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1.
Front Immunol ; 12: 709759, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603283

RESUMO

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.


Assuntos
Anticorpos Antivirais/sangue , Infecções Assintomáticas , Linfócitos T CD4-Positivos/imunologia , COVID-19/patologia , Mediadores da Inflamação/sangue , SARS-CoV-2/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Contagem de Linfócito CD4 , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Humanos , Inflamação/imunologia , Interleucina-18/sangue , Macrófagos/imunologia , Monócitos/imunologia , Oncostatina M/sangue , Fosfoproteínas/imunologia , Domínios Proteicos/imunologia , Proteína S100A12/sangue , Glicoproteína da Espícula de Coronavírus/imunologia , Fator de Crescimento Transformador alfa/sangue
2.
Sci Rep ; 11(1): 16174, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376712

RESUMO

Oncostatin M (OSM) is a pleiotropic, interleukin-6 family inflammatory cytokine that plays an important role in inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis, and cancer progression and metastasis. Recently, elevated OSM levels have been found in the serum of COVID-19 patients in intensive care units. Multiple anti-OSM therapeutics have been investigated, but to date no OSM small molecule inhibitors are clinically available. To pursue a high-throughput screening and structure-based drug discovery strategy to design a small molecule inhibitor of OSM, milligram quantities of highly pure, bioactive OSM are required. Here, we developed a reliable protocol to produce highly pure unlabeled and isotope enriched OSM from E. coli for biochemical and NMR studies. High yields (ca. 10 mg/L culture) were obtained in rich and minimal defined media cultures. Purified OSM was characterized by mass spectrometry and circular dichroism. The bioactivity was confirmed by induction of OSM/OSM receptor signaling through STAT3 phosphorylation in human breast cancer cells. Optimized buffer conditions yielded 1H, 15N HSQC NMR spectra with intense, well-dispersed peaks. Titration of 15N OSM with a small molecule inhibitor showed chemical shift perturbations for several key residues with a binding affinity of 12.2 ± 3.9 µM. These results demonstrate the value of bioactive recombinant human OSM for NMR-based small molecule screening.


Assuntos
Descoberta de Drogas/métodos , Oncostatina M/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Espectroscopia de Ressonância Magnética/métodos , Simulação de Acoplamento Molecular , Oncostatina M/química , Oncostatina M/metabolismo , Fosforilação , Ligação Proteica , Fator de Transcrição STAT3/metabolismo , Bibliotecas de Moléculas Pequenas/química
3.
Transl Vis Sci Technol ; 10(9): 6, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34347033

RESUMO

Purpose: Retinitis pigmentosa (RP) is caused by mutations in more than 60 genes. Mutation-independent approaches to its treatment by exogeneous administration of neurotrophic factors that will preserve existing retinal anatomy and visual function are a rational strategy. Ciliary neurotrophic factor (CNTF) and oncostatin M (OSM) are two potent survival factors for neurons. However, growth factors degrade rapidly if administered directly. A sustained delivery of growth factors is required for translating their potential therapeutic benefit into patients. Methods: Stable and biocompatible nanoparticles (NP) that incorporated with CNTF and OSM (CNTF- and OSM-NP) were formulated. Both NP-trophic factors were tested in vitro using photoreceptor progenitor cells (PPC) and retinal ganglion progenitor cells (RGPC) derived from induced pluripotent stem cells and in vivo using an optic nerve crush model for glaucoma and the Royal College of Surgeons rat, model of RP (n = 8/treatment) by intravitreal delivery. Efficacy was evaluated by electroretinography and optokinetic response. Retinal histology and a whole mount analysis were performed at the end of experiments. Results: Significant prosurvival and pro-proliferation effects of both complexes were observed in both photoreceptor progenitor cells and RGPC in vitro. Importantly, significant RGC survival and preservation of vision and photoreceptors in both complex-treated animals were observed compared with control groups. Conclusions: These results demonstrate that NP-trophic factors are neuroprotective both in vitro and in vivo. A single intravitreal delivery of both NP-trophic factors offered neuroprotection in animal models of retinal degeneration. Translational Relevance: Sustained nanoparticle delivery of neurotrophic factors may offer beneficial effects in slowing down progressive retinal degenerative conditions, including retinitis pigmentosa, age-related macular degeneration, and glaucoma.


