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1.
Biomed Pharmacother ; 176: 116861, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38850649

RESUMO

Mitoxantrone resistant variant of SW620 line was developed, characterized and subsequently used as a model system to determine oncostatin M ability to modulate MDR phenomenon. The selection regimen allowed for overexpression of ABCG2 and ABCB1 both at the RNA and protein level, which was further confirmed by functional assays. Oncostatin M supplementation resulted in partial reversal of MDR phenotype by decreasing overexpression of ABCG2 demonstrating for the first time the ability of this cytokine for selective down-regulation of one of MDR proteins.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Resistencia a Medicamentos Antineoplásicos , Mitoxantrona , Proteínas de Neoplasias , Oncostatina M , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Mitoxantrona/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Oncostatina M/metabolismo , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética
2.
Cell Biochem Funct ; 42(4): e4068, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38817105

RESUMO

Evidence is accumulating that osteal macrophages, in addition to bone-resorbing osteoclasts and bone-forming osteoblasts, participate vitally in bone remodeling process. Oncostatin M (OSM), an inflammatory cytokine belonging to interleukin-6 superfamily, is recognized as an essential factor secreted by osteal macrophages to orchestrate bone remodeling. Osteoprotegerin (OPG) produced by osteoblasts regulates osteoclastogenesis. We have reported that bone morphogenetic protein-4 (BMP-4) stimulates OPG synthesis in MC3T3-E1 osteoblast-like cells, and that SMAD1/5/8(9), p38 mitogen-activated protein kinase (MAPK), and p70 S6 kinase are involved in the OPG synthesis. The present study aims to investigate the effect of OSM on the synthesis of OPG stimulated by BMP-4 in osteoblasts. OSM suppressed the release and the mRNA expression of OPG upregulated by BMP-4 in MC3T3-E1 cells. Neither the BMP-4-induced phosphorylation of SMAD1/5/9 nor that of p38 MAPK was affected by OSM. On the other hand, the phosphorylation of p70 S6 kinase stimulated by BMP-4 was considerably suppressed by OSM. These results strongly suggest that OSM suppresses the BMP-4-stimulated OPG synthesis via inhibition of the p70 S6 kinase-mediated pathway in osteoblast-like cells.


Assuntos
Proteína Morfogenética Óssea 4 , Oncostatina M , Osteoblastos , Osteoprotegerina , Proteínas Quinases S6 Ribossômicas 70-kDa , Animais , Camundongos , Oncostatina M/farmacologia , Oncostatina M/metabolismo , Osteoblastos/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/citologia , Osteoprotegerina/metabolismo , Osteoprotegerina/biossíntese , Proteína Morfogenética Óssea 4/metabolismo , Proteína Morfogenética Óssea 4/farmacologia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Fosforilação/efeitos dos fármacos , Linhagem Celular
3.
Immunity ; 57(6): 1345-1359.e5, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38692280

RESUMO

Regulatory T (Treg) cells in epidydimal visceral adipose tissue (eVAT) of lean mice and humans regulate metabolic homeostasis. We found that constitutive or punctual depletion of eVAT-Treg cells reined in the differentiation of stromal adipocyte precursors. Co-culture of these precursors with conditional medium from eVAT-Treg cells limited their differentiation in vitro, suggesting a direct effect. Transcriptional comparison of adipocyte precursors, matured in the presence or absence of the eVAT-Treg-conditioned medium, identified the oncostatin-M (OSM) signaling pathway as a key distinction. Addition of OSM to in vitro cultures blocked the differentiation of adipocyte precursors, while co-addition of anti-OSM antibodies reversed the ability of the eVAT-Treg-conditioned medium to inhibit in vitro adipogenesis. Genetic depletion of OSM (specifically in Treg) cells or of the OSM receptor (specifically on stromal cells) strongly impaired insulin sensitivity and related metabolic indices. Thus, Treg-cell-mediated control of local progenitor cells maintains adipose tissue and metabolic homeostasis, a regulatory axis seemingly conserved in humans.


