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Experimental Cell Research Oct 2020Hereditary transthyretin amyloidosis (ATTR) is caused by amyloid deposition of misfolded transthyretin (TTR) in various tissues. Recently, reduction of circulating serum...
Hereditary transthyretin amyloidosis (ATTR) is caused by amyloid deposition of misfolded transthyretin (TTR) in various tissues. Recently, reduction of circulating serum TTR, achieved via silencing oligonucleotides, was introduced as therapy of ATTR amyloidosis. We explored the impact of Serpin Family A Member 1 (SERPINA1) on TTR mRNA and protein expression. Oncostatin M (OSM) induced SERPINA1 in hepatoma cells and mice, while concomitantly TTR expression was significantly reduced. SERPINA1 knockdown resulted in specific elevated TTR expression in hepatoma cells; however other genes belonging to the group of acute phase proteins were unaffected. In mice, serum TTR was elevated after mSERPINA1 knockdown throughout antisense treatment. Following SERPINA1 knockdown, TTR deposition in several tissues, including dorsal root ganglia and intestine, was found to be increased, however numbers did not exceed significance levels. The data suggest that SERPINA1 is a co-factor of TTR expression. Our findings provide novel insight in the regulation of TTR and reveal a role of SERPINA1 in the pathogenesis of ATTR amyloidosis.
Topics: Amyloid Neuropathies, Familial; Animals; Humans; Mice; Prealbumin; RNA, Messenger; alpha 1-Antitrypsin
PubMed: 32768500
DOI: 10.1016/j.yexcr.2020.112217 -
International Journal of Molecular... Aug 2021Epithelial-mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression,... (Review)
Review
Epithelial-mesenchymal plasticity (EMP) plays critical roles during embryonic development, wound repair, fibrosis, inflammation and cancer. During cancer progression, EMP results in heterogeneous and dynamic populations of cells with mixed epithelial and mesenchymal characteristics, which are required for local invasion and metastatic dissemination. Cancer development is associated with an inflammatory microenvironment characterized by the accumulation of multiple immune cells and pro-inflammatory mediators, such as cytokines and chemokines. Cytokines from the interleukin 6 (IL-6) family play fundamental roles in mediating tumour-promoting inflammation within the tumour microenvironment, and have been associated with chronic inflammation, autoimmunity, infectious diseases and cancer, where some members often act as diagnostic or prognostic biomarkers. All IL-6 family members signal through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and are able to activate a wide array of signalling pathways and transcription factors. In general, IL-6 cytokines activate EMP processes, fostering the acquisition of mesenchymal features in cancer cells. However, this effect may be highly context dependent. This review will summarise all the relevant literature related to all members of the IL-6 family and EMP, although it is mainly focused on IL-6 and oncostatin M (OSM), the family members that have been more extensively studied.
Topics: Animals; Epithelial-Mesenchymal Transition; Humans; Inflammation Mediators; Interleukin-6; Neoplasms
PubMed: 34361105
DOI: 10.3390/ijms22158334 -
Clinical, Cosmetic and Investigational... 2023The underlying pathophysiology linking psoriasis vulgaris (PV) and metabolic syndrome (MetS) is not fully understood. The present study aimed to investigate the serum...
PURPOSE
The underlying pathophysiology linking psoriasis vulgaris (PV) and metabolic syndrome (MetS) is not fully understood. The present study aimed to investigate the serum level of interleukin (IL)-9 and tissue levels of IL-9 and its receptor in PV patients with MetS and analyze the correlation of IL-9 levels with psoriasis disease severity and MetS.
METHODS
This study enrolled 75 PV patients with MetS, 57 PV patients without MetS, 20 healthy blood donors, and 7 healthy skin donors. Clinical, socio-demographic, and anthropometric data were obtained from all individuals. Fasting blood glucose, insulin, lipid profile levels, and serum levels of IL-9 and IL-17A were measured. The expression of IL-9 and its receptor in skin specimens in PV patients and healthy controls was determined using immunohistochemistry. Normal human epidermal keratinocytes were stimulated with five pro-inflammatory cytokines (tumor necrosis factor-α, oncostatin M, IL-22, IL-17A, and IL-1α) to establish a psoriatic keratinocyte model and subsequently treated with IL-9. Their mRNA levels of antimicrobial peptides and chemokines were measured using quantitative real-time polymerase chain reaction.