Assuntos
Nanopartículas , Degeneração Retiniana , Animais , Fator Neurotrófico Ciliar , Humanos , Oncostatina M , Ratos , Degeneração Retiniana/tratamento farmacológico , Células Ganglionares da Retina , Roedores
4.
Exp Eye Res ; 210: 108708, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34332990

RESUMO

Elevated intraocular pressure (IOP) is a significant risk factor for vision loss due to glaucoma, which is a major cause of blindness worldwide. Glaucoma filtration surgery (GFS) is an important method to reduce IOP by guidance of aqueous humor into a newly built filtration bleb in the conjunctiva; management of the wound healing mechanism is essential for the success of GFS. Here, we investigated the roles of interleukin (IL)-6 family members during the wound healing process after GFS. At the surgical site, the expression levels of genes encoding IL-6, oncostatin M (OSM), their receptors, and collagen I were elevated at 3 h after GFS, whereas the levels of genes encoding transforming growth factor (TGF)-ß, α-smooth muscle actin (SMA), type IV collagen, and fibronectin were elevated at 3 days after GFS. IL-6 trans-signaling and OSM signaling suppressed TGF-ß-induced expression of α-SMA and collagen IV, as well as activation of the non-canonical TGF-ß pathway, suggesting that IL-6 and OSM may aid in controlling the phase transition from inflammation to proliferation and remodeling. The suppressive effects of OSM were accompanied by STAT3 activation, such that STAT1 function was complementary to STAT3. Taken together, these observations indicated that IL-6 family members constitute early response genes after GFS, which can suppress TGF-ß-induced expression of late response genes at the surgical site after GFS.


Assuntos
Fator Neurotrófico Ciliar/metabolismo , Túnica Conjuntiva/patologia , Interleucina-6/metabolismo , Fator Inibidor de Leucemia/metabolismo , Oncostatina M/metabolismo , Cicatrização/fisiologia , Actinas/metabolismo , Animais , Western Blotting , Colágeno Tipo IV/metabolismo , Túnica Conjuntiva/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Glaucoma/cirurgia , Humanos , Coelhos , Reação em Cadeia da Polimerase em Tempo Real , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Trabeculectomia , Fator de Crescimento Transformador beta/farmacologia
5.
J Pediatr Gastroenterol Nutr ; 73(3): 352-357, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34117193

RESUMO

OBJECTIVES: This study aimed to determine whether mRNA expression of oncostatin-M (OSM) and its receptor (OSMR) in initial, pre-treatment intestinal biopsies is predictive of response to tumor necrosis factor antagonists (anti-TNF) in a pediatric inflammatory bowel disease (IBD) cohort. Secondary outcomes correlated OSM and OSMR expression with demographic variables; IBD type, extent, phenotype, and severity; laboratory values; and endoscopic findings. METHODS: A retrospective chart review was conducted on 98 pediatric patients. Patients' clinical courses were stratified as follows: failed anti-TNF (n = 14), quiescent on anti-TNF (n = 36), anti-TNF naïve (n = 19), and age-matched non-IBD controls (n = 29). The mRNA from each patient's pre-treatment ileal or colonic biopsy was isolated, and expression of OSM and OSMR was analyzed. RESULTS: There was no difference in OSM or OSMR expression among the three IBD groups; however, expression was significantly higher in patients with IBD than non-IBD controls (P < 0.001). OSM and OSMR were more highly expressed in patients with ulcerative colitis (UC) with a Mayo score of 3 (P = 0.0092 and P = 0.0313, respectively). High OSM expression correlated with severe disease activity indices at diagnosis (P = 0.002), anemia at diagnosis (P = 0.0236), and need for immunomodulators (P = 0.0193) and steroids (P = 0.0273) during patients' clinical courses. CONCLUSIONS: OSM and OSMR expression were not predictive of response to anti-TNF in our pediatric cohort. OSM expression did correlate with IBD compared with healthy controls as well as with several clinical indicators of severe IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Subunidade beta de Receptor de Oncostatina M/genética , Oncostatina M/genética , Criança , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral
6.
J Exp Med ; 218(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34132743

