortality in patients with bladder, stomach, colorectal, and endometrial cancers. Also, the co-expression network analysis showed a strong correlation between IL-11 and the genes of metastasis pathway and the genes related to the inflammation process. Finally, regarding drug sensitivity, IL-11 expression level can be introduced as a remarkable biomarker for cancer detection due to area under curve (AUC). CONCLUSION: Altered expression of the IL-11 gene is observed in 13 common cancers and is associated with prognosis and mortality rate in patients. Moreover, this gene can be considered a prognostic biomarker in different types of cancer, such as CRC.
Asunto(s)
Neoplasias Colorrectales , Interleucina-11 , Humanos , Biomarcadores , Neoplasias Colorrectales/patología , Inflamación , Interleucina-11/genéticaRESUMEN
Interleukin-11 (IL-11) is a member of the IL-6 family of cytokines and is an important factor for bone homeostasis. IL-11 binds to and signals via the membrane-bound IL-11 receptor (IL-11R, classic signaling) or soluble forms of the IL-11R (sIL-11R, trans-signaling). Mutations in the IL11RA gene, which encodes the IL-11R, are associated with craniosynostosis, a human condition in which one or several of the sutures close prematurely, resulting in malformation of the skull. The biological mechanisms of how mutations within the IL-11R are linked to craniosynostosis are mostly unexplored. In this study, we analyze two variants of the IL-11R described in craniosynostosis patients: p.T306_S308dup, which results in a duplication of three amino-acid residues within the membrane-proximal fibronectin type III domain, and p.E364_V368del, which results in a deletion of five amino-acid residues in the so-called stalk region adjacent to the plasma membrane. The stalk region connects the three extracellular domains to the transmembrane and intracellular region of the IL-11R and contains cleavage sites for different proteases that generate sIL-11R variants. Using a combination of bioinformatics and different biochemical, molecular, and cell biology methods, we show that the IL-11R-T306_S308dup variant does not mature correctly, is intracellularly retained, and does not reach the cell surface. In contrast, the IL-11R-E364_V368del variant is fully biologically active and processed normally by proteases, thus allowing classic and trans-signaling of IL-11. Our results provide evidence that mutations within the IL11RA gene may not be causative for craniosynostosis and suggest that other regulatory mechanism(s) are involved but remain to be identified.
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Craneosinostosis , Interleucina-11 , Humanos , Receptores de Interleucina-11/genética , Receptores de Interleucina-11/química , Receptores de Interleucina-11/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Transducción de Señal , Craneosinostosis/genética , Péptido Hidrolasas/metabolismo , Receptores de Interleucina-6/genética , Receptor gp130 de Citocinas/genéticaRESUMEN
Interleukin 11 (IL11) is an elusive member of the IL6 family of cytokines. While initially thought to be a haematopoietic and cytoprotective factor, more recent data show instead that IL11 is redundant for haematopoiesis and toxic. In this review, the reasons that led to the original misunderstandings of IL11 biology, which are now understandable, are explained with particular attention on the use of recombinant human IL11 in mice and humans. Following tissue injury, as part of an evolutionary ancient homeostatic response, IL11 is secreted from damaged mammalian cells to signal via JAK/STAT3, ERK/P90RSK, LKB1/mTOR and GSK3ß/SNAI1 in autocrine and paracrine. This activates a program of mesenchymal transition of epithelial, stromal, and endothelial cells to cause inflammation, fibrosis, and stalled endogenous tissue repair, leading to organ failure. The role of IL11 signalling in cell- and organ-specific pathobiology is described, the large unknowns about IL11 biology are discussed and the promise of targeting IL11 signalling as a therapeutic approach is reviewed.
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Células Endoteliales , Interleucina-11 , Animales , Humanos , Ratones , Fibrosis , Interleucina-11/genética , Transducción de SeñalRESUMEN
Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family ß-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.
Asunto(s)
Citocinas , Interleucina-11 , Humanos , Interleucina-11/genética , Receptor gp130 de Citocinas/genética , Interleucina-6/metabolismo , Antígenos CD/metabolismo , Glicoproteínas de Membrana/metabolismo , Receptores de Interleucina-6/metabolismoRESUMEN
Cardiac fibrosis is a common pathological process in heart disease, representing a therapeutic target. Transforming growth factor ß (TGFß) is the canonical driver of cardiac fibrosis and was recently shown to be dependent on interleukin 11 (IL11) for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and anti-inflammatory in the mouse heart. In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing, and in vivo imaging, we analyzed the effects of IL11 on myocardial fibrosis, inflammation, and cardiac function, challenging previous reports suggesting the cardioprotective potential of IL11. TGFß stimulation of cardiomyocytes caused Il11 upregulation. Compared to wild-type controls, Il11-expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors, and increased inflammatory cells. IL11 expression also activated a program of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.