RESULTS
Serum level of IL-9 and tissue levels of IL-9 and its receptor were upregulated in PV patients with MetS. IL-9 level was positively correlated to IL-17A level; however, no significant correlation of IL-9 level with psoriasis area severity index was observed. IL-9 level had a positive correlation with the presence of MetS and its components. Correspondingly, IL-9 level positively correlated with waist circumference, body mass index, homeostasis model assessment-insulin resistance, blood pressure, and triglyceride level and negatively correlated with high-density lipoprotein cholesterol level. Additionally, IL-9 stimulated the expression of antimicrobial peptides and chemokines in a psoriatic keratinocyte model.
CONCLUSION
Our findings confirmed that higher IL-9 level is associated with PV complicated by MetS, suggesting that IL-9 may be a link between PV and MetS.
PubMed: 37641663
DOI: 10.2147/CCID.S422355 -
Pharmacology 2023Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and...
Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas.
INTRODUCTION
Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and relatively limited treatment options. Oncostatin M (OSM) is a pleiotropic cytokine that was shown to carry both pro- and anti-tumorigenic properties in various cancer types. However, the role of OSM in STSs has not yet been elucidated. Moreover, the potential additive effects of combining OSM and anti-PD-1 therapy have not been carried out so far.
METHODS
The aim of this study was to determine the effects of in vitro OSM administration on liposarcoma, leiomyosarcoma, and myxofibrosarcoma immune cells isolated from peripheral blood and tumor tissues and the potential cooperative nature of OSM and nivolumab in treating these STSs. We designed a cohort study to explore novel histology-driven therapies in our target STSs. The immune cells were isolated from the peripheral blood and tumors of patients with STS, and the proportions and phenotypes of immune cells were evaluated with flow cytometry after cultivation with therapeutic monoclonal antibodies.
RESULTS
The proportion of peripheral CD45+ cells was not affected by OSM but was significantly increased by nivolumab, whereas both treatments had an effect on CD8+ T cells. In tumor tissues, CD8+ T cell and CD45‒ TRAIL+ cell cultures were boosted by nivolumab and significantly enriched by OSM. Our data suggest that OSM may play a role in the treatment of leiomyosarcoma, myxofibrosarcoma, and liposarcoma.
CONCLUSION
In conclusion, the biological efficacy of OSM is reflected in the tumor microenvironment rather than in the peripheral blood of the patients in our cohort, and nivolumab could potentiate its mechanism of action in selected cases. Nevertheless, more histotype-tailored studies are needed to fully understand the functions of OSM in STSs.
Topics: Humans; Oncostatin M; Nivolumab; Leiomyosarcoma; Cohort Studies; Liposarcoma; T-Lymphocytes; Tumor Microenvironment
PubMed: 36996792
DOI: 10.1159/000529811 -
Molecular Metabolism Dec 2021Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into...
OBJECTIVE
Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state.
METHODS
Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively.
RESULTS
Inguinal WAT of HFD-fed gp130 mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = -0.413, p < 0.001, n = 66).
CONCLUSIONS
Our data support the notion that OSM negatively regulates thermogenesis in WAT and thus may be an attractive target for treating obesity.
Topics: 3T3-L1 Cells; Adipocytes, White; Animals; Cells, Cultured; Cytokine Receptor gp130; Humans; Male; Mice; Oncostatin M; STAT3 Transcription Factor
PubMed: 34547509
DOI: 10.1016/j.molmet.2021.101341 -
Immunity Mar 2021Pathologic roles of innate immunity in neurologic disorders are well described, but their beneficial aspects are less understood. Dectin-1, a C-type lectin receptor...
Pathologic roles of innate immunity in neurologic disorders are well described, but their beneficial aspects are less understood. Dectin-1, a C-type lectin receptor (CLR), is largely known to induce inflammation. Here, we report that Dectin-1 limited experimental autoimmune encephalomyelitis (EAE), while its downstream signaling molecule, Card9, promoted the disease. Myeloid cells mediated the pro-resolution function of Dectin-1 in EAE with enhanced gene expression of the neuroprotective molecule, Oncostatin M (Osm), through a Card9-independent pathway, mediated by the transcription factor NFAT. Furthermore, we find that the Osm receptor (OsmR) functioned specifically in astrocytes to reduce EAE severity. Notably, Dectin-1 did not respond to heat-killed Mycobacteria, an adjuvant to induce EAE. Instead, endogenous Dectin-1 ligands, including galectin-9, in the central nervous system (CNS) were involved to limit EAE. Our study reveals a mechanism of beneficial myeloid cell-astrocyte crosstalk regulated by a Dectin-1 pathway and identifies potential therapeutic targets for autoimmune neuroinflammation.