RESUMO

The wound healing process that occurs after spinal cord injury is critical for maintaining tissue homeostasis and limiting tissue damage, but eventually results in a scar-like environment that is not conducive to regeneration and repair. A better understanding of this dichotomy is critical to developing effective therapeutics that target the appropriate pathobiology, but a major challenge has been the large cellular heterogeneity that results in immensely complex cellular interactions. In this study, we used single-cell RNA sequencing to assess virtually all cell types that comprise the mouse spinal cord injury site. In addition to discovering novel subpopulations, we used expression values of receptor-ligand pairs to identify signaling pathways that are predicted to regulate specific cellular interactions during angiogenesis, gliosis, and fibrosis. Our dataset is a valuable resource that provides novel mechanistic insight into the pathobiology of not only spinal cord injury but also other traumatic disorders of the CNS.


Assuntos
Comunicação Celular , Análise de Célula Única , Traumatismos da Medula Espinal/patologia , Angiopoietinas/metabolismo , Animais , Astrócitos/metabolismo , Quimiotaxia , Feminino , Fibroblastos/metabolismo , Fibrose , Gliose/complicações , Gliose/patologia , Inflamação/patologia , Interleucina-6/metabolismo , Ligantes , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Células Mieloides/patologia , Neuroglia/patologia , Oncostatina M/metabolismo , Receptores de Oncostatina M/metabolismo , Transdução de Sinais , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/imunologia , Fatores de Tempo , Transcriptoma/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Arthritis Res Ther ; 23(1): 141, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990221

RESUMO

BACKGROUND: Informative serum biomarkers for monitoring inflammatory activity and treatment responses in axial spondyloarthritis (axSpA) are lacking. We assessed whether Lipocalin 2 (LCN2) and Oncostatin M (OSM), both having roles in inflammation and bone remodeling, may accurately reflect chronic joint inflammation and treatment response in axSpA. Previous reports in animal models showed involvement of LCN2 and OSM in joint/gut inflammation. We asked whether they also play a role in human axSpA. METHODS: We analyzed a longitudinal observational axSpA cohort (286 patients) with yearly clinical assessments and concurrent measurements of serum LCN2 and OSM (1204 serum samples) for a mean of 4 years. Biomarker levels were correlated with MRI scoring and treatment response. RESULTS: Persistent and transient elevation of LCN2 and OSM were observed in axSpA patients. Persistent elevation of LCN2 or OSM, but not CRP, correlated with sacroiliac joint (SIJ) MRI SPARCC scores (Pearson's correlation p = 0.0005 and 0.005 for LCN2 and OSM respectively), suggesting that LCN2/OSM outperforms CRP as reflective of SIJ inflammation. We observed both concordant and discordant patterns of LCN2 and OSM in relationship to back pain, the cardinal clinical symptom in axSpA. Twenty-six percent (73/286) of the patients remained both clinically and serologically active (CASA). Sixty percent (173/286) of the patients became clinically quiescent, with back pain resolved, but 53% (92/173) of them were serologically active (CQSA), indicating that pain control may not indicate control of joint inflammation, as reflected by positive MRI imaging of SIJ. With respect to treatment responses, transient elevation of LCN2 or OSM over time was predictive of better response to all treatments. CONCLUSION: In axSpA, persistent LCN2 and/or OSM elevation reflects chronic SIJ inflammation and suboptimal treatment response. In our cohort, half of the currently deemed clinically quiescent patients with back pain resolved continued to demonstrate chronic joint inflammation. LCN2 and OSM profiling outperforms CRP as a predictive measure and provides an objective assessment of chronic local inflammation in axSpA patients.


Assuntos
Espondilartrite , Humanos , Inflamação , Lipocalina-2 , Imageamento por Ressonância Magnética , Oncostatina M , Articulação Sacroilíaca , Índice de Gravidade de Doença , Espondilartrite/tratamento farmacológico
8.
Aging (Albany NY) ; 13(10): 14065-14077, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34037532