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Interleucina-11 , Miocitos Cardíacos , Humanos , Animales , Ratones , Interleucina-11/genética , Inflamación/genética , Citocinas , Factor de Crecimiento Transformador beta/genéticaRESUMEN
The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes, and IL-11R+ neutrophils in comparison to matched healthy controls. IL-11+ and granulocyte-macrophage colony-stimulating factor (GM-CSF)+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single-cell RNA sequencing, revealed the highest number of differentially expressed genes in classical monocytes, including up-regulated NFKB1, NLRP3, and IL1B. All CD4+ cell subsets had increased expression of S100A8/9 alarmin genes involved in NLRP3 inflammasome activation. In IL-11R+-sorted cells from the CSF, classical and intermediate monocytes significantly up-regulated the expression of multiple NLRP3 inflammasome-related genes, including complement, IL18, and migratory genes (VEGFA/B) in comparison to blood-derived cells. Therapeutic targeting of this pathway with αIL-11 mAb in mice with RR experimental autoimmune encephalomyelitis (EAE) decreased clinical scores, CNS inflammatory infiltrates, and demyelination. αIL-11 mAb treatment decreased the numbers of NFκBp65+, NLRP3+, and IL-1ß+ monocytes in the CNS of mice with EAE. The results suggest that IL-11/IL-11R signaling in monocytes represents a therapeutic target in RRMS.
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Encefalomielitis Autoinmune Experimental , Inflamasomas , Animales , Ratones , Inflamasomas/metabolismo , Monocitos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Leucocitos Mononucleares/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Sistema Nervioso Central/metabolismo , Movimiento CelularRESUMEN
Emerging evidence has indicated the aberrant expression of PIWI-interacting RNAs (piRNAs) in human cancer cells to regulate tumor development and progression by governing cancer cell stemness. Herein, we identified downregulation of piR-2158 in human breast cancer tumors, especially in ALDH+ breast cancer stem cells (BCSCs) from patients and cell lines, which was further validated in two types of genetically engineered mouse models of breast cancer (MMTV-Wnt and MMTV-PyMT). Enforced overexpression of piR-2158 in basal-like or luminal subtypes of breast cancer cells suppressed cell proliferation, migration, epithelial-mesenchymal transition (EMT) and stemness in vitro. Administration of a dual mammary tumor-targeting piRNA delivery system in mice reduced tumor growth in vivo. RNA-seq, ChIP-seq and luciferase reporter assays demonstrated piR-2158 as a transcriptional repressor of IL11 by competing with AP-1 transcription factor subunit FOSL1 to bind the promoter of IL11. STAT3 signaling mediated piR-2158-IL11 regulation of cancer cell stemness and tumor growth. Moreover, by co-culturing of MDA-MB-231 and HUVECs in vitro and CD31 staining of tumor endothelial cells in vivo, we demonstrated inhibition of angiogenesis by piR-2158-IL11 in breast cancer. In conclusion, the current study not only reveals a novel mechanism through which piR-2158 inhibits mammary gland tumorigenesis via regulating cancer stem cells and tumor angiogenesis, but also provides a novel therapeutic strategy in treatment of breast cancer.
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Neoplasias de la Mama , Humanos , Ratones , Animales , Femenino , Neoplasias de la Mama/patología , Interleucina-11/genética , Células Endoteliales/metabolismo , Transducción de Señal , Mama/patología , Factores de Transcripción/metabolismo , Células Madre Neoplásicas/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión GénicaRESUMEN
All except one cytokine of the Interleukin (IL-)6 family share glycoprotein (gp) 130 as the common ß receptor chain. Whereas Interleukin (IL-)11 signal via the non-signaling IL-11 receptor (IL-11R) and gp130 homodimers, leukemia inhibitory factor (LIF) recruits gp130:LIF receptor (LIFR) heterodimers. Using IL-11 as a framework, we exchange the gp130-binding site III of IL-11 with the LIFR binding site III of LIF. The resulting synthetic cytokimera GIL-11 efficiently recruits the non-natural receptor signaling complex consisting of gp130, IL-11R and LIFR resulting in signal transduction and proliferation of factor-depending Ba/F3 cells. Besides LIF and IL-11, GIL-11 does not activate receptor complexes consisting of gp130:LIFR or gp130:IL-11R, respectively. Human GIL-11 shows cross-reactivity to mouse and rescued IL-6R-/- mice following partial hepatectomy, demonstrating gp130:IL-11R:LIFR signaling efficiently induced liver regeneration. With the development of the cytokimera GIL-11, we devise the functional assembly of the non-natural cytokine receptor complex of gp130:IL-11R:LIFR.
