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1.
Front Immunol ; 12: 685344, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34211472

RESUMO

Vaccination is the best prophylaxis for the prevention of infectious diseases, including coronavirus disease 2019. However, the efficacy of vaccines and onset of adverse reactions vary among individuals. Circulating extracellular vesicles (EVs) regulate the immune responses after vaccination by delivering microRNAs (miRNAs) to myeloid and lymphoid cells. Among these, miR-192 levels in serum EVs increase with aging, in an IL-6-dependent manner, reducing excessive IL-6 expression in aged mice, creating a negative feedback loop. Excessive IL-6 expression reduces vaccination efficacy in aged mice, while EV miR-192 improves efficacy in these aged mice as well, making this miRNA an interesting focus of study. miR-21 levels in serum EVs also increase with aging, and regulates the expression of IL-12 required for Th1 responses; therefore, EV miR-21 is expected to regulate vaccine efficacy. miR-451a, another important miRNA, is abundant in serum EVs and controls the expression of cytokines, such as type I interferon and IL-6. However, levels differ among individuals and correlate with local inflammatory symptoms experienced after a seasonal flu vaccination. These findings suggest the importance of EV miRNAs as a tool to improve vaccine efficacy and also as biomarkers to predict the immune response and adverse reactions after vaccinations.


Assuntos
Vesículas Extracelulares/metabolismo , Interferon Tipo I/imunologia , Interleucina-6/imunologia , MicroRNAs/sangue , Envelhecimento/sangue , Envelhecimento/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Humanos , Interferon Tipo I/biossíntese , Subunidade p35 da Interleucina-12/biossíntese , Subunidade p35 da Interleucina-12/imunologia , Interleucina-6/biossíntese , MicroRNAs/genética , SARS-CoV-2/imunologia , Células Th1/imunologia , Vacinação
2.
Medicine (Baltimore) ; 100(25): e26426, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160431

RESUMO

INTRODUCTION: Esophagectomy is a major surgery with a high degree of catabolic and post-surgical inflammatory response accompanied by high morbidity and significant mortality. Post-surgical nutritional support via enteral administration of ω-3 fatty acids has been seen to be effective although its bad tolerance. There are few clinical trials with parenteral ω-3 fatty acids in these patients. We propose to investigate the effect of combining a parenteral fish oil lipid emulsion with the standard enteral nutrition (EN) support. MATERIALS AND METHODS: Prospective, single-center, randomized, double-blind study in esophagectomized patients, and treated after surgery with parenteral lipid emulsions of ω-3 fatty acids or a mixture of ω-6 long-chain triglycerides/short-chain triglycerides 50%. These emulsions will be added to the standard nutritional support in continuous infusion until 5 days of treatment have been completed. Patients will be randomized 1:1:1 in Group A receiving 0.4 g/kg/d of fish-oil lipid emulsion and 0.4 g/kg/d of a lipid emulsion mixture of ω-6 long-chain fatty acids (LCT) plus medium-chain fatty acids (MCT) (total dose of 0.8 g/kg/d of lipid emulsion); Group B receiving 0.8 g/kg/d of fish oil lipid emulsion and Group C receiving 0.8 g/kg/d of LCT/MCT emulsion.The main objective is to determine whether 5 days administration of intravenous ω-3 fatty acid lipid emulsion is effective in normalizing interleukin-6 levels compared with LCT/MCT emulsions, and whether a 0.8 g/kg/d dose is more effective than 0.4 g/kg/d. Secondary outcomes include other inflammatory markers such as C-reactive protein, tumor necrosis factor alpha and interleukin-10, and parameters of morbidity, safety, nutrition and mortality.Samples will be collected at the time when surgery is indicated and on days 0, 1, 3, 5 and 21 to determine inflammatory, nutritional, hepatic and safety parameters. In addition, clinical follow-up will be continued throughout the hospital admision and up to 1 year after surgery. DISCUSSION: Studies of ω-3 fatty acids administered parenterally in esophagectomized patients are scarce. This study proposes to investigate the effect of combining fish-oil lipid emulsions administered parenterally with EN support. Potential benefits include fast incorporation of lipids to the cellular membranes and to the inflammatory cascade, and the use of only 1 pharmaconutrient. TRIAL REGISTRATION: FAR-NP-2017-01 EudraCT number: 2016-004978-17.https://reec.aemps.es/reec/public/detail.html searching the EudraCT number. VERSION IDENTIFIER: Version 2, 08/06/2017.