RESUMO

Long noncoding RNAs play key roles in several cancers, but their potential functions in gastroenteropancreatic neuroendocrine neoplasms remain to be investigated. We performed GeneChip assay to explore differentiated lncRNAs in gastric NENs and peri-cancerous tissues. The regulation of HNF1A-AS1 on biological behavior of GEP-NENs cells and in vivo xenograft model was confirmed by CCK8, colony formation assay, transwell, western blot and qRT-PCR. We next detected the potential transcription factors and the binding sites between them with bioinformatic analysis. qRT-PCR was performed to analyze the exact relationship between them. HNF1A-AS1 expression was decreased in gastric NENs tissues (p < 0.01). Over-expression of HNF1A-AS1 suppressed cellular proliferation, migration and invasion. Knockdown of transcription factor 3 inhibited the expression of HNF1A-AS1 and promoted cellular migration and invasion. Oncostatin M was identified as the downstream target of HNF1A-AS1. Inhibition of transforming growth factor-ß activity inhibited HNF1A-AS1/Oncostatin M-mediated epithelial-mesenchymal transition. Our data suggest that transcription factor 3/HNF1A-AS1/Oncostatin M axis inhibits the tumorigenesis and metastasis of gastroenteropancreatic neuroendocrine neoplasms via transforming growth factor-ß signaling.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Transição Epitelial-Mesenquimal/genética , Neoplasias Intestinais/genética , Tumores Neuroendócrinos/genética , Oncostatina M/genética , Neoplasias Pancreáticas/genética , RNA Longo não Codificante/genética , Transdução de Sinais , Neoplasias Gástricas/genética , Transcrição Genética , Fator de Crescimento Transformador beta/metabolismo , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Sobrevivência Celular/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Intestinais/patologia , Invasividade Neoplásica , Tumores Neuroendócrinos/patologia , Oncostatina M/metabolismo , Neoplasias Pancreáticas/patologia , RNA Longo não Codificante/metabolismo , Transdução de Sinais/genética , Neoplasias Gástricas/patologia
9.
Biomolecules ; 11(3)2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800255

RESUMO

The aim of the present study was to study the associations between urine albumin excretion, and a large number of urinary chemokines, cytokines, and growth factors in a normal population. We selected 90 urine samples from individuals without CVD, diabetes, stroke or kidney disease belonging to the Prospective Investigation of the Vasculature in Uppsala Seniors Study (41 males and 49 females, all aged 75 years). Urinary cytokine levels were analyzed with two multiplex assays (proximity extension assays) and the cytokine levels were correlated with urine albumin. After adjustment for sex, body mass index (BMI), estimated glomerular filtration rate (eGFR), smoking and multiplicity testing, 11 biomarkers remained significantly associated with urine albumin: thrombospondin 2, interleukin 6, interleukin 8, hepatocyte growth factor, matrix metalloproteinase-12 (MMP-12), C-X-C motif chemokine 9, tumor necrosis factor receptor superfamily member 11B, osteoprotegerin, growth-regulated alpha protein, C-X-C motif chemokine 6, oncostatin-M (OSM) and fatty acid-binding protein, intestinal, despite large differences in molecular weights. In this study, we found associations between urinary albumin and both small and large urine proteins. Additional studies are warranted to identify cytokine patterns and potential progression markers in various renal diseases.


Assuntos
Albuminúria/urina , Quimiocinas/urina , Citocinas/urina , Fator de Crescimento de Hepatócito/urina , Idoso , Feminino , Taxa de Filtração Glomerular/fisiologia , Humanos , Interleucina-6/metabolismo , Interleucina-6/urina , Interleucina-8/urina , Masculino , Oncostatina M/urina , Trombospondinas/urina
10.
Biochim Biophys Acta Gen Subj ; 1865(7): 129907, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33845142