Assuntos
Adipócitos , Diferenciação Celular , Homeostase , Resistência à Insulina , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Humanos , Camundongos , Adipócitos/metabolismo , Diferenciação Celular/imunologia , Oncostatina M/metabolismo , Transdução de Sinais , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/citologia , Gordura Intra-Abdominal/imunologia , Células Estromais/metabolismo , Camundongos Endogâmicos C57BL , Técnicas de Cocultura , Adipogenia , Células Cultivadas , Masculino , Tecido Adiposo/metabolismo , Tecido Adiposo/citologia , Meios de Cultivo Condicionados/farmacologia
4.
Transl Res ; 271: 93-104, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38797433

RESUMO

Hepatopulmonary syndrome (HPS) is a serious pulmonary complication in the advanced stage of liver disease. The occurrence of pulmonary edema in HPS patients is life-threatening. Increased pulmonary vascular permeability is an important mechanism leading to pulmonary edema, and endothelial glycocalyx (EG) is a barrier that maintains stable vascular permeability. However, in HPS, whether the pulmonary vascular EG changes and its regulatory mechanism are still unclear. Spleen derived monocytes are involved in the pathogenesis of HPS. However, whether they regulate the pulmonary vascular permeability in HPS patients or rats and what is the mechanism is still unclear. Healthy volunteers and HPS patients with splenectomy or not were enrolled in this study. We found that the respiration of HPS patients was significantly improved in response to splenectomy, while the EG degradation and pulmonary edema were aggravated. In addition, HPS patients expressed higher levels of oncostatin M (OSM) and fibroblast growth factor (FGF). Subsequently, the co-culture system of monocytes and human umbilical vein endothelial cells (HUVECs) was constructed. It was found that monocytes secreted OSM and activated the FGF/FGFR1 signaling pathway in HUVECs. Then, an HPS rat model was constructed by common bile duct ligation (CBDL) for in vivo verification. HPS rats were intravenously injected with OSM recombinant protein and/or TNF-α into the rats via tail vein 30 min before CBDL. The results showed that the respiration of HPS rats was improved after splenectomy, while the degradation of EG in pulmonary vessels and vascular permeability were increased, and pulmonary edema was aggravated. Moreover, the expression of OSM and FGF was upregulated in HPS rats, while both were downregulated after splenectomy. Intravenous injection of exogenous OSM eliminated the effect of splenectomy on FGF and improved EG degradation. It can be seen that during HPS, spleen-derived monocytes secrete OSM to promote pulmonary vascular EG remodeling by activating the FGF/FGFR1 pathway, thereby maintaining stable vascular permeability, and diminishing pulmonary edema. This study provides a promising therapeutic target for the treatment of HPS.


Assuntos
Permeabilidade Capilar , Síndrome Hepatopulmonar , Monócitos , Oncostatina M , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Transdução de Sinais , Baço , Animais , Humanos , Síndrome Hepatopulmonar/metabolismo , Masculino , Monócitos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Baço/metabolismo , Oncostatina M/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Ratos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Esplenectomia , Ratos Sprague-Dawley , Pulmão/metabolismo , Pulmão/irrigação sanguínea , Feminino , Pessoa de Meia-Idade , Adulto , Glicocálix/metabolismo
5.
Cell Rep Med ; 5(4): 101498, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38569555

RESUMO

Progressive weakness and muscle loss are associated with multiple chronic conditions, including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy; however, available anticytokine therapies failed to prevent muscle wasting in cancer patients. Here, we show that oncostatin M (OSM) is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes using the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing reveals the induction of various muscle atrophy-related genes, including Atrogin1. OSM overexpression in mice causes muscle wasting, whereas muscle-specific deletion of the OSM receptor (OSMR) and the neutralization of circulating OSM preserves muscle mass and function in tumor-bearing mice. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.


Assuntos
Neoplasias , Oncostatina M , Qualidade de Vida , Animais , Humanos , Camundongos , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Neoplasias/patologia , Oncostatina M/genética , Oncostatina M/metabolismo , Oncostatina M/farmacologia
6.
Front Endocrinol (Lausanne) ; 15: 1227196, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38449853

