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Abstract Objective To explore IL11 co-expression profiles in our previously reported RNA-sequencing dataset of OA articular cartilage, in interaction with IL6, and to investigate the effects of hrIL11 administration as potential therapeutic strategy for OA articular cartilage using our biomimetic aged human osteochondral explant model of OA. Methods We used RNA-sequencing datasets of macroscopically preserved and lesioned OA articular cartilage (N = 35 patients). Spearman correlations were calculated between IL11 and IL6 expression levels and genes expressed in cartilage (N = 20048 genes). Osteochondral explants were isolated from macroscopically preserved and lesioned areas of the joint and were kept in culture for two weeks, with or without exposure to 200ng/ml hrIL11. Results We found no overlap in correlating genes between IL11 and IL6, indicating their distinct roles in articular cartilage. Moreover, we identified more genes being correlated to IL11 in the lesioned compared to preserved articular cartilage (N = 203 and 106 genes, respectively). Upon treatment of ex vivo OA articular cartilage with hrIL11, we overall observed unbeneficial effects on chondrocyte phenotype, as illustrated by upregulation of MMP13, EPAS1, RUNX2, and POSTN. We did not observe significant differences in Mankin scores upon addition of hrIL11. Conclusion The current study showed that treatment of OA articular cartilage with hrIL11 is unlikely to be beneficial despite previous indications of hrIL11 as potential druggable target. These findings underscore the importance of functionally investigating OA risk genes. Better understanding of IL11 signaling and the underlying pathways is necessary towards the development of OA treatment strategy.

Nearly every fifth adult in the United States and many older adults worldwide are affected by chronic kidney disease (CKD), which can progress to kidney failure requiring invasive kidney replacement therapy. In this review, we briefly examine the pathophysiology of CKD and discuss emerging mechanisms involving the physiological resolution of kidney injury by transforming growth factor beta 1 (TGFβ1) and interleukin-11 (IL-11), as well as the pathological consequences of IL-11 overproduction, which misguides repair processes, ultimately culminating in CKD. Taking these mechanisms into account, we offer an overview of the efficacy of plant-dominant dietary patterns in preventing and managing CKD, while also addressing their limitations in terms of restoring kidney function or preventing kidney failure. In conclusion, this paper outlines novel regeneration strategies aimed at developing a reno-regenerative diet to inhibit IL-11 and promote repair mechanisms in kidneys affected by CKD. [ABSTRACT FROM AUTHOR]

Jiaming He,1,2,* Tiankuo Luan,3,* Gang Zhao,4 Yingxue Yang5 1Laboratory of Stem Cells and Tissue Engineering, Department of Histology and Embryology, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Department of Anatomy, Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Gastroenterology, Wushan County People’s Hospital of Chongqing, Chongqing, 404700, People’s Republic of China; 5Department of Gastroenterology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingxue Yang, Email yangyingxue@hospital.cqmu.edu.cnBackground: The objective is to create an IRGPI (Immune-related genes prognostic index), which could predict the survival and effectiveness of immune checkpoint inhibitor (ICI) treatment for lung adenocarcinoma (LUAD).Methods: By applying weighted gene co-expression network analysis (WGCNA), we ascertained 13 genes associated with immune functions. An IRGPI was constructed using four genes through multicox regression, and its validity was assessed in the GEO dataset. Next, we explored the immunological and molecular attributes and advantages of ICI treatment in subcategories delineated by IRGPI. The model genes were also validated by the random forest tree, and functional experiments were conducted to validate it.Results: The IRGPI relied on the genes CD79A, IL11, CTLA-4, and CD27. Individuals categorized as low-risk exhibited significantly improved overall survival in comparison to those classified as high-risk. Extensive findings indicated that the low-risk category exhibited associations with immune pathways, significant infiltration of CD8 T cells, M1 macrophages, and CD4 T cells, a reduced rate of gene mutations, and improved sensitivity to ICI therapy. Conversely, the higher-risk group displayed metabolic signals, elevated frequencies of TP53, KRAS, and KEAP1 mutations, escalated levels of NK cells, M0, and M2 macrophage infiltration, and a diminished response to ICI therapy. Additionally, our study unveiled that the downregulation of IL11 effectively impedes the proliferation and migration of lung carcinoma cells, while also inducing cell cycle arrest.Conclusion: IRGPI is a biomarker with significant potential for predicting the effectiveness of ICI treatment in LUAD patients and is closely related to the microenvironment and clinicopathological characteristics. Keywords: lung adenocarcinoma, immune-related genes, bioinformatics, prognostic index, IL11

Abstract Macrophage filopodia, which are dynamic nanotube-like protrusions, have mainly been studied in the context of pathogen clearance. The mechanisms by which they facilitate intercellular communication and mediate tissue inflammation remain poorly understood. Here, we show that macrophage filopodia produce a unique membrane structure called “filopodial tip vesicle” (FTV) that originate from the tip of macrophages filopodia. Filopodia tip-derived particles contain numerous internal-vesicles and function as cargo storage depots via nanotubular transport. Functional studies indicate that the shedding of FTV from filopodia tip allows the delivery of many molecular signalling molecules to fibroblasts. We observed that FTV derived from M1 macrophages and high glucose (HG)-stimulated macrophages (HG/M1-ftv) exhibit an enrichment of the chemokine IL11, which is critical for fibroblast transdifferentiation. HG/M1-ftv induce renal interstitial fibrosis in diabetic mice, while FTV inhibition or targeting FTV IL11- alleviates renal interstitial fibrosis, suggesting that the HG/M1-ftv IL11 pathway may be a novel mechanism underlying renal fibrosis in diabetic nephropathy. Collectively, FTV release could represent a novel function by which filopodia contribute to cell biological processes, and FTV is potentially associated with macrophage filopodia-related fibrotic diseases. Video Abstract