RESUMO

BACKGROUND: Oncostatin M (OSM) and leukemia inhibitory factor (LIF) are two important pro-inflammatory cytokines of the interleukin-6 (IL-6) family. The two cytokines mediated signaling was recently found to be closely associated with cancer and chronic inflammation, which represent promising therapeutic targets for the treatment of many solid tumors and inflammatory disease. As the most closely related members, cross-reactivity of them may result in undesired activation of off-target cells, leading to toxicity or lack of efficacy of the therapeutic effects. However, the mechanism of the cross-reactivity of OSM and LIF is not well understood. METHODS: In this work, protein-protein docking, molecular dynamics (MD) simulations with explicit solvent and post endpoints binding free energy (BFE) analysis were carried out to further understand the structural and energetic principles of interactions between the two cytokines and the shared receptor LIFR. RESULTS: For the first time, the simulation given a computational model of OSM-LIFR interaction, and provided significant insights into the mechanism of OSM and LIF cross-react with LIFR. The identified common features shared by OSM and LIF bind to LIFR involving 10 "conserved" residues (90% similarity) distributed at the binding site III comprised of AB loop, BC loop and D helix. In addition, 11 shared residues were identified in LIFR contribute 77.85% and 84.63% energies for OSM and LIF binding, which play a critical role in the formation of the two cytokine-receptor complexes. Moreover, the "nonconserved" residues at the same position of cytokines such as Asp41 in OSM and Pro51 in LIF as well as the three residues (Glu338, Asn201 and Glu260) in LIFR were also discovered. CONCLUSIONS: These important information may facilitate the rational design of novel chemical or biological agents with less toxicity and improved efficacy.


Assuntos
Subunidade alfa de Receptor de Fator Inibidor de Leucemia/metabolismo , Fator Inibidor de Leucemia/química , Fator Inibidor de Leucemia/metabolismo , Oncostatina M/química , Oncostatina M/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Reações Cruzadas , Humanos , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Homologia de Sequência
11.
Int J Mol Sci ; 22(8)2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923774

RESUMO

Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68+, CD163+ and CD206+ macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure.


Assuntos
Cardiomiopatias/metabolismo , Granuloma/metabolismo , Miocárdio/metabolismo , Oncostatina M/metabolismo , Proteínas Associadas a Pancreatite/metabolismo , Sarcoidose/metabolismo , Adulto , Apoptose , Aurora Quinases/metabolismo , Cardiomiopatias/patologia , Proliferação de Células , Proteínas do Citoesqueleto/metabolismo , Feminino , Granuloma/patologia , Histonas/metabolismo , Humanos , Antígeno Ki-67/metabolismo , Macrófagos/metabolismo , Macrófagos/fisiologia , Masculino , Proteínas de Membrana/metabolismo , Proteínas dos Microfilamentos/metabolismo , Pessoa de Meia-Idade , Sarcoidose/patologia
12.
Molecules ; 26(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924385

RESUMO

The role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80+ KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver regeneration. In pre- or post-PHx, the clearance of KCs by intraperitoneal injection of the anti-F4/80 antibody (α-F4/80) was performed to study the distinct role of F4/80+ KCs during the regenerative process. In RNA sequencing of isolated F4/80+ KCs, the initiation phase was compared with the progression phase. Immunohistochemistry and immunofluorescence staining of Ki67, HNF-4α, CD-31, and F4/80 and Western blot of the TGF-ß2 pathway were performed. Depletion of F4/80+ KCs in pre-PHx delayed the peak of hepatocyte proliferation from 48 h to 120 h, whereas depletion in post-PHx unexpectedly led to persistent inhibition of hepatocyte proliferation, indicating the distinct role of F4/80+ KCs in the initiation and progression phases of liver regeneration. F4/80+ KC depletion in post-PHx could significantly increase TGF-ß2 serum levels, while TGF-ßRI partially rescued the impaired proliferation of hepatocytes. Additionally, F4/80+ KC depletion in post-PHx significantly lowered the expression of oncostatin M (OSM), a key downstream mediator of interleukin-6, which is required for hepatocyte proliferation during liver regeneration. In vivo, recombinant OSM (r-OSM) treatment alleviated the inhibitory effect of α-F4/80 on the regenerative progression. Collectively, F4/80+ KCs release OSM to inhibit TGF-ß2 activation, sustaining hepatocyte proliferation by releasing a proliferative brake.


Assuntos
Antígenos de Diferenciação/metabolismo , Macrófagos do Fígado/metabolismo , Regeneração Hepática/fisiologia , Fígado/metabolismo , Fígado/cirurgia , Oncostatina M/metabolismo , Fator de Crescimento Transformador beta2/metabolismo , Animais , Antígenos de Diferenciação/imunologia , Western Blotting , Células Cultivadas , Hepatectomia , Hepatócitos/metabolismo , Imuno-Histoquímica , Fígado/citologia , Regeneração Hepática/genética , Masculino , Camundongos , Microscopia de Fluorescência , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Fator de Crescimento Transformador beta2/genética
13.
Immunity ; 54(3): 401-403, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33691129

RESUMO

Dectin-1 is known for promoting anti-fungal responses through the signaling molecule Card9. In this issue of Immunity, Deerhake et al. now report that during autoimmune neuroinflammation, Dectin-1 can promote a neuroprotective feed-forward pathway through Card9-independent upregulation of Oncostatin M.