RESUMO

Introduction: Axial spondyloarthritis (axSpA) is a heterogeneous disease that can be represented by radiographic axSpA (r-axSpA) and non-radiographic axSpA (nr-axSpA). This study aimed to evaluate the relationship between the markers of inflammation and bone turnover in r-axSpA patients and nr-axSpA patients. Methods: A cross-sectional study included 29 r-axSpA patients, 10 nr-axSpA patients, and 20 controls matched for age and sex. Plasma markers related to bone remodeling such as human procollagen type 1 N-terminal propeptide (P1NP), sclerostin, tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator of nuclear factor kappa B ligand (RANKL), and osteoprotegerin (OPG) were measured by an ELISA kit. A panel of 92 inflammatory molecules was analyzed by proximity extension assay. Results: R-axSpA patients had decreased plasma levels of P1NP, a marker of bone formation, compared to controls. In addition, r-axSpA patients exhibited decreased plasma levels of sclerostin, an anti-anabolic bone hormone, which would not explain the co-existence of decreased plasma P1NP concentration; however, sclerostin levels could also be influenced by inflammatory processes. Plasma markers of osteoclast activity were similar in all groups. Regarding inflammation-related molecules, nr-axSpA patients showed increased levels of serum interleukin 13 (IL13) as compared with both r-axSpA patients and controls, which may participate in the prevention of inflammation. On the other hand, r-axSpA patients had higher levels of pro-inflammatory molecules compared to controls (i.e., IL6, Oncostatin M, and TNF receptor superfamily member 9). Correlation analysis showed that sclerostin was inversely associated with IL6 and Oncostatin M among others. Conclusion: Altogether, different inflammatory profiles may play a role in the development of the skeletal features in axSpA patients particularly related to decreased bone formation. The relationship between sclerostin and inflammation and the protective actions of IL13 could be of relevance in the axSpA pathology, which is a topic for further investigation.


Assuntos
Espondiloartrite Axial não Radiográfica , Humanos , Oncostatina M , Estudos Transversais , Interleucina-13 , Interleucina-6 , Inflamação/diagnóstico por imagem , Biomarcadores
7.
Cells ; 13(3)2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38334621

RESUMO

Interleukin-6 (IL-6) superfamily cytokines play critical roles during human pregnancy by promoting trophoblast differentiation, invasion, and endocrine function, and maintaining embryo immunotolerance and protection. In contrast, the unbalanced activity of pro-inflammatory factors such as interferon gamma (IFNγ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at the maternal-fetal interface have detrimental effects on trophoblast function and differentiation. This study demonstrates how the IL-6 cytokine family member oncostatin M (OSM) and STAT3 activation regulate trophoblast fusion and endocrine function in response to pro-inflammatory stress induced by IFNγ and GM-CSF. Using human cytotrophoblast-like BeWo (CT/BW) cells, differentiated in villous syncytiotrophoblast (VST/BW) cells, we show that beta-human chorionic gonadotrophin (ßhCG) production and cell fusion process are affected in response to IFNγ or GM-CSF. However, those effects are abrogated with OSM by modulating the activation of IFNγ-STAT1 and GM-CSF-STAT5 signaling pathways. OSM stimulation enhances the expression of STAT3, the phosphorylation of STAT3 and SMAD2, and the induction of negative regulators of inflammation (e.g., IL-10 and TGFß1) and cytokine signaling (e.g., SOCS1 and SOCS3). Using STAT3-deficient VST/BW cells, we show that STAT3 expression is required for OSM to regulate the effects of IFNγ in ßhCG and E-cadherin expression. In contrast, OSM retains its modulatory effect on GM-CSF-STAT5 pathway activation even in STAT3-deficient VST/BW cells, suggesting that OSM uses STAT3-dependent and -independent mechanisms to modulate the activation of pro-inflammatory pathways IFNγ-STAT1 and GM-CSF-STAT5. Moreover, STAT3 deficiency in VST/BW cells leads to the production of both a large amount of ßhCG and an enhanced expression of activated STAT5 induced by GM-CSF, independently of OSM, suggesting a key role for STAT3 in ßhCG production and trophoblast differentiation through STAT5 modulation. In conclusion, our study describes for the first time the critical role played by OSM and STAT3 signaling pathways to preserve and regulate trophoblast biological functions during inflammatory stress.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Interferon gama , Gravidez , Feminino , Humanos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interferon gama/farmacologia , Interferon gama/metabolismo , Oncostatina M/farmacologia , Oncostatina M/metabolismo , Fator de Transcrição STAT5/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais , Trofoblastos/metabolismo , Fator de Transcrição STAT3/metabolismo
8.
Talanta ; 271: 125726, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38316076