IL6 is a proinflammatory cytokine that binds to membrane-bound IL6 receptor (IL6R) or soluble IL6R to signal via gp130 in cis or trans, respectively. We tested the hypothesis that sgp130Fc, which is believed to be a selective IL6 trans-signalling inhibitor, is in fact a non-specific inhibitor of gp130 signalling. In human cancer and primary cells, sgp130Fc inhibited IL6, IL11, OSM and CT1 cis-signalling. The IC50 values of sgp130Fc for IL6 and OSM cis-signalling were markedly (20- to 200-fold) lower than the concentrations of sgp130Fc used in mouse studies and clinical trials. sgp130 inhibited IL6 and OSM signalling in the presence of an ADAM10/17 inhibitor and the absence of soluble IL6R or OSMR, with effects that were indistinguishable from those of a gp130 neutralising antibody. These data show that sgp130Fc does not exclusively block IL6 trans-signalling and reveal instead that broad inhibition of gp130 signalling likely underlies its therapeutic effects. This proposes global or modular inhibition of gp130 as a therapeutic approach for treating human disease. [ABSTRACT FROM AUTHOR]

Abstract Background The pathogenic mechanisms shared between kidney stones and diabetes at the transcriptional level remain elusive, and the molecular mechanisms by which resveratrol exerts its protective effects against these conditions require further investigation. Methods To address these gaps in knowledge, we conducted a comprehensive analysis of microarray and RNA-seq datasets to elucidate shared biomarkers and biological pathways involved in the pathogenesis of kidney stones and diabetes. An assortment of bioinformatic approaches was employed to illuminate the common molecular markers and associated pathways, thereby contributing to the identification of innovative therapeutic targets. Further investigation into the molecular mechanisms of resveratrol in preventing these conditions was conducted using molecular docking simulation and first-principles calculations. Results The study identified 11 potential target genes associated with kidney stones and diabetes through the intersection of genes from weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs) screening. Among these, Interleukin 11 (IL11) emerged as a pivotal hub gene and a potential diagnostic biomarker for both conditions, particularly in males. Expression analysis of IL11 demonstrated elevated levels in kidney stones and diabetes groups compared to controls. Additionally, IL11 exhibited correlations with specific cell types and differential expression in normal and pathological conditions. Gene set enrichment analysis (GSEA) highlighted significant disparities in biological processes, pathways, and immune signatures associated with IL11. Moreover, molecular docking simulation of resveratrol towards IL11 and a first-principles investigation of Ca adsorption on the resveratrol surface provided structural evidence for the development of resveratrol-based drugs for these conditions. Conclusions Overall, this investigation illuminates the discovery of common molecular mechanisms underlying kidney stones and diabetes, unveils potential diagnostic biomarkers, and elucidates the significance of IL11 in these conditions. It also provides insights into IL11 as a promising therapeutic target and highlights the role of resveratrol. Nonetheless, further research is warranted to enhance our understanding of IL11 targeting mechanisms and address any limitations in the study.

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFβ. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFβ signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFβ at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFβ-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.

Bone allografts are widely used as osteoconductive support to guide bone regrowth. Bone allografts are more than a scaffold for the immigrating cells as they maintain some bioactivity of the original bone matrix. Yet, it remains unclear how immigrating cells respond to bone allografts. To this end, we have evaluated the response of mesenchymal cells exposed to acid lysates of bone allografts (ALBA). RNAseq revealed that ALBA has a strong impact on the genetic signature of gingival fibroblasts, indicated by the increased expression of IL11, AREG, C11orf96, STC1, and GK—as confirmed by RT-PCR, and for IL11 and STC1 by immunoassays. Considering that transforming growth factor-β (TGF-β) is stored in the bone matrix and may have caused the expression changes, we performed a proteomics analysis, TGF-β immunoassay, and smad2/3 nuclear translocation. ALBA neither showed detectable TGF-β nor was the lysate able to induce smad2/3 translocation. Nevertheless, the TGF-β receptor type I kinase inhibitor SB431542 significantly decreased the expression of IL11, AREG, and C11orf96, suggesting that other agonists than TGF-β are responsible for the robust cell response. The findings suggest that IL11, AREG, and C11orf96 expression in mesenchymal cells can serve as a bioassay reflecting the bioactivity of the bone allografts. [ABSTRACT FROM AUTHOR]

Macrophage filopodia, which are dynamic nanotube-like protrusions, have mainly been studied in the context of pathogen clearance. The mechanisms by which they facilitate intercellular communication and mediate tissue inflammation remain poorly understood. Here, we show that macrophage filopodia produce a unique membrane structure called "filopodial tip vesicle" (FTV) that originate from the tip of macrophages filopodia. Filopodia tip-derived particles contain numerous internal-vesicles and function as cargo storage depots via nanotubular transport. Functional studies indicate that the shedding of FTV from filopodia tip allows the delivery of many molecular signalling molecules to fibroblasts. We observed that FTV derived from M1 macrophages and high glucose (HG)-stimulated macrophages (HG/M1-ftv) exhibit an enrichment of the chemokine IL11, which is critical for fibroblast transdifferentiation. HG/M1-ftv induce renal interstitial fibrosis in diabetic mice, while FTV inhibition or targeting FTV IL11- alleviates renal interstitial fibrosis, suggesting that the HG/M1-ftvIL11 pathway may be a novel mechanism underlying renal fibrosis in diabetic nephropathy. Collectively, FTV release could represent a novel function by which filopodia contribute to cell biological processes, and FTV is potentially associated with macrophage filopodia-related fibrotic diseases. 8XMabVtTRQ4kBojsCRSFmY Video Abstract [ABSTRACT FROM AUTHOR]