Assuntos
Esofagectomia/reabilitação , Emulsões Gordurosas Intravenosas/administração & dosagem , Óleos de Peixe/administração & dosagem , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/terapia , Adulto , Terapia Combinada/métodos , Método Duplo-Cego , Nutrição Enteral , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Feminino , Humanos , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Nutrição Parenteral/métodos , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/imunologia , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
3.
PLoS One ; 16(6): e0252818, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1264219

RESUMO

Most deaths from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection occur in older subjects. We assessed the utility of serum inflammatory markers interleukin-6 (IL-6), C reactive protein (CRP), and ferritin (Roche, Indianapolis, IN), and SARS-CoV-2 immunoglobulin G (IgG), immunoglobulin M (IgM), and neutralizing antibodies (Diazyme, Poway, CA). In controls, non-hospitalized subjects, and hospitalized subjects assessed for SARS-CoV-2 RNA (n = 278), median IgG levels in arbitrary units (AU)/mL were 0.05 in negative subjects, 14.83 in positive outpatients, and 30.61 in positive hospitalized patients (P<0.0001). Neutralizing antibody levels correlated significantly with IgG (r = 0.875; P<0.0001). Having combined values of IL-6 ≥10 pg/mL and CRP ≥10 mg/L occurred in 97.7% of inpatients versus 1.8% of outpatients (odds ratio 3,861, C statistic 0.976, P = 1.00 x 10-12). Antibody or ferritin levels did not add significantly to predicting hospitalization. Antibody testing in family members and contacts of SARS-CoV-2 RNA positive cases (n = 759) was invaluable for case finding. Persistent IgM levels were associated with chronic COVID-19 symptoms. In 81,624 screened subjects, IgG levels were positive (≥1.0 AU/mL) in 5.21%, while IgM levels were positive in 2.96% of subjects. In positive subjects median IgG levels in AU/mL were 3.14 if <30 years of age, 4.38 if 30-44 years of age, 7.89 if 45-54 years of age, 9.52 if 55-64 years of age, and 10.64 if ≥65 years of age (P = 2.96 x 10-38). Our data indicate that: 1) combined IL-6 ≥10 pg/mL and CRP ≥10 mg/L identify SARS-CoV-2 positive subjects requiring hospitalization; 2) IgG levels were significantly correlated with neutralizing antibody levels with a wide range of responses; 3) IgG levels have significant utility for case finding in exposed subjects; 4) persistently elevated IgM levels are associated with chronic symptoms; and 5) IgG levels are significantly higher in positive older subjects than their younger counterparts.


Assuntos
COVID-19/sangue , Inflamação/sangue , Adulto , Fatores Etários , Idoso , Envelhecimento , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/imunologia , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/imunologia , Feminino , Ferritinas/sangue , Ferritinas/imunologia , Hospitalização , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Inflamação/diagnóstico , Inflamação/epidemiologia , Inflamação/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação
4.
PLoS One ; 16(6): e0252818, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34111164

RESUMO

Most deaths from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection occur in older subjects. We assessed the utility of serum inflammatory markers interleukin-6 (IL-6), C reactive protein (CRP), and ferritin (Roche, Indianapolis, IN), and SARS-CoV-2 immunoglobulin G (IgG), immunoglobulin M (IgM), and neutralizing antibodies (Diazyme, Poway, CA). In controls, non-hospitalized subjects, and hospitalized subjects assessed for SARS-CoV-2 RNA (n = 278), median IgG levels in arbitrary units (AU)/mL were 0.05 in negative subjects, 14.83 in positive outpatients, and 30.61 in positive hospitalized patients (P<0.0001). Neutralizing antibody levels correlated significantly with IgG (r = 0.875; P<0.0001). Having combined values of IL-6 ≥10 pg/mL and CRP ≥10 mg/L occurred in 97.7% of inpatients versus 1.8% of outpatients (odds ratio 3,861, C statistic 0.976, P = 1.00 x 10-12). Antibody or ferritin levels did not add significantly to predicting hospitalization. Antibody testing in family members and contacts of SARS-CoV-2 RNA positive cases (n = 759) was invaluable for case finding. Persistent IgM levels were associated with chronic COVID-19 symptoms. In 81,624 screened subjects, IgG levels were positive (≥1.0 AU/mL) in 5.21%, while IgM levels were positive in 2.96% of subjects. In positive subjects median IgG levels in AU/mL were 3.14 if <30 years of age, 4.38 if 30-44 years of age, 7.89 if 45-54 years of age, 9.52 if 55-64 years of age, and 10.64 if ≥65 years of age (P = 2.96 x 10-38). Our data indicate that: 1) combined IL-6 ≥10 pg/mL and CRP ≥10 mg/L identify SARS-CoV-2 positive subjects requiring hospitalization; 2) IgG levels were significantly correlated with neutralizing antibody levels with a wide range of responses; 3) IgG levels have significant utility for case finding in exposed subjects; 4) persistently elevated IgM levels are associated with chronic symptoms; and 5) IgG levels are significantly higher in positive older subjects than their younger counterparts.


