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1.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069671

RESUMO

Inflammatory bowel disease is characterized by the infiltration of immune cells and chronic inflammation. The immune inhibitory receptor, CD200R, is involved in the downregulation of the activation of immune cells to prevent excessive inflammation. We aimed to define the role of CD200R ligand-CD200 in the experimental model of intestinal inflammation in conventionally-reared mice. Mice were given a dextran sodium sulfate solution in drinking water. Bodyweight loss was monitored daily and the disease activity index was calculated, and a histological evaluation of the colon was performed. TNF-α production was measured in the culture of small fragments of the distal colon or bone marrow-derived macrophages (BMDMs) cocultured with CD200+ cells. We found that Cd200-/- mice displayed diminished severity of colitis when compared to WT mice. Inflammation significantly diminished CD200 expression in WT mice, particularly on vascular endothelial cells and immune cells. The co-culture of BMDMs with CD200+ cells inhibited TNF-α secretion. In vivo, acute colitis induced by DSS significantly increased TNF-α secretion in colon tissue in comparison to untreated controls. However, Cd200-/- mice secreted a similar level of TNF-α to WT mice in vivo. CD200 regulates the severity of DSS-induced colitis in conventionally-reared mice. The presence of CD200+ cells decreases TNF-α production by macrophages in vitro. However, during DDS-induced intestinal inflammation secretion of TNF-α is independent of CD200 expression.


Assuntos
Antígenos CD/genética , Inflamação/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Antígenos CD/metabolismo , Colite/patologia , Colo/patologia , Citocinas/metabolismo , Células Endoteliais/metabolismo , Feminino , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Inflamação/genética , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/fisiopatologia , Macrófagos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/metabolismo , Fator de Necrose Tumoral alfa/imunologia
2.
Viruses ; 13(5)2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064802

RESUMO

The role of the adaptive microenvironment components in severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection is widely researched, but remains unclear. Studying the common dynamics of adaptive immune response changes can help understand the pathogenesis of coronavirus disease 2019 (COVID-19), especially in critical patients. The aim of the present study was to determine the cytokines concentration and leukocyte subpopulations profiles in the severe COVID-19 (n = 23) and critical (n = 18) COVID-19 group distinguished by the computed tomography (CT) severity score. We observed lower percentage of lymphocyte subpopulation, higher neutrophils to lymphocytes ratio (NLR) and higher IL-6 concentration in critical COVID-19 group than in severe group. CT severity score was negative correlated with proportion of lymphocytes, lymphocytes T, CD4+ cells, Treg cells and NK cells and positive correlated with neutrophils, NLR, and IL-6. In critical group more correlations between cytokines and lymphocytes were observed, mainly between TNF-α, IL-1ß and lymphocyte subpopulations. The collective assessment of the cytokine profile, leukocyte subpopulations and the CT severity score can help to characterize and differentiate patient in advanced COVID-19 than the study of single parameters. We have shown that the interconnection of elements of the adaptive microenvironment can play an important role in critical COVID-19 cases.


Assuntos
COVID-19/imunologia , Citocinas/análise , Leucócitos/citologia , Adulto , Idoso , COVID-19/metabolismo , Citocinas/imunologia , Feminino , Humanos , Interleucina-1beta/imunologia , Células Matadoras Naturais/imunologia , Contagem de Leucócitos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Linfócitos T Reguladores/imunologia , Tomografia Computadorizada por Raios X , Fator de Necrose Tumoral alfa/imunologia
3.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805757