Damaged cells that appear as a consequence of invasive dental procedures or in response to dental materials are supposed to release damage-associated signals. These damage-associated signals not only support tissue regeneration but might also contribute to unwanted fibrosis. The aim of this study was to identify a molecular target that reflects how fibroblasts respond to necrotic oral tissue cells. To simulate the cell damage, we prepared necrotic cell lysates by sonication of the osteocytic cell line IDG-SW3 and exposed them to gingival fibroblasts. RNAseq revealed a moderate increase in IL11 expression in the gingival fibroblasts, a pleiotropic cytokine involved in fibrosis and inflammation, and also in regeneration following trauma. Necrotic lysates of the human squamous carcinoma cell lines HSC2 and TR146, as well as of gingival fibroblasts, however, caused a robust increase in IL11 expression in the gingival fibroblasts. Consistently, immunoassay revealed significantly increased IL11 levels in the gingival fibroblasts when exposed to the respective lysates. Considering that IL11 is a TGF-β target gene, IL11 expression was partially blocked by SB431542, a TGF-β receptor type I kinase inhibitor. Moreover, lysates from the HSC2, TR146, and gingival fibroblasts caused a moderate smad2/3 nuclear translocation in the gingival fibroblasts. Taken together and based on IL11 expression, our findings show that fibroblasts are sensitive to damaged oral tissue cells. [ABSTRACT FROM AUTHOR]

SARS-CoV-2, the cause of the COVID-19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood. In this study, transcriptomics analysis revealed that both WNT5A and IL11 were significantly up-regulated in A549 cells expressing individual accessory proteins ORF6, ORF8, ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate). IL11 is a member of the IL6 family of cytokines. IL11 signaling-related genes were also differentially expressed. Bioinformatics analysis disclosed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease and functional assays confirmed their association with profibrotic cell responses. Subsequently, data comparison with lung cell lines infected with SARS-CoV-2 or lung biopsies from patients with COVID-19, evidenced altered profibrotic gene expression that matched those obtained in this study. Our results show ORF6, ORF8, ORF9b and ORF9c involvement in inflammatory and profibrotic responses. Thus, these accessory proteins could be targeted by new therapies against COVID-19 disease. [ABSTRACT FROM AUTHOR]

Background: The pathogenic mechanisms shared between kidney stones and diabetes at the transcriptional level remain elusive, and the molecular mechanisms by which resveratrol exerts its protective effects against these conditions require further investigation. Methods: To address these gaps in knowledge, we conducted a comprehensive analysis of microarray and RNA-seq datasets to elucidate shared biomarkers and biological pathways involved in the pathogenesis of kidney stones and diabetes. An assortment of bioinformatic approaches was employed to illuminate the common molecular markers and associated pathways, thereby contributing to the identification of innovative therapeutic targets. Further investigation into the molecular mechanisms of resveratrol in preventing these conditions was conducted using molecular docking simulation and first-principles calculations. Results: The study identified 11 potential target genes associated with kidney stones and diabetes through the intersection of genes from weighted gene co-expression network analysis (WGCNA) and differentially expressed genes (DEGs) screening. Among these, Interleukin 11 (IL11) emerged as a pivotal hub gene and a potential diagnostic biomarker for both conditions, particularly in males. Expression analysis of IL11 demonstrated elevated levels in kidney stones and diabetes groups compared to controls. Additionally, IL11 exhibited correlations with specific cell types and differential expression in normal and pathological conditions. Gene set enrichment analysis (GSEA) highlighted significant disparities in biological processes, pathways, and immune signatures associated with IL11. Moreover, molecular docking simulation of resveratrol towards IL11 and a first-principles investigation of Ca adsorption on the resveratrol surface provided structural evidence for the development of resveratrol-based drugs for these conditions. Conclusions: Overall, this investigation illuminates the discovery of common molecular mechanisms underlying kidney stones and diabetes, unveils potential diagnostic biomarkers, and elucidates the significance of IL11 in these conditions. It also provides insights into IL11 as a promising therapeutic target and highlights the role of resveratrol. Nonetheless, further research is warranted to enhance our understanding of IL11 targeting mechanisms and address any limitations in the study. [ABSTRACT FROM AUTHOR]

SARS-CoV-2, the cause of the COVID-19 pandemic, possesses eleven accessory proteins encoded in its genome. Their roles during infection are still not completely understood. In this study, transcriptomics analysis revealed that both WNT5A and IL11 were significantly up-regulated in A549 cells expressing individual accessory proteins ORF6, ORF8, ORF9b or ORF9c from SARS-CoV-2 (Wuhan-Hu-1 isolate). IL11 is a member of the IL6 family of cytokines. IL11 signaling-related genes were also differentially expressed. Bioinformatics analysis disclosed that both WNT5A and IL11 were involved in pulmonary fibrosis idiopathic disease and functional assays confirmed their association with profibrotic cell responses. Subsequently, data comparison with lung cell lines infected with SARS-CoV-2 or lung biopsies from patients with COVID-19, evidenced altered profibrotic gene expression that matched those obtained in this study. Our results show ORF6, ORF8, ORF9b and ORF9c involvement in inflammatory and profibrotic responses. Thus, these accessory proteins could be targeted by new therapies against COVID-19 disease.