Topics: Animals; Astrocytes; Brain; CARD Signaling Adaptor Proteins; Cell Communication; Cells, Cultured; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Galectins; Gene Expression Regulation; Lectins, C-Type; Mice, Inbred C57BL; Mice, Knockout; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Myeloid Cells; Neurogenic Inflammation; Oncostatin M; Oncostatin M Receptor beta Subunit; Peptide Fragments; Receptors, Mitogen; Signal Transduction; Mice
PubMed: 33581044
DOI: 10.1016/j.immuni.2021.01.004 -
Experimental Physiology Jul 2020What is the central question of this study? What controls the proliferation and apoptosis in the pathogenesis of psoriasis? What is the main finding and its importance?...
NEW FINDINGS
What is the central question of this study? What controls the proliferation and apoptosis in the pathogenesis of psoriasis? What is the main finding and its importance? The pathogenesis psoriasis involves abnormal homeostasis of keratinocytes, with hyperproliferation and decreasing apoptosis. An inhibitor of apoptosis protein family molecule, Livin, is highly expressed in psoriasis vulgaris lesional skin tissue. Expression of Livin was upregulated at transcription and protein levels after stimulation with oncostatin M (OSM). OSM promoted the survival of HaCaT cells in oxidative stress conditions. Expression of Livin and proliferation of HaCaT cells stimulated by OSM was regulated through ERK and STAT3 signalling pathways. This study might provide new insights into targeted therapy for psoriasis.
ABSTRACT
Psoriasis is an immune-mediated chronic inflammatory disease. Abnormal homeostasis of keratinocytes, with hyperproliferation and decreasing apoptosis, is involved in the pathogenesis of psoriasis. Here, we report that an inhibitor of apoptosis protein family molecule, Livin, is highly expressed in psoriasis vulgaris lesional skin tissue at transcription and protein levels. Importantly, the expression level of Livin is related to the severity of psoriasis. The aim of the study was to investigate the regulation and functions of Livin in keratinocytes stimulated by the pro-inflammatory cytokine oncostatin M (OSM). The expression of Livin in HaCaT cells at mRNA and protein levels was measured by real-time PCR and Western blotting after OSM stimulation. The cell proliferation was measured by a 5-ethynyl-2'-deoxyuridine incorporation assay. Cell death was induced by the exogenous hydrogen peroxide (H O ) stress model, detected by 7-amino-actinomycin D staining and analysed by flow cytometry. Livin was overexpressed by a lentiviral transduction system to validate the roles of OSM and Livin in HaCaT cells. Specific inhibitors of ERK (U0126) and STAT3 (cryptotanshinone) were applied to investigate the signalling pathways involved in the regulation of Livin expression by OSM. The expression of Livin was upregulated after stimulation with OSM. OSM promoted the proliferation and survival of HaCaT cells. The expression of Livin and the proliferation of HaCaT cells induced by OSM were regulated through the ERK and STAT3 signalling pathways. We conclude that OSM promotes HaCaT cell proliferation and survival in conditions of oxidative stress.
Topics: Adaptor Proteins, Signal Transducing; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; HaCaT Cells; Humans; Inhibitor of Apoptosis Proteins; Keratinocytes; Neoplasm Proteins; Oncostatin M; Oxidative Stress; Psoriasis; STAT3 Transcription Factor; Signal Transduction; Up-Regulation
PubMed: 32359099
DOI: 10.1113/EP088584 -
Gastroenterology Research and Practice 2019To detect the expression of the Oncostatin M (OSM) gene and encoded protein in the mucosal epithelium of chronic gastritis, intestinal metaplasia (IM), low-grade...
OBJECTIVE
To detect the expression of the Oncostatin M (OSM) gene and encoded protein in the mucosal epithelium of chronic gastritis, intestinal metaplasia (IM), low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), early gastric cancer (EGC), and advanced gastric cancer (AGC) samples and to explore the correlation and clinicopathological significance of OSM expression in the process of gastric carcinogenesis.
METHODS
The expression levels of OSM in chronic gastritis, IM, LGIN, HGIN, EGC, and AGC samples were detected by gene chip, real-time quantitative PCR, and immunohistochemical methods. The expression levels of OSM in the gastric mucosa were analyzed, and its correlation with clinical pathology was studied.