RESUMO

Tumor necrosis factor-alpha (TNF-α) is a multifunctional Th1 cytokine and one of the most important inflammatory cytokines. In pregnancy, TNF-α influences hormone synthesis, placental architecture, and embryonic development. It was also shown that increased levels of TNF-α are associated with pregnancy loss and preeclampsia. Increased TNF-α levels in complicated pregnancy draw attention to trophoblast biology, especially migratory activity, syncytialisation, and endocrine function. Additionally, elevated TNF-α levels may affect the maternal-fetal relationship by altering the secretory profile of placental immunomodulatory factors, which in turn affects maternal immune cells. There is growing evidence that metabolic/pro-inflammatory cytokines can program early placental functions and growth in the first trimester of pregnancy. Furthermore, early pregnancy placenta has a direct impact on fetal development and maternal immune system diseases that release inflammatory (e.g., TNF-α) and immunomodulatory factors, such as chronic inflammatory rheumatic, gastroenterological, or dermatological diseases, and may result in an abnormal release of cytokines and chemokines in syncytiotrophoblasts. Pregnancy poses a challenge in the treatment of chronic disease in patients who plan to have children. The activity of the disease, the impact of pregnancy on the course of the disease, and the safety of pharmacotherapy, including anti-rheumatic agents, in pregnancy should be considered.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Gastrite/tratamento farmacológico , Fármacos Gastrointestinais/uso terapêutico , Primeiro Trimestre da Gravidez/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Aleitamento Materno , Certolizumab Pegol/uso terapêutico , Etanercepte/uso terapêutico , Feminino , Gastrite/imunologia , Gastrite/patologia , Humanos , Infliximab/uso terapêutico , Parto/efeitos dos fármacos , Gravidez , Primeiro Trimestre da Gravidez/imunologia , Equilíbrio Th1-Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/imunologia
4.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-33800290

RESUMO

Tumor necrosis factor alpha (TNF-α) was initially recognized as a factor that causes the necrosis of tumors, but it has been recently identified to have additional important functions as a pathological component of autoimmune diseases. TNF-α binds to two different receptors, which initiate signal transduction pathways. These pathways lead to various cellular responses, including cell survival, differentiation, and proliferation. However, the inappropriate or excessive activation of TNF-α signaling is associated with chronic inflammation and can eventually lead to the development of pathological complications such as autoimmune diseases. Understanding of the TNF-α signaling mechanism has been expanded and applied for the treatment of immune diseases, which has resulted in the development of effective therapeutic tools, including TNF-α inhibitors. Currently, clinically approved TNF-α inhibitors have shown noticeable potency in a variety of autoimmune diseases, and novel TNF-α signaling inhibitors are being clinically evaluated. In this review, we briefly introduce the impact of TNF-α signaling on autoimmune diseases and its inhibitors, which are used as therapeutic agents against autoimmune diseases.


Assuntos
Doenças Autoimunes , Fatores Imunológicos/uso terapêutico , Transdução de Sinais , Fator de Necrose Tumoral alfa , Animais , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Doença Crônica , Humanos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
5.
BMC Infect Dis ; 21(1): 347, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849463

RESUMO

BACKGROUND: Recently developed immunosuppressive drugs, especially TNF antagonists, may enhance the risk of granulomatous infections, including leprosy. We aimed to evaluate the leprosy detection rate in patients under immunosuppression due to rheumatological, dermatological and gastroenterological diseases. METHODS: We performed a systematic review of the literature by searching the PubMed, EMBASE, LILACS, Web of Science and Scielo databases through 2018. No date or language restrictions were applied. We included all articles that reported the occurrence of leprosy in patients under medication-induced immunosuppression. RESULTS: The search strategy resulted in 15,103 articles; finally, 20 articles were included, with 4 reporting longitudinal designs. The detection rate of leprosy ranged from 0.13 to 116.18 per 100,000 patients/year in the USA and Brazil, respectively. In the meta-analysis, the detection rate of cases of leprosy per 100,000 immunosuppressed patients with rheumatic diseases was 84 (detection rate = 0.00084; 95% CI = 0.0000-0.00266; I2 = 0%, p = 0.55). CONCLUSION: Our analysis showed that leprosy was relatively frequently detected in medication-induced immunosuppressed patients suffering from rheumatological diseases, and further studies are needed. The lack of an active search for leprosy in the included articles precluded more precise conclusions. TRIAL REGISTRATION: This review is registered in PROSPERO with the registry number CRD42018116275 .