Introduction: Interstitial lung disease (ILD) is a heterogenous group of lung disorders where destruction and incomplete regeneration of the lung parenchyma often results in persistent architectural distortion of the pulmonary scaffold. Continuous mesenchyme-centered, disease-relevant signaling likely initiates and perpetuates the fibrotic remodeling process, specifically targeting the epithelial cell compartment, thereby destroying the gas exchange area. Methods: With the aim of identifying functional mediators of the lung mesenchymal-epithelial crosstalk with potential as new targets for therapeutic strategies, we developed a 3D organoid co-culture model based on human induced pluripotent stem cell-derived alveolar epithelial type 2 cells that form alveolar organoids in presence of lung fibroblasts fromfibrotic-ILD patients, in our study referring to cases of pulmonary fibrosis, as well as control cell line (IMR-90). Results: While organoid formation capacity and size was comparable in the presence of fibrotic-ILD or control lung fibroblasts, metabolic activity was significantly increased in fibrotic-ILD co-cultures. Alveolar organoids cultured with fibrotic-ILD fibroblasts further demonstrated reduced stem cell function as reflected by reduced Surfactant Protein C gene expression together with an aberrant basaloid-prone differentiation program indicated by elevated Cadherin 2, Bone Morphogenic Protein 4 and Vimentin transcription. To screen for key mediators of the misguided mesenchymal-to-epithelial crosstalk with a focus on disease-relevant inflammatory processes, we used mass spectrometry and characterized the secretome of end stage fibrotic-ILD lung fibroblasts in comparison to non-chronic lung disease (CLD) patient fibroblasts. Out of the over 2000 proteins detected by this experimental approach, 47 proteins were differentially abundant comparing fibrotic-ILD and non-CLD fibroblast secretome. The fibrotic-ILD secretome profile was dominated by chemokines, including CXCL1, CXCL3, and CXCL8, interfering with growth factor signaling orchestrated by Interleukin 11 (IL11), steering fibrogenic cell-cell communication, and proteins regulating extracellular matrix remodeling including epithelial-tomesenchymal transition. When in turn treating alveolar organoids with IL11, we recapitulated the co-culture results obtained with primary fibrotic-ILD fibroblasts including changes in metabolic activity. Conclusion: We identified mediators likely contributing to the diseaseperpetuating mesenchymal-to-epithelial crosstalk in ILD. In our alveolar organoid co-cultures, we were able to highlight the importance of fibroblastinitiated aberrant epithelial differentiation and confirmed IL11 as a key player in fibrotic-ILD pathogenesis by unbiased fibroblast secretome analysis. [ABSTRACT FROM AUTHOR]

IntroductionInterstitial lung disease (ILD) is a heterogenous group of lung disorders where destruction and incomplete regeneration of the lung parenchyma often results in persistent architectural distortion of the pulmonary scaffold. Continuous mesenchyme-centered, disease-relevant signaling likely initiates and perpetuates the fibrotic remodeling process, specifically targeting the epithelial cell compartment, thereby destroying the gas exchange area.MethodsWith the aim of identifying functional mediators of the lung mesenchymal-epithelial crosstalk with potential as new targets for therapeutic strategies, we developed a 3D organoid co-culture model based on human induced pluripotent stem cell-derived alveolar epithelial type 2 cells that form alveolar organoids in presence of lung fibroblasts from fibrotic-ILD patients, in our study referring to cases of pulmonary fibrosis, as well as control cell line (IMR-90).ResultsWhile organoid formation capacity and size was comparable in the presence of fibrotic-ILD or control lung fibroblasts, metabolic activity was significantly increased in fibrotic-ILD co-cultures. Alveolar organoids cultured with fibrotic-ILD fibroblasts further demonstrated reduced stem cell function as reflected by reduced Surfactant Protein C gene expression together with an aberrant basaloid-prone differentiation program indicated by elevated Cadherin 2, Bone Morphogenic Protein 4 and Vimentin transcription. To screen for key mediators of the misguided mesenchymal-to-epithelial crosstalk with a focus on disease-relevant inflammatory processes, we used mass spectrometry and characterized the secretome of end stage fibrotic-ILD lung fibroblasts in comparison to non-chronic lung disease (CLD) patient fibroblasts. Out of the over 2000 proteins detected by this experimental approach, 47 proteins were differentially abundant comparing fibrotic-ILD and non-CLD fibroblast secretome. The fibrotic-ILD secretome profile was dominated by chemokines, including CXCL1, CXCL3, and CXCL8, interfering with growth factor signaling orchestrated by Interleukin 11 (IL11), steering fibrogenic cell-cell communication, and proteins regulating extracellular matrix remodeling including epithelial-to-mesenchymal transition. When in turn treating alveolar organoids with IL11, we recapitulated the co-culture results obtained with primary fibrotic-ILD fibroblasts including changes in metabolic activity.ConclusionWe identified mediators likely contributing to the disease-perpetuating mesenchymal-to-epithelial crosstalk in ILD. In our alveolar organoid co-cultures, we were able to highlight the importance of fibroblast-initiated aberrant epithelial differentiation and confirmed IL11 as a key player in fibrotic-ILD pathogenesis by unbiased fibroblast secretome analysis.