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Hepatectomía , Interleucina-11 , Ratones , Animales , Humanos , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/metabolismo , Interleucina-11/genética , Receptores de Interleucina-11 , Antígenos CD/metabolismo , Interleucina-6/metabolismo , Transducción de Señal , Subunidad alfa del Receptor del Factor Inhibidor de LeucemiaRESUMEN
The study of the role of cytokines in various pathological conditions of the body is a topical area in modern biomedicine. Understanding the physiological roles played by cytokines will aid in finding applications for them as pharmacological agents in clinical practice. Interleukin 11 (IL-11) was discovered in 1990 in fibrocyte-like bone marrow stromal cells, but there has been increased interest in this cytokine in recent years. IL-11 has been shown to correct inflammatory pathways in the epithelial tissues of the respiratory system, where the main events occur during SARS-CoV-2 infection. Further research in this direction will probably support the use of this cytokine in clinical practice. The cytokine plays a significant role in the central nervous system; local expression by nerve cells has been shown. Studies show the involvement of IL-11 in the mechanisms of development of a number of pathologies of the nervous system, and therefore it seems relevant to generalize and analyze the experimental data obtained in this direction. This review summarizes information that shows the involvement of IL-11 in the mechanisms of development of brain pathologies. In the near future this cytokine will likely find clinical application for the correction of mechanisms that are involved in the formation of pathological conditions of the nervous system.
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COVID-19 , Interleucina-11 , Humanos , Antígenos CD/metabolismo , COVID-19/genética , Receptor gp130 de Citocinas , Citocinas/farmacología , Interleucina-11/genética , Sistema Nervioso/metabolismo , SARS-CoV-2/metabolismoRESUMEN
BACKGROUND: Marfan Syndrome (MFS) is an inherited connective tissue disorder caused by mutations in the FBN1 (fibrillin-1) gene. Lung abnormalities are common in MFS, but their pathogenesis is poorly understood. IL11 (interleukin-11) causes aortic disease in a mouse model of MFS and was studied here in the lung. METHODS: We examined histological and molecular phenotypes in the lungs of Fbn1C1041G/+ mice (mouse model of Marfan Syndrome [mMFS]), an established mouse model of MFS. To identify IL11-expressing cells, we used immunohistochemistry on lungs of 4- and 16-week-old Fbn1C1041G/+:Il11EGFP/+ reporter mice. We studied the effects of IL11 inhibition by RT-qPCR, immunoblots and histopathology in lungs from genetic or pharmacologic models: (1) 16-week-old IL11 receptor (IL11RA) knockout mMFS mice (Fbn1C1041G/+:Il11ra1-/- mice) and (2) in mMFS mice administered IgG control or interleukin-11 receptor antibodies twice weekly from 4 to 24 weeks of age. RESULTS: mMFS lungs showed progressive loss and enlargement of distal airspaces associated with increased proinflammatory and profibrotic gene expression as well as matrix metalloproteinases 2, 9, and 12. IL11 was increased in mMFS lungs and localized to smooth muscle and endothelial cells in young mMFS mice in the Fbn1C1041G/+:Il11EGFP/+ reporter strain and in fibroblasts, in older mice. In mMFS mice, genetic (Fbn1C1041G/+:Il11ra1-/-) or pharmacologic (anti-interleukin-11 receptor) inhibition of IL11 signaling reduced lung emphysema, fibrosis, and inflammation. This protective effect was associated with reduced pathogenic ERK1/2 signaling and lower metalloproteinase 2, 9, and 12 expression. CONCLUSIONS: IL11 causes lung disease in mMFS. This reveals a shared IL11-driven disease mechanism in lung and aorta in MFS and suggests inhibition of IL11 signaling as a holistic approach for treating multiorgan morbidity in MFS.