Assuntos
Gastroenteropatias/tratamento farmacológico , Imunossupressores/uso terapêutico , Hanseníase/diagnóstico , Doenças Reumáticas/tratamento farmacológico , Dermatopatias/tratamento farmacológico , Gastroenteropatias/patologia , Humanos , Imunossupressores/efeitos adversos , Hanseníase/etiologia , Estudos Longitudinais , Doenças Reumáticas/patologia , Dermatopatias/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
6.
Front Immunol ; 12: 578548, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815355

RESUMO

Objectives: To explore the potential role of CD3+CD8+CD161high TCRVα7.2+ mucosal-associated invariant T (MAIT) cells in the pathogenesis of primary biliary cholangitis (PBC). Methods: We enrolled 55 patients with PBC, 69 healthy controls (HCs), and 8 patients with hepatic hemangioma. Circulating MAIT cells and their chemokine receptor profiles and cytokine production were quantified using flow cytometry. Liver-resident MAIT cells were examined by immunofluorescence staining. CXCL12-mediated chemotaxis of MAIT cells was measured using a transwell migration assay. Plasma interleukin (IL)-18 was measured using ELISA, and cytokine production in IL-18-stimulated MAIT cells was detected using flow cytometry. Result: Peripheral MAIT cells were found to be significantly lower in patients with PBC (3.0 ± 3.2% vs. 9.4 ± 8.0%, p < 0.01) and negatively correlated with alkaline phosphatase (ALP) levels (r = -0.3209, p < 0.05). Liver immunofluorescence staining suggested that MAIT cells might accumulate in PBC liver. MAIT cells from patients with PBC expressed higher levels of CXCR4 (84.8 ± 18.0% vs. 58.7 ± 11.4%, p < 0.01), and the expression of CXCL12 was higher in PBC liver. CXCL12 promoted MAIT cell chemotaxis (70.4 ± 6.8% vs. 52.2 ± 3.5%, p < 0.01), which was attenuated by CXCR4 antagonist. MAIT cells from PBC produced significantly more interferon-γ (IFN-γ) (88.3 ± 4.2% vs. 64.2 ± 10.1%, p < 0.01), tumor necrosis factor-α (TNF-α) (93.0 ± 1.1% vs. 80.1 ± 5.3%, p < 0.01), Granzyme B (89.3 ± 3.3% vs. 72.1 ± 7.0%, p < 0.01), and perforin (46.8 ± 6.6% vs. 34.8 ± 7.7%, p < 0.05). MAIT cells from PBC expressed higher levels of IL18-Rα (83.8 ± 10.2% vs. 58.3 ± 8.7%, p < 0.01). Plasma IL-18 was more abundant in patients with PBC (286.8 ± 75.7 pg/ml vs. 132.9 ± 78.1 pg/ml, p < 0.01). IL-18 promoted IFN-γ production in MAIT cells (74.9 ± 6.6% vs. 54.7 ± 6.7%, p < 0.01), which was partially attenuated by blocking IL-18R (68.6 ± 8.3% vs. 43.5 ± 4.2%, p < 0.01). Conclusion: Mucosal-associated invariant T cells from patients with PBC accumulated in the liver via CXCL12-CXCR4-mediated chemotaxis, produced pro-inflammatory cytokines, and contributed to portal inflammation, which was potentially mediated by elevated IL-18. Targeting MAIT cells might be a therapeutic approach for PBC.


Assuntos
Quimiocina CXCL12/imunologia , Cirrose Hepática Biliar/imunologia , Fígado/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Receptores CXCR4/imunologia , Adulto , Fosfatase Alcalina/imunologia , Fosfatase Alcalina/metabolismo , Quimiocina CXCL12/metabolismo , Quimiotaxia/imunologia , Feminino , Granzimas/imunologia , Granzimas/metabolismo , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-18/imunologia , Interleucina-18/metabolismo , Fígado/metabolismo , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/metabolismo , Perforina/imunologia , Perforina/metabolismo , Receptores CXCR4/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
7.
J Biol Chem ; 296: 100630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33823154

RESUMO

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.