Assuntos
COVID-19/sangue , Inflamação/sangue , Adulto , Fatores Etários , Idoso , Envelhecimento , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/imunologia , COVID-19/diagnóstico , COVID-19/epidemiologia , COVID-19/imunologia , Feminino , Ferritinas/sangue , Ferritinas/imunologia , Hospitalização , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Imunoglobulina M/sangue , Imunoglobulina M/imunologia , Inflamação/diagnóstico , Inflamação/epidemiologia , Inflamação/imunologia , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , SARS-CoV-2/isolamento & purificação
5.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070915

RESUMO

Systemic inflammation induced by periodontitis is suggested to be the link between periodontitis and cardiovascular disease. The aim of this work was to explore the oral microbiome in periodontitis in relation to disease severity and systemic inflammation. The saliva and subgingival microbiome from periodontal pocket samples of patients with severe (n = 12) and mild periodontitis (n = 13) were analyzed using metagenomic shotgun sequencing. The taxa and pathways abundances were quantified. The diversity was assessed and the abundances to phenotype associations were performed using ANCOM and linear regression. A panel of inflammatory markers was measured in blood and was associated with taxa abundance. The microbial diversity and species richness did not differ between severe and mild periodontitis in either saliva or periodontal pockets. However, there were significant differences in the microbial composition between severe and mild periodontitis in the subgingival microbiome (i.e., pocket samples) and, in a lower grade, in saliva, and this is positively associated with systemic inflammatory markers. The "red complex" and "cluster B" abundances in periodontal pockets were strongly associated with inflammatory markers interleukin-6 and the white blood cell count. Our data suggest that systemic inflammation in severe periodontitis may be driven by the oral microbiome and may support the indirect (inflammatory) mechanism for the association between periodontitis and cardiovascular disease.


Assuntos
Metagenoma , Microbiota/genética , Periodontite/microbiologia , Periodonto/microbiologia , Idoso , Biomarcadores/metabolismo , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/microbiologia , Doenças Cardiovasculares/patologia , Feminino , Expressão Gênica , Variação Genética , Humanos , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/genética , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos/imunologia , Leucócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Periodontite/complicações , Periodontite/imunologia , Periodontite/patologia , Periodonto/imunologia , Periodonto/patologia , Fenótipo , Filogenia , Índice de Gravidade de Doença
6.
Front Immunol ; 12: 675678, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1231339

RESUMO

Background: Restraining maladaptive inflammation is considered a rationale strategy to treat severe coronavirus disease-19 (COVID-19) but available studies with selective inhibitors of pro-inflammatory cytokines have not provided unequivocal evidence of survival advantage. Late administration is commonly regarded as a major cause of treatment failure but the optimal timing for anti-cytokine therapy initiation in COVID-19 patients has never been clearly established. Objectives: To identify a window of therapeutic opportunity for maximizing the efficacy of interleukin (IL)-1 and IL-6 blockade in COVID-19. Methods: Survival at the longest available follow-up was assessed in severe hyper-inflamed COVID-19 patients treated with anakinra, tocilizumab, sarilumab, or standard of care, stratified according to respiratory impairment at the time of treatment initiation. Results: 107 patients treated with biologics and 103 contemporary patients treated with standard of care were studied. After a median of 106 days of follow-up (range 3-186), treatment with biologics was associated with a significantly higher survival rate compared to standard therapy when initiated in patients with a PaO2/FiO2 ≥ 100 mmHg (p < 0.001). Anakinra reduced mortality also in patients with PaO2/FiO2 < 100 mmHg (p = 0.04). Conclusions: IL-1 and IL-6 blocking therapies are more likely to provide survival advantage in hyper-inflamed COVID-19 patients when initiated before the establishment of severe respiratory failure.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19 , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Interleucina-1/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , SARS-CoV-2/imunologia , Idoso , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/mortalidade , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Interleucina-1/imunologia , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Taxa de Sobrevida
7.
Front Immunol ; 12: 642860, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1231336