Cell senescence is one of the most important forms of injury induced by cardiovascular and other ischemic diseases. Fibroblasts are important participants in tissue repair after ischemic injury and the main source of IL11 secretion. However, the roles of oxygen–glucose deprivation (OGD) and IL11 in promoting fibroblast senescence and their regulatory mechanisms remain unclear. This study selected the NIH3T3 and L929 fibroblast cell lines as research objects. We found that OGD could induce the expression of p53, P16, p21, and collagen in fibroblasts. In the condition of OGD, when IL11 intervened, fibroblasts' senescence and collagen expression were changed. Some studies have found that changes in kynurenine (KYN) metabolism are related to aging diseases, and indoleamine 2,3-dioxygenase 1 (IDO1) is a key rate-limiting enzyme in the KYN metabolic pathway. We found that KYN secretion decreased after OGD increased fibroblast senescence, and inhibition of IL11 promoted IDO1 and increased KYN secretion. These results suggest that OGD may promote fibroblast senescence and collagen expression via IL11 inhibition of the IDO1/KYN metabolic pathway. Therefore, the revealed mechanism of OGD-promoted fibroblast senescence could provide an effective theoretical basis for the clinical treatment of aging-related ischemic diseases. [ABSTRACT FROM AUTHOR]

Breast cancer is one of the most lethal malignancies among women; however, the underlying molecular mechanism involved in the progression and metastasis of breast cancer remains unclear. Numerous studies have confirmed that long noncoding RNAs are abnormally expressed in breast cancer and play crucial roles in cell proliferation and metastasis. In the study, we evaluated the functional role and detailed mechanism of DGUOK-AS1 in breast cancer progression and metastasis. DGUOK-AS1 knockdown suppressed proliferation, migration, and invasion of breast cancer cells in vitro and in vivo. Mechanistically, miR-204-5p was identified as an inhibitory target of DGUOK-AS1, which served as a tumor suppressor in breast cancer. Significantly, we found that the ectopic expression of miR-204-5p could counteract DGUOK-AS1-mediated promotion of cell proliferation and metastasis in breast cancer. Moreover, IL-11 was found to be the downstream target of miR-204-5p, and DGUOK-AS1 could protect IL-11 from miR-204-5p-mediated degradation. DGUOK-AS1 overexpression promoted breast cancer cell migration, angiogenesis, and macrophage migration, mediating by the increased secretion of IL-11, which was extremely important for cancer progression. Collectively, our studies reveal that DGUOK-AS1/miR-204-5p/IL-11 axis plays a significant role in the progression and metastasis of breast cancer, and DGUOK-AS1 might be a novel biomarker and therapeutic target for breast cancer.

Interleukin-11 (IL11) is important for fibrosis and inflammation, but its role in the pancreas is unclear. In pancreatitis, fibrosis, inflammation and organ dysfunction are associated with pancreatic stellate cell (PSC)-to-myofibroblast transformation. Here, we show that IL11 stimulation of PSCs, which specifically express IL11RA in the pancreas, results in transient STAT3 phosphorylation, sustained ERK activation and PSC activation. In contrast, IL6 stimulation of PSCs caused sustained STAT3 phosphorylation but did not result in ERK activation or PSC transformation. Pancreatitis factors, including TGFβ, CTGF and PDGF, induced IL11 secretion from PSCs and a neutralising IL11RA antibody prevented PSC activation by these stimuli. This revealed an important ERK-dependent role for autocrine IL11 activity in PSCs. In mice, IL11 was increased in the pancreas after pancreatic duct ligation, and in humans, IL11 and IL11RA levels were elevated in chronic pancreatitis. Following pancreatic duct ligation, administration of anti-IL11RA to mice reduced pathologic (ERK, STAT, NF-κB) signalling, pancreatic atrophy, fibrosis and pro-inflammatory cytokine (TNFα, IL6 and IL1β) levels. This is the first description of IL11-mediated activation of PSCs, and the data suggest IL11 as a stromal therapeutic target in pancreatitis. [ABSTRACT FROM AUTHOR]

Among several interleukin (IL)-6 family members, only IL-6 and IL-11 require a gp130 protein homodimer for intracellular signaling due to lack of intracellular signaling domain in the IL-6 receptor (IL-6R) and IL-11R. We previously reported enhanced decidual IL-6 and IL-11 levels at the maternal-fetal interface with significantly higher peri-membranous IL-6 immunostaining in adjacent interstitial trophoblasts in preeclampsia (PE) vs. gestational age (GA)-matched controls. This led us to hypothesize that competitive binding of these cytokines to the gp130 impairs extravillous trophoblast (EVT) differentiation, proliferation and/or invasion. Using global microarray analysis, the current study identified inhibition of interferon-stimulated gene 15 (ISG15) as the only gene affected by both IL-6 plus IL-11 vs. control or IL-6 or IL-11 treatment of primary human cytotrophoblast cultures. ISG15 immunostaining was specific to EVTs among other trophoblast types in the first and third trimester placental specimens, and significantly lower ISG15 levels were observed in EVT from PE vs. GA-matched control placentae (p = 0.006). Induction of primary trophoblastic stem cell cultures toward EVT linage increased ISG15 mRNA levels by 7.8-fold (p = 0.004). ISG15 silencing in HTR8/SVneo cultures, a first trimester EVT cell line, inhibited invasion, proliferation, expression of ITGB1 (a cell migration receptor) and filamentous actin while increasing expression of ITGB4 (a receptor for hemi-desmosomal adhesion). Moreover, ISG15 silencing further enhanced levels of IL-1β-induced pro-inflammatory cytokines (CXCL8, IL-6 and CCL2) in HTR8/SVneo cells. Collectively, these results indicate that ISG15 acts as a critical regulator of EVT morphology and function and that diminished ISG15 expression is associated with PE, potentially mediating reduced interstitial trophoblast invasion and enhancing local inflammation at the maternal-fetal interface. Thus, agents inducing ISG15 expression may provide a novel therapeutic approach in PE.