Assuntos
Astrócitos , Transdução de Sinais , Astrócitos/metabolismo , Humanos , Inflamação , Oncostatina M/metabolismo , Regulação para Cima
14.
Cells ; 10(3)2021 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673583

RESUMO

Pro-inflammatory cytokines are considered to play a major role in osteoarthritis (OA), yet so far, the specific cytokines involved in the pathology of OA have not been identified. Oncostatin M (OSM) is a cytokine from the interleukin 6 (IL-6) family that has been shown to be elevated in synovial fluid of most rheumatoid arthritis (RA) patients, but only in a limited subset of OA patients. Little is known about OSM in the different joint tissues during OA and how its expression correlates with hallmarks of disease. Here, we mapped OSM expression in the joint tissues of two rat models of arthritis: an acute inflammatory model and an instability-induced osteoarthritic model. OSM expression was correlated with hallmarks of OA, namely cartilage damage, synovitis, and osteophyte formation. Reanalysis of an existing dataset on cytokine profiling of OA synovial fluid was performed to assess pattern differences between patients positive and negative for OSM. In the inflammatory model, OSM expression correlated with synovitis and osteophyte formation but not with cartilage damage. On the contrary, in the instability model of OA, an increase in synovitis, cartilage damage, and osteophyte formation was observed without changes in OSM expression. In line with these findings, synovial fluid of OA patients with detectable OSM contained higher levels of other inflammatory cytokines, namely interferon gamma (IFN-γ), IL-1α and tumor necrosis factor alpha (TNF-α), likely indicating a more inflammatory state. Taken together these data indicate OSM might play a prominent role in inflammatory phenotypes of OA.


Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Artrite Experimental/genética , Inflamação/fisiopatologia , Oncostatina M/metabolismo , Oncostatina M/uso terapêutico , Osteoartrite/genética , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Fenótipo , Ratos
15.
World Neurosurg ; 149: e437-e446, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33567366

RESUMO

BACKGROUND: Despite progress in the detection of biological molecules that contribute to intracranial aneurysm (IA) development, many pathophysiological mechanisms remain unclear, particularly with regard to predicting IA rupture. In this study, we aimed to identify hub genes and construct a new model to predict IA rupture. METHODS: Four datasets (62 ruptured IAs, 16 unruptured IAs, and 31 normal controls) were downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified between the IAs and normal controls. All overlapping genes were analyzed using weighted gene co-expression network analysis. Functional enrichment analyses were performed using key modules. We then intersected the key module genes with DEGs. Protein-protein interaction networks were assessed to identify key hub genes. Least absolute shrinkage and selection operator logistic regression analysis was performed to construct a prediction model. A receiver operating characteristic curve was constructed to evaluate the reliability of the scoring system. RESULTS: After intersection and normalization, 433 DEGs were identified and 15,388 genes were selected for weighted gene co-expression network analysis. The black module with 1145 genes exhibited the highest correlation with IA rupture. Many potential mechanisms are involved, such as the inflammatory response, innate immune response, extracellular exosome, and extracellular space. Thirty hub genes were selected from the protein-protein interaction, and 4 independent risk genes, TNFAIP6, NCF2, OSM, and IRAK3, were identified in the least absolute shrinkage and selection operator logistic regression model. CONCLUSIONS: Our prediction model not only serves as a useful tool for assessing the risk of IA rupture, but the key genes identified herein could also serve as biomarkers and therapeutic targets.