RESUMO

Oncostatin M (OSM) is an interleukin-6 (IL-6) member family cytokine implicated in the pathogenesis of chronic diseases including inflammatory bowel disease (IBD). OSM is a novel diagnostic biomarker over-expressed in the serum of IBD patients. This paper reports on the first electrochemical OSM immunosensor, developed using a multistep fabrication process aimed at covalently immobilizing OSM antibodies on a mixed self-assembled monolayer coated gold working electrode. Cyclic voltammetry, atomic force microscopy (AFM), IR spectroscopy and optical characterizations were used to validate the sensor functionalization protocol. Electrochemical impedance spectroscopy (EIS) measurements were performed to assess the reliability of the immunosensor preparation and to verify the antibody-antigen complexes formation. The label-free immunosensor showed high sensitivity identifying OSM at clinically relevant concentrations (37-1000 pg mL-1) with low detection limit of 2.86 pg mL-1. Both sensitivity and selectivity of the proposed immunosensor were also demonstrated in human serum in the presence of interfering biomarkers, making it an innovative potential platform for the OSM biomarker detection in IBD patients' serum.


Assuntos
Técnicas Biossensoriais , Doenças Inflamatórias Intestinais , Humanos , Técnicas Biossensoriais/métodos , Oncostatina M , Reprodutibilidade dos Testes , Anticorpos Imobilizados/química , Imunoensaio/métodos , Biomarcadores , Doenças Inflamatórias Intestinais/diagnóstico
9.
Invest Ophthalmol Vis Sci ; 65(1): 22, 2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38190125

RESUMO

Purpose: Continuous vision loss due to vasoproliferative eye disease still represents an unsolved issue despite anti-vascular endothelial growth factor (VEGF) therapy. The impact of signal transducer and activator of transcription 3 (STAT3) signaling on retinal angiogenesis and its potential use as a therapeutic target remain controversial. In vitro, oncostatin M (OSM), as a strong STAT3 activator, possesses robust proangiogenic activity. This study investigated to what extent the proangiogenic effects of OSM translate to the in vivo setting of vasoproliferative eye disease. Methods: The in vitro effect of OSM on endothelial cells was investigated in the spheroid sprouting assay and through RNA sequencing. The mouse model for oxygen-induced retinopathy (OIR) was used to evaluate the impact of OSM in vivo. Signaling patterns were measured by western blot and retinal cryosections. Primary Müller cell cultures were used to evaluate the effect of OSM on the Müller cell secretome. Murine retinal vascular endothelial cells were isolated from OIR retinas using fluorescence-activated cell sorting (FACS) and were used for RNA sequencing. Results: Although OSM induced pro-angiogenic responses in vitro, in the OIR model intravitreal injection of OSM reduced retinal neovascularization by 65.2% and vaso-obliteration by 45.5% in Müller cells. Injecting OSM into the vitreous activated the STAT3 signaling pathway in multiple retinal cell types, including Müller cells. In vitro, OSM treatment increased CXCL10 secretion. RNA sequencing of sorted vascular endothelial cells at OIR P17 following OSM treatment indicated downregulation of angiogenesis- and mitosis-associated genes. Conclusions: In vivo, OSM reveals a beneficial angiomodulatory effect by activating Müller cells and changing their secretome. The data highlight contradictions between cytokine-induced effects in vitro and in vivo depending on the cell types mediating the effect.


Assuntos
Neovascularização Patológica , Oncostatina M , Doenças Retinianas , Animais , Camundongos , Células Endoteliais , Células Ependimogliais , Retina
10.
J Clin Invest ; 134(6)2024 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-38236642

RESUMO

Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6-induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Segunda Neoplasia Primária , Ataxias Espinocerebelares , Humanos , Camundongos , Animais , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Interleucina-6/genética , Oncostatina M , Plasticidade Celular , Linhagem Celular Tumoral , Recidiva Local de Neoplasia , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Microambiente Tumoral
11.
Curr Osteoporos Rep ; 22(1): 80-95, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38198032