Purpose: Autologous bone is used for augmentation in the course of oral implant placement. Bone grafts release paracrine signals that can modulate mesenchymal cell differentiation in vitro. The detailed genetic response of the bone-derived fibroblasts to these paracrine signals has remained elusive. Paracrine signals accumulate in bone-conditioned medium (BCM) prepared from porcine cortical bone chips. Materials and Methods: In this study, bone-derived fibroblasts were exposed to BCM followed by a whole genome expression profiting and downstream quantitative reverse transciptase polymerase chain reaction of the most strongly regulated genes. Results: The data show that ADM, IL11, IL33, N0X4, PRG4, and PTX3 were differentially expressed in response to BCM in bone-derived fibroblasts. The transforming growth factor beta (TGF-/3) receptor 1 antagonist SB431542 blocked the effect of BCM on the expression of the gene panel, except for IL33. Conclusion: These in vitro results extend existing evidence that cortical bone chips release paracrine signals that provoke a robust genetic response in mesenchymal cells that is not exclusively mediated via the TGF-/3 receptor. The present data provide further insights into the process of graft consolidation. [ABSTRACT FROM AUTHOR]

Objectives Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls. Methods We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping. Results In patients with SSc, serum IL11 levels are elevated as compared with healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11 receptor α-subunit and the glycoprotein 130 (gp130) co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signalling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacological inhibition of ERK. Conclusions These data reveal that autocrine IL11-dependent ERK activity alone or downstream of TGFβ stimulation promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc. [ABSTRACT FROM AUTHOR]

In fibroblasts, TGFβ1 stimulates IL11 upregulation that leads to an autocrine loop of IL11-dependent pro-fibrotic protein translation. The signaling pathways downstream of IL11, which acts via IL6ST, are contentious with both STAT3 and ERK implicated. Here we dissect IL11 signaling in fibroblasts and study IL11-dependent protein synthesis pathways in the context of approved anti-fibrotic drug mechanisms of action. We show that IL11-induced ERK activation drives fibrogenesis and while STAT3 phosphorylation (pSTAT3) is also seen, this appears unrelated to fibroblast activation. Ironically, recombinant human IL11, which has been used extensively in mouse experiments to infer STAT3 activity downstream of IL11, increases pSTAT3 in Il11ra1 null mouse fibroblasts. Unexpectedly, inhibition of STAT3 was found to induce severe proteotoxic ER stress, generalized fibroblast dysfunction and cell death. In contrast, inhibition of ERK prevented fibroblast activation in the absence of ER stress. IL11 stimulated an axis of ERK/mTOR/P70RSK protein translation and its selectivity for Collagen 1 synthesis was ascribed to an EPRS-regulated, ribosome stalling mechanism. Surprisingly, the anti-fibrotic drug nintedanib caused dose-dependent ER stress and lesser pSTAT3 expression. Pirfenidone had no effect on ER stress whereas anti-IL11 specifically inhibited the ERK/mTOR axis while reducing ER stress. These studies define the translation-specific signaling pathways downstream of IL11, intersect immune and metabolic signaling and reveal unappreciated effects of nintedanib.

Background: Islet dysfunction is the main pathological process of type 2 diabetes mellitus (T2DM). Fibrosis causes islet dysfunction, but the current mechanism is still unclear. Here, bioinformatics analysis identified gene clusters closely related to T2DM and differentially expressed genes related to fibrosis, and animal models verified the roles of these genes.Methods: Human islet transcriptomic datasets were obtained from the Gene Expression Omnibus (GEO), and weighted gene coexpression network analysis (WGCNA) was applied to screen the key gene modules related to T2DM and analyze the correlations between the modules and clinical characteristics. Enrichment analysis was performed to identify the functions and pathways of the key module genes. WGCNA, protein-protein interaction (PPI) analysis and receiver operating characteristic (ROC) curve analysis were used to screen the hub genes. The hub genes were verified in another GEO dataset, the islets of high-fat diet (HFD)-fed Sprague-Dawley rats were observed by H&E and Masson’s trichrome staining, the fibrotic proteins were verified by immunofluorescence, and the hub genes were tested by immunohistochemistry.Results: The top 5,000 genes were selected according to the median absolute deviation, and 18 modules were analyzed. The yellow module was highly associated with T2DM, and its positive correlation with glycated hemoglobin (HbA1c) was significantly stronger than that with body mass index (BMI). Enrichment analysis revealed that extracellular matrix organization, the collagen-containing extracellular matrix and cytokine−cytokine receptor interaction might influence T2DM progression. The top three hub genes, interleukin 6 (IL6), IL11 and prostaglandin-endoperoxide synthase 2 (PTGS2), showed upregulated expression in T2DM. In the validation dataset, IL6, IL11, and PTGS2 levels were upregulated in T2DM, and IL6 and PTGS2 expression was positively correlated with HbA1c and BMI; however, IL11 was positively correlated only with HbA1c. In HFD-fed Sprague-Dawley rats, the positive of IL6 and IL11 in islets was stronger, but PTGS2 expression was not significantly altered. The extent of fibrosis, irregular cellular arrangement and positive actin alpha 2 (ACTA2) staining in islets was significantly greater in HFD-fed rats than in normal diet-fed rats.Conclusion: Glucotoxicity is a major factor leading to increased IL6 and IL11 expression, and IL6-and IL11-induced fibrosis might be involved in islet dysfunction.