Assuntos
Aneurisma Roto/genética , Aneurisma Intracraniano/genética , Aneurisma Roto/imunologia , Aneurisma Roto/metabolismo , Moléculas de Adesão Celular/genética , Bases de Dados Genéticas , Exossomos/genética , Espaço Extracelular/genética , Redes Reguladoras de Genes , Humanos , Imunidade Inata/genética , Inflamação/genética , Quinases Associadas a Receptores de Interleucina-1/genética , Aneurisma Intracraniano/imunologia , Aneurisma Intracraniano/metabolismo , Modelos Logísticos , NADPH Oxidases/genética , Oncostatina M/genética , Mapas de Interação de Proteínas , Curva ROC , Reprodutibilidade dos Testes , Medição de Risco , Transcriptoma
16.
Infect Immun ; 89(4)2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33526570

RESUMO

Pneumonia is a major public health concern, causing significant morbidity and mortality annually despite the broad use of antimicrobial agents. Underlying many of the severe sequelae of acute lung infections is dysfunction of the immune response, which remains incompletely understood yet is an attractive target of adjunct therapy in pneumonia. Here, we investigate the role of oncostatin M (OSM), a pleiotropic cytokine of the interleukin-6 (IL-6) family, and how its signaling modulates multiple innate immune pathways during pneumonia. Previously, we showed that OSM is necessary for neutrophil recruitment to the lungs during pneumonia by stimulating STAT3-driven CXCL5 expression. In this study, transcriptional profiling of whole-lung pneumonia with OSM neutralization revealed 241 differentially expressed genes following only 6 h of infection. Many downregulated genes are associated with STAT1, STAT3, and interferon signaling, suggesting these pathways are induced by OSM early in pneumonia. Interestingly, STAT1 and STAT3 activation was subsequently upregulated with OSM neutralization by 24 h, suggesting that OSM interruption dysregulates these central signaling pathways. When we investigated the source of OSM in pneumonia, neutrophils and, to a lesser extent, macrophages appear to be primary sources, suggesting a positive feedback loop of OSM production by neutrophils. From these studies, we conclude that OSM produced by recruited neutrophils tunes early innate immune signaling pathways, improving pneumonia outcomes.


Assuntos
Neutrófilos/imunologia , Neutrófilos/metabolismo , Oncostatina M/metabolismo , Pneumonia/etiologia , Pneumonia/metabolismo , Transdução de Sinais , Animais , Biomarcadores , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Pneumonia/patologia
17.
Immunity ; 54(3): 484-498.e8, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33581044

RESUMO

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.


Assuntos
Astrócitos/imunologia , Encéfalo/patologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Lectinas Tipo C/metabolismo , Esclerose Múltipla/imunologia , Células Mieloides/imunologia , Inflamação Neurogênica/imunologia , Receptores Mitogênicos/metabolismo , Animais , Comunicação Celular , Células Cultivadas , Modelos Animais de Doenças , Galectinas/metabolismo , Regulação da Expressão Gênica , Lectinas Tipo C/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glicoproteína Mielina-Oligodendrócito/imunologia , Oncostatina M/genética , Oncostatina M/metabolismo , Subunidade beta de Receptor de Oncostatina M/metabolismo , Fragmentos de Peptídeos/imunologia , Receptores Mitogênicos/genética , Transdução de Sinais
18.
Jpn J Ophthalmol ; 65(1): 144-153, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33403505

RESUMO

PURPOSE: Vernal keratoconjunctivitis (VKC) is a severe and recurrent allergic conjunctivitis, the mechanism of which is not well understood. In this study, we investigated the role of oncostatin M (OSM) in the pathogenesis of VKC, with a focus on tissue remodeling. STUDY DESIGN: Clinical and experimental. PATIENTS AND METHODS: The OSM concentrations in tear fluid samples obtained from VKC patients and healthy controls were measured using ELISA, and the expression of OSM mRNA and protein in giant papillae resected from VKC patients was investigated using RT-PCR and immunohistochemistry, respectively. In cultured human conjunctival epithelial cells (HconEpiCs), expression of OSM receptor ß (OSMRß) was detected using immunocytochemical and FACS analyses. Finally, we investigated whether recombinant OSM activated STAT1 and STAT3 to induce the expression of various genes related to tissue remodeling in HconEpiCs, by using Western blot analysis, microarray analysis, and RT-PCR. RESULTS: The OSM concentration was higher in the tear fluid of VKC patients than in that of the healthy controls, and strong expression of OSM mRNA was found in the giant papillae. We also detected T cells expressing OSM in the giant papillae. In addition, HconEpiCs showed surface expression of OSMRß. Recombinant human OSM strongly activated both STAT1 and STAT3 in HconEpiCs and induced various tissue remodeling-related genes, including MMP-1, MMP-3, IL-24, IL-20, serpinB3, S100A7, tenascin C, and SOCS3. CONCLUSION: Our results suggest that OSM is one of the key molecules involved in remodeling of giant papillae in VKC.