RESUMO

Cytokine storm (CS), an excessive release of proinflammatory cytokines upon overactivation of the innate immune system, came recently to the focus of interest because of its role in the life-threatening consequences of certain immune therapies and viral diseases, including CAR-T cell therapy and Covid-19. Because complement activation with subsequent anaphylatoxin release is in the core of innate immune stimulation, studying the relationship between complement activation and cytokine release in an in vitro CS model holds promise to better understand CS and identify new therapies against it. We used peripheral blood mononuclear cells (PBMCs) cultured in the presence of autologous serum to test the impact of complement activation and inhibition on cytokine release, testing the effects of liposomal amphotericin B (AmBisome), zymosan and bacterial lipopolysaccharide (LPS) as immune activators and heat inactivation of serum, EDTA and mini-factor H (mfH) as complement inhibitors. These activators induced significant rises of complement activation markers C3a, C4a, C5a, Ba, Bb, and sC5b-9 at 45 min of incubation, with or without ~5- to ~2,000-fold rises of IL-1α, IL-1ß, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13 and TNFα at 6 and 18 h later. Inhibition of complement activation by the mentioned three methods had differential inhibition, or even stimulation of certain cytokines, among which effects a limited suppressive effect of mfH on IL-6 secretion and significant stimulation of IL-10 implies anti-CS and anti-inflammatory impacts. These findings suggest the utility of the model for in vitro studies on CS, and the potential clinical use of mfH against CS.


Assuntos
COVID-19/imunologia , Ativação do Complemento , Síndrome da Liberação de Citocina/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Leucócitos Mononucleares/imunologia , Modelos Imunológicos , SARS-CoV-2/imunologia , COVID-19/patologia , Fator H do Complemento/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia
8.
Front Immunol ; 12: 668507, 2021.
Artigo em Inglês | MEDLINE | ID: covidwho-1226979

RESUMO

SARS-COV-2 virus is responsible for the ongoing devastating pandemic. Since the early phase of the pandemic, the "cytokine-storm" appeared a peculiar aspect of SARS-COV-2 infection which, at least in the severe cases, is responsible for respiratory treat damage and subsequent multi-organ failure. The efforts made in the last few months elucidated that the cytokine-storm results from a complex network involving cytokines/chemokines/infiltrating-immune-cells which orchestrate the aberrant immune response in COVID-19. Clinical and experimental studies aimed at depicting a potential "immune signature" of SARS-COV-2, identified three main "actors," namely the cytokine IL-6, the chemokine CXCL10 and the infiltrating immune cell type macrophages. Although other cytokines, chemokines and infiltrating immune cells are deeply involved and their role should not be neglected, based on currently available data, IL-6, CXCL10, and infiltrating macrophages could be considered prototype factors representing each component of the immune system. It rapidly became clear that a strong and continuous interplay among the three components of the immune response is mandatory in order to produce a severe clinical course of the disease. Indeed, while IL-6, CXCL10 and macrophages alone would not be able to fully drive the onset and maintenance of the cytokine-storm, the establishment of a IL-6/CXCL10/macrophages axis is crucial in driving the sequence of events characterizing this condition. The present review is specifically aimed at overviewing current evidences provided by both in vitro and in vivo studies addressing the issue of the interplay among IL-6, CXCL10 and macrophages in the onset and progression of cytokine storm. SARS-COV-2 infection and the "cytokine storm."


Assuntos
COVID-19/imunologia , Quimiocina CXCL10/imunologia , Síndrome da Liberação de Citocina/imunologia , Interleucina-6/imunologia , Macrófagos/imunologia , COVID-19/complicações , COVID-19/virologia , Quimiocinas/imunologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Humanos , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia
9.
Front Immunol ; 12: 642860, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995361

RESUMO

Cytokine storm (CS), an excessive release of proinflammatory cytokines upon overactivation of the innate immune system, came recently to the focus of interest because of its role in the life-threatening consequences of certain immune therapies and viral diseases, including CAR-T cell therapy and Covid-19. Because complement activation with subsequent anaphylatoxin release is in the core of innate immune stimulation, studying the relationship between complement activation and cytokine release in an in vitro CS model holds promise to better understand CS and identify new therapies against it. We used peripheral blood mononuclear cells (PBMCs) cultured in the presence of autologous serum to test the impact of complement activation and inhibition on cytokine release, testing the effects of liposomal amphotericin B (AmBisome), zymosan and bacterial lipopolysaccharide (LPS) as immune activators and heat inactivation of serum, EDTA and mini-factor H (mfH) as complement inhibitors. These activators induced significant rises of complement activation markers C3a, C4a, C5a, Ba, Bb, and sC5b-9 at 45 min of incubation, with or without ~5- to ~2,000-fold rises of IL-1α, IL-1ß, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13 and TNFα at 6 and 18 h later. Inhibition of complement activation by the mentioned three methods had differential inhibition, or even stimulation of certain cytokines, among which effects a limited suppressive effect of mfH on IL-6 secretion and significant stimulation of IL-10 implies anti-CS and anti-inflammatory impacts. These findings suggest the utility of the model for in vitro studies on CS, and the potential clinical use of mfH against CS.