It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for Il11 exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kã), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kã inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kã in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kã inhibition as a glioblastoma therapy. [ABSTRACT FROM AUTHOR]

Drug repurposing is a valuable approach in delivering new cancer therapeutics rapidly into the clinic. Existing safety and patient tolerability data for drugs already in clinical use represent an untapped resource in terms of identifying therapeutic agents for off-label protein targets. The multicellular effects of STAT3 mediated by a range of various upstream signaling pathways make it an attractive therapeutic target with utility in a range of diseases including cancer, and has led to the development of a variety of STAT3 inhibitors. Moreover, heightened STAT3 transcriptional activation in tumor cells and within the cells of the tumor microenvironment contribute to disease progression. Consequently, there are many STAT3 inhibitors in preclinical development or under evaluation in clinical trials for their therapeutic efficacy predominantly in inflammatory diseases and cancer. Despite these advances, many challenges remain in ultimately providing STAT3 inhibitors to patients as cancer treatments, highlighting the need not only for a better understanding of the mechanisms associated with STAT3 activation, but also how various pharmaceutical agents suppress STAT3 activity in various cancers. In this review we discuss the importance of STAT3-dependent functions in cancer, review the status of compounds designed as direct-acting STAT3 inhibitors, and describe some of the strategies for repurposing of drugs as STAT3 inhibitors for cancer therapy. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-11 is upregulated in a wide variety of fibro-inflammatory diseases such as systemic sclerosis, rheumatoid arthritis, pulmonary fibrosis, inflammatory bowel disease, kidney disease, drug-induced liver injury, and nonalcoholic steatohepatitis. IL-11 is a member of the IL-6 cytokine family and has several distinct properties that define its unique and nonredundant roles in disease. The IL-11 receptor is highly expressed on stromal, epithelial and polarized cells, where noncanonical IL-11 signaling drives the three pathologies common to all fibro-inflammatory diseases—myofibroblast activation, parenchymal cell dysfunction, and inflammation—while also inhibiting tissue regeneration. This cytokine has been little studied, and publications on IL-11 peaked in the early 1990s, when it was largely misunderstood. Here we describe recent advances in our understanding of IL-11 biology, outline how misconceptions as to its function came about, and highlight the large potential of therapies targeting IL-11 signaling for treating human disease. [ABSTRACT FROM AUTHOR]

Bone is a major target for metastases in the most frequent solid tumors, which result in severe complications and are a major cause of pain. A bone metastasis gene expression signature was identified using human breast cancer cells in a mouse model. The bone metastasis-related genes encode secretory and cell surface proteins implicated in bone-homing ( CXCR4), angiogenesis ( CTGF and FGF5), invasion ( MMP- 1 and ADAMTS1), and osteoclast recruitment ( IL11). This signature superimposes on the 70-gene poor prognosis gene expression signature for breast cancer, and only ADAMTS1, CTGF and IL11 were found to be overexpressed in human primary breast cancers with bone relapse. We analyzed the expression of the six bone metastasis-related genes in bone metastases from patients with different types of solid tumors, to assess its relevance in human clinical samples. MMP- 1, CXCR4, FGF5 and CTGF were found to be overexpressed in tumor cells of human bone metastases when compared to a human normal epithelial cell line. All the analyzed genes were overexpressed in the tumor cells of breast cancer bone metastases when compared to normal breast tissue. We did not detect any differences between the expression of these genes in bone metastases from breast cancer or from other types of solid tumors. Importantly, there was a significant correlation between the expressions of IL11/ CTGF, IL11/ ADAMTS1, CTGF/ CXCR4, CTGF/ ADAMTS1, and MMP- 1/ ADAMTS1, supporting the cooperative function of these proteins in the bone microenvironment, and the potential functional role of these genes in the establishment of bone metastases in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Cytokine production by the endometrial stromal and decidual cells is essential for successful differentiation of the endometrial stromal cells and uterine leukocytes to sustain pregnancy. Interleukin-11 and -15 (IL-11 and IL-15) secreted by the stromal and decidual cells are two key modulators of the process of decidualization and natural killer cell (NK) activity in the uterus and are essential for pregnancy. However, limited information exists on the maternal factors that regulate the production of these cytokines by the stromal cells. In this study, we investigated the role of homeobox A10 (HOXA10) in the regulation of expression of genes encoding the decidualization markers insulin-like growth factor binding protein-1 (IGFBP1), prolactin and the cytokines IL-11 and IL-15 by endometrial stromal and decidual cells in vitro. The results demonstrated that the expression of IGFBP1, Prolactin (PRL), HOXA10, IL11, and IL15 are co-regulated during steroid hormone-mediated decidualization of human endometrial stromal cells in vitro. In the predecidual cells, downregulation of HOXA10 by siRNA suppresses IGFBP1 and IL15, but increases IL11 expression. In the decidualized cells, knocking down HOXA10 inhibits IGFBP1 and PRL expression but elevates the expression of IL11 and IL15. In addition, our data also demonstrate that transient inhibition of HOXA10 expression in the predecidual cells does not influence its ability to subsequently decidualize or affect cytokine expression, suggesting that steroid hormone-mediated decidualization and cytokine production in vitro does not require HOXA10 preconditioning. [Copyright &y& Elsevier]

Abstract: Blastocyst implantation into a receptive endometrium is critical to the establishment of pregnancy and is tightly regulated by factors within the blastocyst–endometrial micro-environment. Leukemia inhibitory factor (LIF) and interleukin-11 (IL11) have key roles during implantation. Female mice with a null mutation in the LIF or IL11RA gene are infertile due to a complete failure of implantation or a defective differentiation/decidualization response to the implanting blastocyst, respectively. LIF and IL11 deficiency during pregnancy is associated with infertility and miscarriage in women. Numerous cell populations at the maternal–fetal interface are regulated by LIF/IL11 including the endometrial epithelium, decidualizing stroma, placental trophoblasts and leukocytes. This review focuses on the roles of LIF/IL11 during early pregnancy and highlights their potential as contraceptive targets and therapeutic agents for infertility. [Copyright &y& Elsevier]