Assuntos
Conjuntivite Alérgica , Túnica Conjuntiva , Conjuntivite Alérgica/diagnóstico , Humanos , Oncostatina M/genética , RNA Mensageiro , Lágrimas
19.
Acta Neurol Scand ; 143(5): 530-537, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33492677

RESUMO

OBJECTIVES: Multiple cytokines have been implicated in aneurysmal subarachnoid hemorrhage (aSAH), but tumor necrosis factor superfamily 14 (LIGHT/TNFSF14) and oncostatin-M (OSM) have not been previously explored. AIMS OF THE STUDY: The primary objective of this study was to examine the relationship between TNFSF14 and OSM levels and survival. Our secondary goal was to investigate a potential association between these markers and the incidence of delayed cerebral ischemia (DCI). MATERIALS & METHODS: We consecutively recruited 60 patients with a clinical diagnosis of aSAH. LIGHT/TNFSF14 and OSM serum concentrations were determined by ELISA. The primary endpoint was survival at Day 30, while development of DCI was assessed as secondary outcome. RESULTS: Patients had significantly higher levels of both markers than the control group (median of LIGHT: 18.1 pg/ml vs. 7 pg/ml; p = 0.01; median of OSM: 10.3 pg/ml vs. 2.8 pg/ml, p < 0.001). Significantly lower serum level of LIGHT/TNFSF14 was found in nonsurviving patients (n = 9) compared with survivors (n = 51; p = 0.011). Based on ROC analysis, serum LIGHT/TNFSF14 with a cutoff value of >7.95 pg/ml predicted 30-day survival with a sensitivity of 71% and specificity of 78% (Area: 0.763; 95% CI: 0.604-0.921, p = 0.013). In addition, it was also a predictor of DCI with a sensitivity of 72.7% and a specificity of 62.5% (AUC: 0.702; 95% CI: 0.555-0.849, p = 0.018). Based on binary logistic regression analysis, LIGHT/TNFSF14 was found to be independently associated with 30-day mortality, but not with DCI. CONCLUSION: In this cohort, a higher serum level of LIGHT/TNFSF14 was associated with increased survival of patients with aSAH.


Assuntos
Biomarcadores/sangue , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/mortalidade , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oncostatina M/sangue , Curva ROC
20.
J Neurochem ; 157(6): 1821-1837, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32885411

RESUMO

Hyperalgesic priming is characterized by enhanced nociceptor sensitization by pronociceptive mediators, prototypically PGE2 . Priming has gained interest as a mechanism underlying the transition to chronic pain. Which stimuli induce priming and what cellular mechanisms are employed remains incompletely understood. In adult male rats, we present the cytokine Oncostatin M (OSM), a member of the IL-6 family, as an inducer of priming by a novel mechanism. We used a high content microscopy based approach to quantify the activation of endogenous PKA-II and ERK of thousands sensory neurons in culture. Incubation with OSM increased and prolonged ERK activation by agents that increase cAMP production such as PGE2 , forskolin, and cAMP analogs. These changes were specific to IB4/CaMKIIα positive neurons, required protein translation, and increased cAMP-to-ERK signaling. In both, control and OSM-treated neurons, cAMP/ERK signaling involved RapGEF2 and PKA but not Epac. Similar enhancement of cAMP-to-ERK signaling could be induced by GDNF, which acts mostly on IB4/CaMKIIα-positive neurons, but not by NGF, which acts mostly on IB4/CaMKIIα-negative neurons. In vitro, OSM pretreatment rendered baseline TTX-R currents ERK-dependent and switched forskolin-increased currents from partial to full ERK-dependence in small/medium sized neurons. In summary, priming induced by OSM uses a novel mechanism to enhance and prolong coupling of cAMP/PKA to ERK1/2 signaling without changing the overall pathway structure.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Hiperalgesia/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Oncostatina M/toxicidade , Animais , Antineoplásicos/toxicidade , Humanos , Hiperalgesia/induzido quimicamente , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
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