RESUMO

PURPOSE OF THE REVIEW: The bone and hematopoietic tissues coemerge during development and are functionally intertwined throughout mammalian life. Oncostatin M (OSM) is an inflammatory cytokine of the interleukin-6 family produced by osteoblasts, bone marrow macrophages, and neutrophils. OSM acts via two heterodimeric receptors comprising GP130 with either an OSM receptor (OSMR) or a leukemia inhibitory factor receptor (LIFR). OSMR is expressed on osteoblasts, mesenchymal, and endothelial cells and mice deficient for the Osm or Osmr genes have both bone and blood phenotypes illustrating the importance of OSM and OSMR in regulating these two intertwined tissues. RECENT FINDINGS: OSM regulates bone mass through signaling via OSMR, adaptor protein SHC1, and transducer STAT3 to both stimulate osteoclast formation and promote osteoblast commitment; the effect on bone formation is also supported by action through LIFR. OSM produced by macrophages is an important inducer of neurogenic heterotopic ossifications in peri-articular muscles following spinal cord injury. OSM produced by neutrophils in the bone marrow induces hematopoietic stem and progenitor cell proliferation in an indirect manner via OSMR expressed by bone marrow stromal and endothelial cells that form hematopoietic stem cell niches. OSM acts as a brake to therapeutic hematopoietic stem cell mobilization in response to G-CSF and CXCR4 antagonist plerixafor. Excessive OSM production by macrophages in the bone marrow is a key contributor to poor hematopoietic stem cell mobilization (mobilopathy) in people with diabetes. OSM and OSMR may also play important roles in the progression of several cancers. It is increasingly clear that OSM plays unique roles in regulating the maintenance and regeneration of bone, hematopoietic stem and progenitor cells, inflammation, and skeletal muscles. Dysregulated OSM production can lead to bone pathologies, defective muscle repair and formation of heterotopic ossifications in injured muscles, suboptimal mobilization of hematopoietic stem cells, exacerbated inflammatory responses, and anti-tumoral immunity. Ongoing research will establish whether neutralizing antibodies or cytokine traps may be useful to correct pathologies associated with excessive OSM production.


Assuntos
Compostos Heterocíclicos , Ossificação Heterotópica , Animais , Humanos , Camundongos , Células Endoteliais/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Mamíferos/metabolismo , Oncostatina M/genética , Oncostatina M/metabolismo , Oncostatina M/farmacologia
12.
Cell Mol Gastroenterol Hepatol ; 17(2): 219-235, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37879404

RESUMO

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.


Assuntos
Vírus da Hepatite B , Hepatite B , Camundongos , Animais , Humanos , Vírus da Hepatite B/genética , Antígenos de Superfície da Hepatite B , Oncostatina M/farmacologia , Antígenos E da Hepatite B , Interleucina-6 , Camundongos Endogâmicos C57BL , Transdução de Sinais , Hepatite B/tratamento farmacológico , Interferons , Replicação Viral
13.
Exp Hematol ; 130: 104131, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38000729

RESUMO

Age-associated clonal hematopoiesis (CH) occurs due to somatic mutations accrued in hematopoietic stem cells (HSCs) that confer a selective growth advantage in the context of aging. The mechanisms by which CH-mutant HSCs gain this advantage with aging are not comprehensively understood. Using unbiased transcriptomic approaches, we identified Oncostatin M (OSM) signaling as a candidate contributor to age-related Dnmt3a-mutant CH. We found that Dnmt3a-mutant HSCs from young adult mice (3-6 months old) subjected to acute OSM stimulation do not demonstrate altered proliferation, apoptosis, hematopoietic engraftment, or myeloid differentiation. Dnmt3a-mutant HSCs from young mice do transcriptionally upregulate an inflammatory cytokine network in response to acute in vitro OSM stimulation as evidenced by significant upregulation of the genes encoding IL-6, IL-1ß, and TNFα. OSM-stimulated Dnmt3a-mutant HSCs also demonstrate upregulation of the anti-inflammatory genes Socs3, Atf3, and Nr4a1. In the context of an aged bone marrow (BM) microenvironment, Dnmt3a-mutant HSCs upregulate proinflammatory genes but not the anti-inflammatory genes Socs3, Atf3, and Nr4a1. The results from our studies suggest that aging may exhaust the regulatory mechanisms that HSCs employ to resolve inflammatory states in response to factors such as OSM.