Assuntos
Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Fatores Imunológicos/farmacologia , Interleucina-18/genética , Receptores de Interleucina-18/genética , Anti-Inflamatórios/metabolismo , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/biossíntese , COVID-19/tratamento farmacológico , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Regulação da Expressão Gênica , Células HEK293 , Humanos , Fatores Imunológicos/biossíntese , Inflamação , Interferon gama/genética , Interferon gama/imunologia , Interleucina-18/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Síndrome de Ativação Macrofágica/tratamento farmacológico , NF-kappa B/genética , NF-kappa B/imunologia , Cultura Primária de Células , Receptores de Interleucina-18/antagonistas & inibidores , Receptores de Interleucina-18/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
8.
J Int Med Res ; 49(3): 3000605211002695, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33745336

RESUMO

Over the past several decades, studies have demonstrated the existence of bi-directional relationships between periodontal disease and systemic conditions. Periodontitis is a polymicrobial and multifactorial disease involving both host and environmental factors. Tissue destruction is primarily associated with hyperresponsiveness of the host resulting in release of inflammatory mediators. Pro-inflammatory cytokines play a major role in bacterial stimulation and tissue destruction. In addition, these cytokines are thought to underlie the associations between periodontitis and systemic conditions. Current research suggests that increased release of cytokines from host cells, referred to as the cytokine storm, is associated with disease progression in patients with coronavirus disease 2019 (COVID-19). An intersection between periodontitis and pulmonary disease is biologically plausible. Hence, we reviewed the evidence linking COVID-19, cytokines, and periodontal disease. Plaque control is essential to prevent exchange of bacteria between the mouth and the lungs, reducing the risk of lung disease. Understanding these associations may help identify individuals at high risk and deliver appropriate care at early stages.


Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Placa Dentária/imunologia , Interações Hospedeiro-Patógeno/imunologia , Periodontite/imunologia , SARS-CoV-2/patogenicidade , Estresse Psicológico/imunologia , COVID-19/complicações , COVID-19/genética , COVID-19/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/virologia , Placa Dentária/complicações , Placa Dentária/genética , Placa Dentária/virologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/patologia , Pulmão/virologia , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Periodontite/complicações , Periodontite/genética , Periodontite/virologia , SARS-CoV-2/imunologia , Transdução de Sinais , Estresse Psicológico/complicações , Estresse Psicológico/genética , Estresse Psicológico/virologia , Dente/imunologia , Dente/patologia , Dente/virologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
9.
Clin Immunol ; 226: 108714, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33741504

RESUMO

Lipopolysaccharide (LPS) and monophosphoryl lipid A (MPLA) induce, overall, similar transcriptional profiles in healthy individuals, although LPS has been shown to more potently induce pro-inflammatory cytokines. We explore herein whether MPLA could be considered as a synthetic replacement of LPS in immune functional assays to study anergy of immune cells in septic patients. Ex vivo whole blood stimulation with MPLA revealed a lower induction of the TNFα secreted protein in 20 septic patients (SP) compared to 10 healthy volunteers (HV), in agreement with monocyte anergy. Principal component analysis of the 93-gene molecular response to MPLA and LPS stimulation found that the main variability was driven by stimulation in HV and by pathophysiology in SP. MPLA was a stronger inducer of the HLA family genes than LPS in both populations, arguing for divergent signalling pathways downstream of TLR-4. In addition, MPLA appeared to present a more informative stratification potential within the septic population.