Asunto(s)
Interleucina-11 , Síndrome de Marfan , Enfisema Pulmonar , Animales , Ratones , Modelos Animales de Enfermedad , Células Endoteliales/metabolismo , Fibrilina-1/genética , Interleucina-11/genética , Subunidad alfa del Receptor de Interleucina-11 , Síndrome de Marfan/complicaciones , Síndrome de Marfan/genética , Síndrome de Marfan/patología , Metaloproteinasa 2 de la Matriz/genética , Ratones Noqueados , Enfisema Pulmonar/complicaciones , Enfisema Pulmonar/genéticaRESUMEN
Tracheal stenosis (TS) is a multifactorial and heterogeneous disease that can easily lead to respiratory failure and even death. Interleukin-11 (IL-11) has recently received increased attention as a fibrogenic factor, but its function in TS is uncertain. This study aimed to investigate the role of IL-11 in TS regulation based on clinical samples from patients with TS and a rat model of TS produced by nylon brush scraping. Using lentiviral vectors expressing shRNA (lentivirus-shRNA) targeting the IL-11 receptor (IL-11Rα), we lowered IL-11Rα levels in the rat trachea. Histological and immunostaining methods were used to evaluate the effects of IL-11Rα knockdown on tracheal injury, molecular phenotype, and fibrosis in TS rats. We show that IL-11 was significantly elevated in circulating serum and granulation tissue in patients with TS. In vitro, TGFß1 dose-dependently stimulated IL-11 secretion from human tracheal epithelial cells (Beas-2b) and primary rat tracheal fibroblasts (PRTF). IL-11 transformed the epithelial cell phenotype to the mesenchymal cell phenotype by activating the ß-catenin pathway. Furthermore, IL-11 activated the atypical ERK signaling pathway, stimulated fibroblasts proliferation, and transformed fibroblasts into alpha-smooth muscle actin (α-SMA) positive myofibroblasts. IL-11-neutralizing antibodies (IL-11NAb) or ERK inhibitors (U0126) inhibited IL-11 activity and downregulated fibrotic responses involving TGFß/SMAD signaling. In vivo, IL-11Rα knockdown rats showed unobstructed tracheal lumen, relatively intact epithelial structure, and significantly reduced granulation tissue proliferation and collagen fiber deposition. Our findings confirm that IL-11 may be a target for future drug prevention and treatment of tracheal stenosis.
Asunto(s)
Tráquea , Estenosis Traqueal , Humanos , Ratas , Animales , Tráquea/metabolismo , Tráquea/patología , Estenosis Traqueal/genética , Estenosis Traqueal/tratamiento farmacológico , Estenosis Traqueal/metabolismo , Interleucina-11/genética , Interleucina-11/metabolismo , Fibrosis , Células Epiteliales/metabolismo , Fibroblastos/metabolismo , FenotipoRESUMEN
Exercise results in mechanical loading of the bone and stimulates energy expenditure in the adipose tissue. It is therefore likely that the bone secretes factors to communicate with adipose tissue in response to mechanical loading. Interleukin (IL)-11 is known to be expressed in the bone, it is upregulated by mechanical loading, enhances osteogenesis and suppresses adipogenesis. Here, we show that systemic IL-11 deletion (IL-11-/-) results in reduced bone mass, suppressed bone formation response to mechanical loading, enhanced expression of Wnt inhibitors, and suppressed Wnt signaling. At the same time, the enhancement of bone resorption by mechanical unloading was unaffected. Unexpectedly, IL-11-/- mice have increased systemic adiposity and glucose intolerance. Osteoblast/osteocyte-specific IL-11 deletion in osteocalcin-Cre;IL-11fl/fl mice have reduced serum IL-11 levels, blunted bone formation under mechanical loading, and increased systemic adiposity similar to IL-11-/- mice. Adipocyte-specific IL-11 deletion in adiponectin-Cre;IL-11fl/fl did not exhibit any abnormalities. We demonstrate that osteoblast/osteocyte-derived IL-11 controls both osteogenesis and systemic adiposity in response to mechanical loading, an important insight for our understanding of osteoporosis and metabolic syndromes.