Assuntos
Medula Óssea , Células-Tronco Hematopoéticas , Animais , Camundongos , Anti-Inflamatórios , Hematopoese/genética , Oncostatina M/genética
15.
Int J Radiat Oncol Biol Phys ; 118(1): 203-217, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37610394

RESUMO

PURPOSE: Radiation-induced heart fibrosis (RIHF) is a severe consequence of radiation-induced heart damage (RIHD) leading to impaired cardiac function. The involvement of oncostatin M (OSM) and its receptor (OSMR) in RIHD remains unclear. This study aimed to investigate the specific mechanism of OSM/OSMR in RIHF/RIHD. METHODS AND MATERIALS: RNA sequencing was performed on heart tissues from a RIHD mouse model. OSM levels were assessed in serum samples obtained from patients receiving thoracic radiation therapy (RT), as well as in RIHF mouse heart tissues and serum using enzyme-linked immunosorbent assay. Fiber activation was evaluated through costimulation of primary cardiac fibroblasts and NIH3T3 cells with RT and OSM, using Western blotting, immunofluorescence, and quantitative Polymerase Chain Reaction (qPCR). Adeno-associated virus serotype 9-mediated overexpression or silencing of OSM specifically in the heart was performed in vivo to assess cardiac fibrosis levels by transthoracic echocardiography and pathologic examination. The regulatory mechanism of OSM on the transcription level of SMAD4 was further explored in vitro using mass spectrometric analysis, chromatin immunoprecipitation-qPCR, and DNA pull-down. RESULTS: OSM levels were elevated in the serum of patients after thoracic RT as well as in RIHF mouse cardiac endothelial cells and mouse serum. The OSM rate (post-RT/pre-RT) and the heart exposure dose in RT patients showed a positive correlation. Silencing OSMR in RIHF mice reduced fibrosis, while OSMR overexpression increased fibrotic responses. Furthermore, increased OSM promoted histone acetylation (H3K27ac) in the SMAD4 promoter region, influencing SMAD4 transcription and subsequently enhancing fibrotic response. CONCLUSIONS: The findings demonstrated that OSM/OSMR signaling promotes SMAD4 transcription in cardiac fibroblasts through H3K27 hyperacetylation, thereby promoting radiation-induced cardiac fibrosis and manifestations of RIHD.


Assuntos
Células Endoteliais , Fibroblastos , Animais , Humanos , Camundongos , Fibroblastos/metabolismo , Fibrose , Células NIH 3T3 , Oncostatina M/genética , Oncostatina M/metabolismo , Oncostatina M/farmacologia , Receptores de Oncostatina M/metabolismo , Proteína Smad4
16.
Aging Cell ; 23(2): e14043, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38111237

RESUMO

Inflammatory cytokines released by synovium after trauma disturb the gene regulatory network and have been implicated in the pathophysiology of osteoarthritis. A mechanistic understanding of how aging perturbs this process can help identify novel interventions. Here, we introduced network paradigms to simulate cytokine-mediated pathological communication between the synovium and cartilage. Cartilage-specific network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees displaying accelerated cartilage degradation. Next, network-based cytokine inference with pharmacological manipulation uncovered IL6 family member, Oncostatin M (OSM), as a driver of the aberrant matrix remodeling. By implementing a phenotypic drug discovery approach, we identified that the activation of OSM recapitulated an "inflammatory" phenotype of knee osteoarthritis and highlighted high-value targets for drug development and repurposing. These findings offer translational opportunities targeting the inflammation-driven osteoarthritis phenotype.


Assuntos
Osteoartrite do Joelho , Camundongos , Animais , Oncostatina M/genética , Oncostatina M/metabolismo , Inflamação , Fenótipo
18.
Int Marit Health ; 74(4): 243-252, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38111244