Assuntos
COVID-19/imunologia , Ativação do Complemento , Síndrome da Liberação de Citocina/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Leucócitos Mononucleares/imunologia , Modelos Imunológicos , SARS-CoV-2/imunologia , COVID-19/patologia , Fator H do Complemento/imunologia , Síndrome da Liberação de Citocina/patologia , Humanos , Leucócitos Mononucleares/patologia , Leucócitos Mononucleares/virologia
10.
Front Immunol ; 12: 675678, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995419

RESUMO

Background: Restraining maladaptive inflammation is considered a rationale strategy to treat severe coronavirus disease-19 (COVID-19) but available studies with selective inhibitors of pro-inflammatory cytokines have not provided unequivocal evidence of survival advantage. Late administration is commonly regarded as a major cause of treatment failure but the optimal timing for anti-cytokine therapy initiation in COVID-19 patients has never been clearly established. Objectives: To identify a window of therapeutic opportunity for maximizing the efficacy of interleukin (IL)-1 and IL-6 blockade in COVID-19. Methods: Survival at the longest available follow-up was assessed in severe hyper-inflamed COVID-19 patients treated with anakinra, tocilizumab, sarilumab, or standard of care, stratified according to respiratory impairment at the time of treatment initiation. Results: 107 patients treated with biologics and 103 contemporary patients treated with standard of care were studied. After a median of 106 days of follow-up (range 3-186), treatment with biologics was associated with a significantly higher survival rate compared to standard therapy when initiated in patients with a PaO2/FiO2 ≥ 100 mmHg (p < 0.001). Anakinra reduced mortality also in patients with PaO2/FiO2 < 100 mmHg (p = 0.04). Conclusions: IL-1 and IL-6 blocking therapies are more likely to provide survival advantage in hyper-inflamed COVID-19 patients when initiated before the establishment of severe respiratory failure.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , COVID-19 , Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Interleucina-1/antagonistas & inibidores , Interleucina-6/antagonistas & inibidores , SARS-CoV-2/imunologia , Idoso , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/mortalidade , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Interleucina-1/imunologia , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Taxa de Sobrevida
11.
Front Immunol ; 12: 600017, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025636

RESUMO

Epidermal growth factor (EGF) acts as a paracrine and autocrine mediator of cell proliferation and differentiation in various types of epithelial cells, such as sebocytes, which produce the lipid-rich sebum to moisturize the skin. However, sebum lipids via direct contact and by penetrating through the epidermis may have regulatory roles on epidermal and dermal cells as well. As EGF receptor (EGFR) is expressed throughout the proliferating and the lipid-producing layers of sebaceous glands (SGs) in healthy and acne-involved skin, we investigated the effect of EGF on SZ95 sebocytes and how it may alter the changes induced by palmitic acid (PA), a major sebum component with bioactive roles. We found that EGF is not only a potent stimulator of sebocyte proliferation, but also induces the secretion of interleukin (IL)6 and down-regulates the expression of genes involved in steroid and retinoid metabolism. Importantly, when applied in combination with PA, the PA-induced lipid accumulation was decreased and the cells secreted increased IL6 levels. Functional clustering of the differentially regulated genes in SZ95 sebocytes treated with EGF, PA or co-treated with EGF+PA further confirmed that EGF may be a potent inducer of hyperproliferative/inflammatory pathways (IL1 signaling), an effect being more pronounced in the presence of PA. However, while a group of inflammatory genes was up-regulated significantly in EGF+PA co-treated sebocytes, PA treatment in the absence of EGF, regulated genes only related to cell homeostasis. Meta-analysis of the gene expression profiles of whole acne tissue samples and EGF- and EGF+PA -treated SZ95 sebocytes showed that the EGF+PA co-activation of sebocytes may also have implications in disease. Altogether, our results reveal that PA-induced lipid accumulation and inflammation can be modulated by EGF in sebocytes, which also highlights the need for system biological approaches to better understand sebaceous (immuno)biology.