Asunto(s)
Interleucina-11 , Osteocitos , Osteogénesis , Animales , Ratones , Adipogénesis , Interleucina-11/genética , Obesidad , Osteoblastos , Ratones NoqueadosRESUMEN
BACKGROUND: Pulmonary hypertension (PH) associated to idiopathic pulmonary fibrosis (IPF) portends a poor prognosis. IL-11 has been implicated in fibrotic diseases, but their role on pulmonary vessels is unknown. Here we analyzed the contribution of IL-11 to PH in patients with IPF and the potential mechanism implicated. METHODS: Pulmonary arteries, lung tissue and serum of control subjects (n = 20), IPF (n = 20) and PH associated to IPF (n = 20) were used to study the expression and localization of IL-11 and IL-11Rα. Two models of IL-11 and bleomycin-induced lung fibrosis associated to PH were used in Tie2-GFP transgenic mice to evaluate the contribution of IL-11 and endothelial cells to pulmonary artery remodeling. The effect of IL-11 and soluble IL-11Rα on human pulmonary artery endothelial cells and smooth muscle cell transformations and proliferation were analyzed. RESULTS: IL-11 and IL-11Rα were over-expressed in pulmonary arteries and serum of patients with PH associated to IPF vs IPF patients without PH. Recombinant mice (rm)IL-11 induced lung fibrosis and PH in Tie2-GFP mice, activating in vivo EnMT as a contributor of pulmonary artery remodeling and lung fibrosis. Transient transfection of siRNA-IL-11 reduced lung fibrosis and PH in Tie2-GFP bleomycin model. Human (h)rIL-11 and soluble hrIL-11Rα induced endothelial to mesenchymal transition (EnMT) and pulmonary artery smooth muscle cell to myofibroblast-like transformation, cell proliferation and senescence in vitro. CONCLUSIONS: IL-11 and IL-11Rα are overexpressed in pulmonary arteries of PH associated to IPF patients, and contributes to pulmonary artery remodeling and PH.
Asunto(s)
Hipertensión Pulmonar , Fibrosis Pulmonar Idiopática , Animales , Humanos , Ratones , Bleomicina/toxicidad , Células Endoteliales/metabolismo , Hipertensión Pulmonar/metabolismo , Fibrosis Pulmonar Idiopática/inducido químicamente , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/complicaciones , Interleucina-11/genética , Interleucina-11/metabolismo , Interleucina-11/farmacología , Pulmón/metabolismo , Arteria Pulmonar/metabolismo , Remodelación VascularRESUMEN
PURPOSE: To uncover the role of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)/runt-related transcription factor 2 (RUNX2)/interleukin-11 (IL-11) pathway in the activation of Müller glial cells (MGCs) and the breakdown of blood-retina barrier (BRB) during diabetic retinopathy (DR). METHODS: Western blot (WB) detected the activation of MEK/ERK/RUNX2/IL-11 pathway, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) detected IL-11 mRNA levels in high glucose (HG)-exposed MIO-M1 cells. Co-immunoprecipitation (Co-IP) identified the interaction between ERK and RUNX2. Immunofluorescence (IF) measured the co-localization of ERK and RUNX2. Luciferase reporter gene assay identified the transcription activity of IL-11 promoter under HG conditions. Enzyme-linked immunosorbent assay (ELISA) detected IL-11 levels in MIO-M1 cell culture supernatant. WB detected IL-RA protein levels, and Immunofluorescence measured the co-localization of IL-11 and IL-11RA. WB detected MGCs activation marker glial fibrillary acidic protein (GFAP) protein levels. 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay detected the proliferation of MGCs. WB detected the activation of MEK/ERK/RUNX2/IL-11 pathway in streptozotocin (STZ)-induced diabetic mice. ELISA detected IL-11 and IL-11RA levels in mouse retina tissues. QRT-PCR and WB detected tight junction-associated molecules claudin-5, occluding and tight junction protein 1 (ZO-1) mRNA and protein levels in mouse retina tissues, respectively. RESULTS: MEK/ERK/RUNX2/IL-11 pathway was activated in HG-exposed MIO-M1 cells. Additionally, IL-11 bound to IL-11RA on MIO-M1 cells to promote MIO-M1 cell activation and proliferation. In the mouse STZ-induced diabetic model, MEK/ERK/RUNX2/IL-11/IL-11RA pathway was also activated. Finally, the blockade of the pathway mitigated the activation of MGCs and the breakdown of BRB. CONCLUSION: The data suggested that activated MEK/ERK/RUNX2/IL-11/IL-11RA autocrine pathway can promote the activation of MGCs and the breakdown of BRB during DR, implying novel anti-molecular strategies for the treatment of DR.