RESUMO

BACKGROUND: Seafarers, confronted with unique health challenges, occasionally necessitate medical repatriation. This study examines the trends in medical repatriation cases among Filipino seafarers employed by OSM Maritime shipping company over a 10-year period from 2013 to 2022. MATERIALS AND METHODS: Medical records of OSM Maritime seafarers were reviewed, obtaining causes for and dates of medical repatriation. International Classification of Diseases (ICD-11) was utilised to classify repatriation cases. Proportion of repatriation cases were calculated and their annual trends were analysed. RESULTS: Our findings reveal that the majority of repatriation cases are attributed to injury/trauma (19.91%), musculoskeletal (18.40%), gastrointestinal (16.56%), cardiovascular (8.77%), infectious (6.82%), and genitourinary conditions (5.30%). Significantly, the study identifies a declining trend in the proportion of cardiovascular, gastrointestinal, and genitourinary conditions in annual repatriation cases, particularly in ischaemic heart conditions, cholelithiasis, cholecystitis, and urinary calculus. CONCLUSIONS: These results emphasize the critical need for multisectoral collaboration to enhance seafarers' health and well-being. Prioritizing comprehensive care programmes, ensuring safe working conditions, and exploring holistic healthcare initiatives are essential steps to enhance seafarers' occupational health.


Assuntos
Medicina Naval , Saúde Ocupacional , Humanos , Filipinas , Navios , Oncostatina M
19.
Front Immunol ; 14: 1251031, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38035099

RESUMO

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intermittent itchy rash. Type 2 inflammatory cytokines such as interleukin (IL)-4, IL-13, and IL-31 are strongly implicated in AD pathogenesis. Stimulation of IL-31 cognate receptors on C-fiber nerve endings is believed to activate neurons in the dorsal root ganglion (DRG), causing itch. The IL-31 receptor is a heterodimer of OSMRß and IL31RA subunits, and OSMRß can also bind oncostatin M (OSM), a pro-inflammatory cytokine released by monocytes/macrophages, dendritic cells, and T lymphocytes. Further, OSM expression is enhanced in the skin lesions of AD and psoriasis vulgaris patients. Objective: The current study aimed to examine the contributions of OSM to AD pathogenesis and symptom expression. Methods: The expression levels of the OSM gene (OSM) and various cytokine receptor genes were measured in human patient skin samples, isolated human monocytes, mouse skin samples, and mouse DRG by RT-qPCR. Itching responses to various pruritogens were measured in mice by counting scratching episodes. Results: We confirmed overexpression of OSM in skin lesions of patients with AD and psoriasis vulgaris. Monocytes isolated from the blood of healthy subjects overexpressed OSM upon stimulation with IL-4 or GM-CSF. Systemic administration of OSM suppressed IL31RA expression in the mouse DRG and IL-31-stimulated scratching behavior. In contrast, systemic administration of OSM increased the expression of IL-4- and IL-13-related receptors in the DRG. Conclusion: These results suggest that OSM is an important cytokine in the regulation of skin monocytes, promoting the actions of IL-4 and IL-13 in the DRG and suppressing the action of IL-31. It is speculated that OSM released from monocytes in skin modulates the sensitivity of DRG neurons to type 2 inflammatory cytokines and thereby the severity of AD-associated skin itch.


Assuntos
Dermatite Atópica , Psoríase , Humanos , Camundongos , Animais , Oncostatina M/farmacologia , Oncostatina M/metabolismo , Interleucina-4/metabolismo , Gânglios Espinais/metabolismo , Interleucina-13/metabolismo , Prurido/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Dermatite Atópica/metabolismo , Receptores de Interleucina/metabolismo , Psoríase/metabolismo
20.
Front Immunol ; 14: 1258765, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38022540

RESUMO

Rheumatoid arthritis (RA) is a self-immune inflammatory disease characterized by joint damage. A series of cytokines are involved in the development of RA. Oncostatin M (OSM) is a pleiotropic cytokine that primarily activates the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, and other physiological processes such as cell proliferation, inflammatory response, immune response, and hematopoiesis through its receptor complex. In this review, we first describe the characteristics of OSM and its receptor, and the biological functions of OSM signaling. Subsequently, we discuss the possible roles of OSM in the development of RA from clinical and basic research perspectives. Finally, we summarize the progress of clinical studies targeting OSM for the treatment of RA. This review provides researchers with a systematic understanding of the role of OSM signaling in RA, which can guide the development of drugs targeting OSM for the treatment of RA.


Assuntos
Artrite Reumatoide , Transdução de Sinais , Humanos , Oncostatina M , Transdução de Sinais/fisiologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Janus Quinases/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo
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