Assuntos
Hospedeiro Imunocomprometido/imunologia , Lipídeo A/análogos & derivados , Lipopolissacarídeos/imunologia , Sepse/imunologia , Idoso , Idoso de 80 Anos ou mais , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Lipídeo A/imunologia , Masculino , Monócitos/imunologia , Estudos Prospectivos , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/imunologia
10.
Scand J Immunol ; 94(1): e13042, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33772836

RESUMO

We aimed to use a novel standardized whole-blood stimulation system to evaluate differences in the functional immune reconstitution in patients early after allogeneic haematopoietic cell transplantation (HCT). Between April and September 2018, 30 patients undergoing HCT had whole blood samples collected around day -21 (day 0 being the day of haematopoietic cell infusion) and day +28. Whole blood was transferred to TruCulture assays comprising prefilled incubation tubes with cell culture medium and a standardized stimulus. We used a panel of four stimuli (lipopolysaccharide, resiquimod, heat-killed Candida albicans and polyinosinic:polycytidylic acid) and a blank, designed to evaluate the function of critical extra- and intracellular immunological signalling pathways. For each stimulus, the cytokine response was assessed by the concentration of interferon-γ, interleukin (IL)-12p40, IL-10, IL-1ß, IL-6, IL-8, IL-10, IL-12p40, IL-17A and tumour necrosis factor-α using a multiplex Luminex assay. Pre-HCT cytokine responses were globally decreased across several different stimuli. Despite patients receiving immunosuppressive prophylaxis at the time, post-HCT cytokine responses were higher and less intercorrelated than pre-HCT responses, also after adjusting for differences in the leukocyte differential counts. For the resiquimod and heat-killed Candida albicans stimuli, we identified a cluster of patients in whom post-HCT responses were lower than average across several cytokines, indicating a possible functional immune deficiency. Our findings suggest that the standardized whole blood stimulation system can be used to reveal heterogeneity in the in vitro cytokine responses to various stimuli after HCT. Larger studies are needed to address if the functional immune reconstitution after HCT can predict the risk of infections.


Assuntos
Citocinas/imunologia , Rejeição de Enxerto/imunologia , Doença Enxerto-Hospedeiro/imunologia , Reconstituição Imune/imunologia , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Interferon gama/imunologia , Interleucinas/imunologia , Leucócitos/imunologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/imunologia
11.
Front Immunol ; 12: 599345, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33659001

RESUMO

Exposure to environmental hormones such as di(2-ethylhexyl) phthalate (DEHP) has become a critical human health issue globally. This study aimed to investigate the correlations between DEHP/mono-(2-ethylhexyl) phthalate (MEHP) levels and macrophage-associated immune responses and clinical manifestations in dengue virus (DV)-infected patients. Among 89 DV-infected patients, those with DV infection-related gastrointestinal (GI) bleeding (n = 13, 15% of patients) had significantly higher DEHP exposure than those without GI bleeding (n = 76, 85% of patients), which were 114.2 ng/ml versus 52.5 ng/ml ΣDEHP in urine; p = 0.023). In an in vitro study using cultured human monocyte-derived macrophages (MDMs) to investigate the effects of MEHP, treatment increased IL-1ß and TNF-α release but decreased IL-23 release, with negative correlations observed between urine ΣDEHP and serum IL-23 levels in patients. MEHP-treated MDMs had lower antiviral Th17 response induction activity in mixed T-cell response tests. The in vitro data showed that MEHP increased DV viral load and decreased IL-23 release dose-dependently, and adding IL-23 to MEHP-exposed MDMs significantly reduced the DV viral load. MEHP also suppressed IL-23 expression via the peroxisome proliferator-activated receptor-gamma (PPAR-γ) pathway. Further, the PPAR-γ antagonist GW9662 significantly reversed MEHP-induced IL-23 suppression and reduced the DV viral load. These study findings help to explain the associations between high MEHP levels and the high global burden of dengue disease.