Assuntos
Fator de Crescimento Epidérmico/imunologia , Células Epiteliais/imunologia , Ácido Palmítico/farmacologia , Glândulas Sebáceas/imunologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/patologia , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/patologia , Interleucina-6/imunologia , Ácido Palmítico/efeitos adversos , Glândulas Sebáceas/patologia
12.
Front Immunol ; 12: 668507, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33981314

RESUMO

SARS-COV-2 virus is responsible for the ongoing devastating pandemic. Since the early phase of the pandemic, the "cytokine-storm" appeared a peculiar aspect of SARS-COV-2 infection which, at least in the severe cases, is responsible for respiratory treat damage and subsequent multi-organ failure. The efforts made in the last few months elucidated that the cytokine-storm results from a complex network involving cytokines/chemokines/infiltrating-immune-cells which orchestrate the aberrant immune response in COVID-19. Clinical and experimental studies aimed at depicting a potential "immune signature" of SARS-COV-2, identified three main "actors," namely the cytokine IL-6, the chemokine CXCL10 and the infiltrating immune cell type macrophages. Although other cytokines, chemokines and infiltrating immune cells are deeply involved and their role should not be neglected, based on currently available data, IL-6, CXCL10, and infiltrating macrophages could be considered prototype factors representing each component of the immune system. It rapidly became clear that a strong and continuous interplay among the three components of the immune response is mandatory in order to produce a severe clinical course of the disease. Indeed, while IL-6, CXCL10 and macrophages alone would not be able to fully drive the onset and maintenance of the cytokine-storm, the establishment of a IL-6/CXCL10/macrophages axis is crucial in driving the sequence of events characterizing this condition. The present review is specifically aimed at overviewing current evidences provided by both in vitro and in vivo studies addressing the issue of the interplay among IL-6, CXCL10 and macrophages in the onset and progression of cytokine storm. SARS-COV-2 infection and the "cytokine storm."


Assuntos
COVID-19/imunologia , Quimiocina CXCL10/imunologia , Síndrome da Liberação de Citocina/imunologia , Interleucina-6/imunologia , Macrófagos/imunologia , COVID-19/complicações , COVID-19/virologia , Quimiocinas/imunologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Humanos , Sistema Respiratório/imunologia , Sistema Respiratório/virologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia
13.
J Immunother Cancer ; 9(4)2021 04.
Artigo em Inglês | MEDLINE | ID: covidwho-1175186

RESUMO

The ongoing pandemic caused by the novel coronavirus SARS-CoV-2 has disrupted the global economy and strained healthcare systems to their limits. After the virus first emerged in late 2019, the first intervention that demonstrated significant reductions in mortality for severe COVID-19 in large-scale trials was corticosteroids. Additional options that may reduce the burden on the healthcare system by reducing the number of patients requiring intensive care unit support are desperately needed, yet no therapy has conclusively established benefit in randomized studies for the management of moderate or mild cases of disease. Severe COVID-19 disease is characterized by a respiratory distress syndrome accompanied by elevated levels of several systemic cytokines, in a profile that shares several features with known inflammatory pathologies such as hemophagocytic lymphohistiocytosis and cytokine release syndrome secondary to chimeric antigen receptor (CAR) T cell therapy. Based on these observations, modulation of inflammatory cytokines, particularly interleukin (IL)-6, was proposed as a strategy to mitigate severe disease. Despite encouraging recoveries with anti-IL-6 agents, especially tocilizumab from single-arm studies, early randomized trials returned mixed results in terms of clinical benefit with these interventions. Later, larger trials such as RECOVERY and REMAP-CAP, however, are establishing anti-IL-6 in combination with steroids as a potential option for hypoxic patients with evidence of hyperinflammation. We propose that a positive feedback loop primarily mediated by macrophages and monocytes initiates the inflammatory cascade in severe COVID-19, and thus optimal benefit with anti-IL-6 therapies may require intervention during a finite window of opportunity at the outset of hyperinflammation but before fulminant disease causes irreversible tissue damage-as defined clinically by C reactive protein levels higher than 75 mg/L.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/prevenção & controle , Interleucina-6/antagonistas & inibidores , SARS-CoV-2/isolamento & purificação , COVID-19/epidemiologia , COVID-19/virologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/metabolismo , Pandemias , SARS-CoV-2/fisiologia
15.
Trials ; 22(1): 246, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: covidwho-1166928