RESULTS
The expression level of OSM in gastric HGIN and EGC tissues was significantly higher than that in LGIN tissues based on expression profiling ( < 0.001). The expression of the OSM gene in EGC was higher than that in HGIN (unpaired test, < 0.05) and LGIN (unpaired test, < 0.01) by qPCR. The expression of OSM in LGIN was significantly lower than that in HGIN ( = 0.008) and EGC ( = 0.044) by immunohistochemical staining. The expression of OSM in HGIN tissues was significantly higher than that in AGC ( = 0.007).
CONCLUSION
Alterations in the expression of the OSM gene may be involved in the malignant transformation of the gastric mucosal epithelium. Because of the significant difference in the cancerization rate and clinical management between LGIN and HGIN, the difference in the staining intensity of OSM between LGIN and HGIN may be one of the early markers of gastric intraepithelial neoplasia.
PubMed: 31871447
DOI: 10.1155/2019/3616140 -
Cellular and Molecular Gastroenterology... 2024Functional cure is achieved by a limited number of patients with chronic hepatitis B (CHB) after nucleotide analogue(s) and interferon treatment. It is urgent to develop...
BACKGROUND & AIMS
Functional cure is achieved by a limited number of patients with chronic hepatitis B (CHB) after nucleotide analogue(s) and interferon treatment. It is urgent to develop therapies that can help a larger proportion of patients achieve functional cure. The present study was designed to explore the anti-hepatitis B virus (HBV) potency of interleukin-6 family cytokines and to characterize the underlying mechanisms of the cytokine displaying the highest anti-HBV potency.
METHODS
HBV-infected cells were used to screened the anti-HBV potency of interleukin-6 family cytokines. The concentration of oncostatin M (OSM) in patients with chronic HBV infection was examined by enzyme-linked immunosorbent assay. The underlying mechanism of OSM anti-HBV was explored through RNA-seq. C57BL/6 mice injected with rAAV8-1.3HBV were used to explore the suppression effect of OSM on HBV in vivo.
RESULTS
OSM is the most effective of the interleukin-6 family cytokines for suppression of HBV replication (percentage of average inhibition: hepatitis B surface antigen, 34.44%; hepatitis B e antigen, 32.52%; HBV DNA, 61.57%). Hepatitis B e antigen-positive CHB patients with high OSM levels had lower hepatitis B surface antigen and hepatitis B e antigen than those with low levels. OSM activated JAK-STAT signaling pathway promoting the formation of STAT1-IRF9 transcription factor complex. Following this, OSM increased the expression of various genes with known functions in innate and adaptive immunity, which was higher expression in patients with CHB in immune clearance phase than in immune tolerance phase (data from GEO: GSE65359). Interferon-induced transmembrane protein 1, one of the most differentially expressed genes, was identified as an HBV restriction factor involved in OSM-mediated anti-HBV effect. In vivo, we also found OSM significantly inhibited HBV replication and induced expression of antiviral effector interferon-induced transmembrane protein 1.
CONCLUSIONS
Our study shows that OSM remodels the immune response against HBV and exerts potent anti-HBV activity, supporting its further development as a potential therapy for treating CHB.
Topics: Mice; Animals; Humans; Hepatitis B virus; Hepatitis B Surface Antigens; Oncostatin M; Hepatitis B e Antigens; Interleukin-6; Mice, Inbred C57BL; Signal Transduction; Hepatitis B; Interferons; Virus Replication
PubMed: 37879404
DOI: 10.1016/j.jcmgh.2023.10.003 -
Cellular & Molecular Immunology Dec 2021The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis (IAC). How this axis is regulated to modulate IAC remains unknown. Here, we show...
The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis (IAC). How this axis is regulated to modulate IAC remains unknown. Here, we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6, as well as another IL-6 subfamily member, Oncostatin M (OSM). MARCH3 is associated with the IL-6 receptor α-chain (IL-6Rα) and its coreceptor gp130. Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rα at K401 and gp130 at K849 following IL-6 stimulation, leading to their translocation to and degradation in lysosomes. MARCH3 deficiency increases IL-6- and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types. MARCH3 deficiency enhances dextran sulfate sodium (DSS)-induced STAT3 activation, increases the expression of inflammatory cytokines, and exacerbates colitis, as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer in mice. In addition, MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types. Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation, inflammation, and inflammation-associated carcinogenesis.
Topics: Animals; Carcinogenesis; Colitis; Dextran Sulfate; Disease Models, Animal; Interleukin-6; Mice; Mice, Inbred C57BL; Receptors, Interleukin-6; Signal Transduction; Ubiquitin-Protein Ligases
PubMed: 34785732
DOI: 10.1038/s41423-021-00799-1