Abstract: Blastocyst implantation is dependent on the differentiation of endometrial stromal cells (ESC) into decidual cells. Decidualization of human ESC in vitro is enhanced by interleukin 11 (IL11), with associated changes in gene expression. Genes downstream of IL11 may provide targets for the treatment of implantation failure or the development of non-hormonal contraceptives. This study aimed to examine the effect of IL11 on interleukin 1 beta (IL1B) mRNA and protein expression during in vitro decidualization of ESC. Cells were decidualized with 17β-estradiol and medroxyprogesterone acetate in the presence or absence of exogenous IL11, and IL1B mRNA was quantified by real-time RT–PCR. Inactive proIL1B and bioactive IL1B in cell lysates and conditioned media were measured using specific immunoassays. Secretion of bioactive IL1B from decidualizing ESC was investigated by in vitro stimulation of decidualizing cells with lipopolysaccharide, interferon gamma or human chorionic gonadotropin. Immunohistochemistry was carried out on cycling and pregnant decidua using an antibody specific for bioactive IL1B. Exogenous IL11 increased by 28-fold the abundance of IL1B mRNA in decidualizing ESC, and total immunoreactive IL1B was also increased. However, this was not reflected in bioactive IL1B secretion from these cells, and none of the tested stimuli were able to induce its release. Bioactive IL1B was detected in vivo at very low levels and at discrete foci in late secretory phase and first trimester decidua. This regulation of latent and bioactive IL1B at the fetal–maternal interface may prime decidual cells to respond rapidly to immunological challenge or to signals from the blastocyst during implantation. [Copyright &y& Elsevier]

Background: Interleukin-11 is a pleiotropic cytokine that is known to play an important role in the progression of various forms of cancer by modulating the survival and proliferation of tumour cells. IL11 also demonstrates a structural homology to IL6, the predominant cytokine involved in COVID-19. This makes IL11 a potential therapeutic target in both diseases., Objective: This study aimed to evaluate the impact of the two-point mutations, R135E and R190E, on the stability of IL11 and their effect on the binding affinity of IL11 with its receptor IL11Rα. It is a molecular level analysis based on the existing experimental validation., Methods: Computer-aided drug designing techniques, such as molecular modelling, molecular docking, and molecular dynamics simulations, were employed to determine the consequential effects of the two-point mutations., Results: Our analysis revealed that the two mutations led to a decrease in the overall stability of IL11. This was evident by the increased atomic fluctuations in the mutated regions as well as the corresponding elevation in the deviations seen through RMSD and Rg values. It was also accompanied by a loss in the secondary structural organisation in the mutated proteins. Moreover, mutation R135E led to an increase in the binding affinity of IL11 with IL11Rα and the formation of a more stable complex in comparison to the wild-type protein with its receptor., Conclusion: Mutation R190E led to the formation of a less stable complex than the wild-type, which suggests a decrease in the binding affinity between IL11 and IL11Rα., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Abstract: Blastocyst implantation into the endometrium is critical for the establishment of pregnancy and is tightly regulated by factors within the blastocyst-endometrial micro-environment. Implantation is a continuum involving blastocyst adhesion to the endometrial epithelium followed by trophoblast penetration of the epithelium. The trophoblast proliferates and invades through the endometrium, with a subpopulation acting to remodel the spiral arteries. Trophoblast-endometrial interactions in humans involve carefully orchestrated temporal and spatial alterations in factors that are critical for pregnancy success. Emerging evidence suggests important roles for locally produced cytokines including interleukin 11 and leukemia inhibitory factor in the various stages of implantation. This review focuses on the role of these cytokines in trophoblast-endometrial interactions during the establishment of human pregnancy. [Copyright &y& Elsevier]

Introduction: Endometrial decidualization and associated extracellular matrix (ECM) remodeling are critical events to the establishment of the maternal-fetal interface and successful pregnancy. Here, we investigated the impact of type 1 diabetes on these processes during early embryonic development, in order to contribute to the understanding of the maternal factors associated to diabetic embryopathies., Methods: Alloxan-induced diabetic Swiss female mice were bred after different periods of time to determine the effects of diabetes progression on the development of gestational complications. Furthermore, the analyses focused on decidual development as well as mRNA expression, protein deposition and ultrastructural organization of decidual ECM., Results: Decreased number of implantation sites and decidual dimensions were observed in the group mated 90-110 days after diabetes induction (D), but not in the 50-70D group. Picrosirius staining showed augmentation in the fibrillar collagen network in the 90-110D group and, following immunohistochemical examination, that this was associated with increase in types I and V collagens and decrease in type III collagen and collagen-associated proteoglycans biglycan and lumican. qPCR, however, demonstrated that only type I collagen mRNA levels were increased in the diabetic group. Alterations in the molecular ratio among distinct collagen types and proteoglycans were associated with abnormal collagen fibrillogenesis, analyzed by transmission electron microscopy., Conclusions: Our results support the concept that the development of pregnancy complications is directly related with duration of diabetes (progression of the disease), and that this is a consequence of both systemic factors (i.e. disturbed maternal endocrine-metabolic profile) and uterine factors, including impaired decidualization and ECM remodeling., (Copyright © 2013 Elsevier Ltd. All rights reserved.)