RESUMO

OBJECTIVES: This study is conducted to investigate efficacy of pomegranate juice on inflammatory biomarkers, C-reactive protein (CRP), interleukin 6(IL-6), erythrocyte sedimentation rate (ESR) and complete blood count (CBC) in hospitalized patients with mild to moderate coronavirus disease 2019 (COVID- 19). TRIAL DESIGN: This is a randomized, placebo-controlled, double-blind, parallel 2-arm (1:1 ratio) clinical trial. PARTICIPANTS: Patients with COVID-19 admitted to hospitals in Yasuj City, Kohgiluyeh and Boyer-Ahmad Province, Iran. INCLUSION CRITERIA: Informed consent Patients 18 years of age or older Diagnosis of COVID-19 based on real-time polymerase chain reaction (RT-PCR) test EXCLUSION CRITERIA: Pregnancy or lactation Immunoglobulin A (IgA) level <61 mg/dl Disseminated intravascular coagulation or any other types of coagulopathy Severe congestive heart failure Participation in any clinical trial within 30 days prior to enrollment in this RCT Other contraindications determined by the specialist. INTERVENTION AND COMPARATOR: Intervention: 500 ml pomegranate juice and standard of care hospital treatment for COVID-19 Comparator: matching placebo containing 500 ml of red water and standard of care hospital treatment for COVID-19 Both intervention and comparator to be taken twice a day, after lunch and dinner, for 14 days. CRITERIA FOR DISCONTINUING: Transfer of patients to intensive care unit (ICU) Death Unwillingness to continue participating in the study MAIN OUTCOMES: The main outcomes of this study are levels of inflammatory biomarkers, CRP, IL-6, ESR, and CBC after 14 days of treatment. RANDOMIZATION: Eligible patients will be randomly assigned into the intervention or control group in a 1:1 ratio. Randomization will be performed based on 8 permuted blocks with block sizes of 6 and they will be stratified according to sex and age categories. Randomization sequences will be prepared by the trial's pharmacist using computer-generated random numbers. BLINDING (MASKING): This study is a double-blind clinical trial (participant, researcher). The pomegranate juice and placebo juice are packaged in identical bottles, and the researcher and all the patients will be unaware of the study assignment until the end of the study. To ensure blinding, the randomization sequences will be kept in identical, opaque, sealed, and sequentially numbered envelopes. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): The calculated total sample size is 48 patients, with 24 patients assigned into each group. TRIAL STATUS: The protocol is Version 1.0, on March 3, 2021. Recruitment started on February 28, 2021, and is anticipated to be completed by May 21, 2021. TRIAL REGISTRATION: The Name of registering trial Effects of Pomegranate Juice (Punica Granatum) on Inflammatory Biomarkers and CBC in Patients with COVID-19: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Iranian registry of clinical trials (IRCT) Registration Number: IRCT20150711023153N2 Date of Trial Registration February 28, 2021, retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials҆ website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
COVID-19/terapia , Sucos de Frutas e Vegetais , Romã (Fruta) , Ensaios Clínicos Controlados Aleatórios como Assunto , Contagem de Células Sanguíneas , Sedimentação Sanguínea , Proteína C-Reativa/imunologia , COVID-19/sangue , COVID-19/imunologia , Método Duplo-Cego , Hospitalização , Humanos , Interleucina-6/imunologia , SARS-CoV-2
16.
Int J Mol Med ; 47(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-1197577

RESUMO

The biological abilities of interleukin­6 (IL­6) have been under investigation for nearly 40 years. IL­6 works through an interaction with the complex peptide IL­6 receptor (IL­6R). IL­6 is built with four α­chain nanostructures, while two different chains, IL­6Rα (gp80) and gp130/IL6ß (gp130), are included in IL­6R. The three­dimensional shapes of the six chains composing the IL­6/IL­6R complex are the basis for the nanomolecular roles of IL­6 signalling. Genes, pseudogenes and competitive endogenous RNAs of IL­6 have been identified. In the present review, the roles played by miRNA in the post­transcriptional regulation of IL­6 expression are evaluated. mRNAs are absorbed via the 'sponge' effect to dynamically balance mRNA levels and this has been assessed with regard to IL­6 transcription efficiency. According to current knowledge on molecular and nanomolecular structures involved in active IL­6 signalling, two different IL­6 models have been proposed. IL­6 mainly has functions in inflammatory processes, as well as in cognitive activities. Furthermore, the abnormal production of IL­6 has been found in patients with severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2; also known as COVID­19). In the present review, both inflammatory and cognitive IL­6 models were analysed by evaluating the cytological and histological locations of IL­6 signalling. The goal of this review was to illustrate the roles of the classic and trans­signalling IL­6 pathways in endocrine glands such as the thyroid and in the central nervous system. Specifically, autoimmune thyroid diseases, disorders of cognitive processes and SARS­CoV­2 virus infection have been examined to determine the contribution of IL­6 to these disease states.


Assuntos
COVID-19/metabolismo , Inflamação/metabolismo , Interleucina-6/metabolismo , Transdução de Sinais , Animais , COVID-19/genética , COVID-19/imunologia , Cognição , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/imunologia , Interleucina-6/análise , Interleucina-6/genética , Interleucina-6/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia
17.
Lancet Respir Med ; 9(6): 643-654, 2021 06.
Artigo em Inglês | MEDLINE | ID: covidwho-1291133

RESUMO

Circulating concentrations of the pleiotropic cytokine interleukin-6 (IL-6) are known to be increased in pro-inflammatory critical care syndromes, such as sepsis and acute respiratory distress syndrome. Elevations in serum IL-6 concentrations in patients with severe COVID-19 have led to renewed interest in the cytokine as a therapeutic target. However, although the pro-inflammatory properties of IL-6 are widely known, the cytokine also has a series of important physiological and anti-inflammatory functions. An adequate understanding of the complex processes by which IL-6 signalling occurs is crucial for the correct interpretation of IL-6 concentrations in the blood or lung, the use of IL-6 as a critical care biomarker, or the design of effective anti-IL-6 strategies. Here, we outline the role of IL-6 in health and disease, explain the different types of IL-6 signalling and their contribution to the net biological effect of the cytokine, describe the approaches to IL-6 inhibition that are currently available, and discuss implications for the future use of treatments such as tocilizumab in the critical care setting.


Assuntos
Anticorpos Monoclonais Humanizados , COVID-19 , Interleucina-6 , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Biomarcadores/sangue , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/terapia , Estado Terminal , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Interleucina-6/imunologia , SARS-CoV-2
18.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925531

RESUMO

The impact of naturally occurring regulatory T cells (nTregs) on the suppression or induction of lung allergic responses in mice depends on the nuclear environment and the production of the pro-inflammatory cytokine interleukin 6 (IL-6). These activities were shown to be different in nTregs derived from wild-type (WT) and CD8-deficient mice (CD8-/-), with increased IL-6 levels in nTregs from CD8-/- mice in comparison to WT nTregs. Thus, identification of the molecular mechanisms regulating IL-6 production is critical to understanding the phenotypic plasticity of nTregs. Electrophoretic mobility shift assays (EMSA) were performed to determine transcription factor binding to four Il-6 promoter loci using nuclear extracts from nTregs of WT and CD8-/- mice. Increased transcription factor binding for each of the Il-6 loci was identified in CD8-/- compared to WT nTregs. The impact of transcription factor binding and a novel short tandem repeat (STR) on Il-6 promoter activity was analyzed by luciferase reporter assays. The Il-6 promoter regions closer to the transcription start site (TSS) were more relevant to the regulation of Il-6 depending on NF-κB, c-Fos, and SP and USF family members. Two Il-6 promoter loci were most critical for the inducibility by lipopolysaccharide (LPS) and tumor necrosis factor α (TNFα). A novel STR of variable length in the Il-6 promoter was identified with diverging prevalence in nTregs from WT or CD8-/- mice. The predominant GT repeat in CD8-/- nTregs revealed the highest luciferase activity. These novel regulatory mechanisms controlling the transcriptional regulation of the Il-6 promoter are proposed to contribute to nTregs plasticity and may be central to disease pathogenesis.


Assuntos
Hipersensibilidade/imunologia , Interleucina-6/imunologia , Pneumopatias/imunologia , Linfócitos T Reguladores/metabolismo , Adaptação Fisiológica/imunologia , Animais , Plasticidade Celular/genética , Plasticidade Celular/imunologia , Citocinas/imunologia , Interleucina-10/imunologia , Interleucina-6/genética , Pneumopatias/genética , Pneumopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , Regiões Promotoras Genéticas , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/metabolismo
19.
Lancet Respir Med ; 9(6): 643-654, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33872590

RESUMO

Circulating concentrations of the pleiotropic cytokine interleukin-6 (IL-6) are known to be increased in pro-inflammatory critical care syndromes, such as sepsis and acute respiratory distress syndrome. Elevations in serum IL-6 concentrations in patients with severe COVID-19 have led to renewed interest in the cytokine as a therapeutic target. However, although the pro-inflammatory properties of IL-6 are widely known, the cytokine also has a series of important physiological and anti-inflammatory functions. An adequate understanding of the complex processes by which IL-6 signalling occurs is crucial for the correct interpretation of IL-6 concentrations in the blood or lung, the use of IL-6 as a critical care biomarker, or the design of effective anti-IL-6 strategies. Here, we outline the role of IL-6 in health and disease, explain the different types of IL-6 signalling and their contribution to the net biological effect of the cytokine, describe the approaches to IL-6 inhibition that are currently available, and discuss implications for the future use of treatments such as tocilizumab in the critical care setting.


Assuntos
Anticorpos Monoclonais Humanizados , COVID-19 , Interleucina-6 , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Biomarcadores/sangue , COVID-19/imunologia , COVID-19/fisiopatologia , COVID-19/terapia , Estado Terminal , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Interleucina-6/imunologia , SARS-CoV-2
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