Assuntos
Antivirais , Vírus da Dengue/imunologia , Dengue/imunologia , Dietilexilftalato/análogos & derivados , Interleucina-23/imunologia , Macrófagos/imunologia , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/farmacologia , Dengue/tratamento farmacológico , Dengue/patologia , Dietilexilftalato/efeitos adversos , Dietilexilftalato/farmacologia , Feminino , Humanos , Interleucina-1beta/imunologia , Macrófagos/fisiologia , Macrófagos/virologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/imunologia
12.
Nat Rev Rheumatol ; 17(4): 213-223, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33686279

RESUMO

Immune checkpoint inhibitors (ICIs) are effective in the treatment of patients with advanced cancer and have emerged as a pillar of standard cancer care. However, their use is complicated by adverse effects known as immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis. ICI-induced inflammatory arthritis is distinguished from other irAEs by its persistence and requirement for long-term treatment. TNF inhibitors are commonly used to treat inflammatory diseases such as rheumatoid arthritis, spondyloarthropathies and inflammatory bowel disease, and have also been adopted as second-line agents to treat irAEs refractory to glucocorticoid treatment. Experiencing an irAE is associated with a better antitumour response after ICI treatment. However, whether TNF inhibition can be safely used to treat irAEs without promoting cancer progression, either by compromising ICI therapy efficacy or via another route, remains an open question. In this Review, we discuss clinical and preclinical studies that address the relationship between TNF, TNF inhibition and cancer. The bulk of the evidence suggests that at least short courses of TNF inhibitors are safe for the treatment of irAEs in patients with cancer undergoing ICI therapy. Data from preclinical studies hint that TNF inhibition might augment the antitumour effect of ICI therapy while simultaneously ameliorating irAEs.


Assuntos
Artrite/induzido quimicamente , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Fator de Necrose Tumoral alfa/imunologia , Artrite/imunologia , Interações Medicamentosas , Sinergismo Farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Neoplasias/imunologia , Medição de Risco , Segurança , Inibidores do Fator de Necrose Tumoral/farmacologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico
13.
Scand J Immunol ; 94(2): e13035, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33655533

RESUMO

INTRODUCTION: The growing incidence of non-tuberculous mycobacteria (NTM) and changes in epidemiological factors have indicated that immune dysregulation may be associated with the emergence of NTM. Minireview entails to acknowledge complex interaction and new ways NTM are evolving around diverse immune status. METHODS: In order to perform this review, we selected peer reviewed, NLM database articles under the terms NTM, mycobacterium complex 'AND' -Host- immune response, immunity regulation, Disease, Single Nucleotide Polymorphism (SNP´s), and -pathogen- followed by a snow ball rolling basis search on immune components and NTM related with diseases distribution. RESULTS: The universal exposure and diversity of NTM are well-documented; however, hospitals seldom establish vigilant control of water quality or immunodeficiencies for patients with NTM infections. Depending on the chemical structures and immune mechanisms presented by various NTM varieties, they can trigger different effects in dendritic and natural killer cells, which release interleukin (IL)-17, tumour necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and rIL-1B. The T helper (Th)2-acquired immune response is responsible for autoimmune responses in patients with NTM infections, and, quite disturbingly, immunocompetent patients have been reported to suffer from NTM infections. CONCLUSION: New technologies and a comprehensive view has taught us; to acknowledge metabolic/immune determinants and trade-offs along transit through mutualism-parasite continuous.


Assuntos
Imunidade Inata/imunologia , Micobactérias não Tuberculosas/imunologia , Virulência/imunologia , Animais , Humanos , Interferon gama/imunologia , Interleucina-17/imunologia , Interleucina-1beta/imunologia , Células Matadoras Naturais/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/imunologia
14.
Int Immunopharmacol ; 94: 107455, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33582592

RESUMO

OBJECTIVE: The aim of this study was to examine the effect of gingival mesenchymal stem cells derived exosomes (GMSC-Exos) on lipopolysaccharide/interferon-gamma (LPS/INF-γ)-induced inflammatory macrophages in a high-lipid microenvironment. MATERIALS AND METHODS: Exosomes were obtained by culturing gingival mesenchymal stem cells (GMSCs) in alpha-MEM with exosome-free fetal bovine serum for 48 h. The control group was produced in vitro by inducing human acute monocytic leukemia cells (THP-1 cells) into naïve macrophages (M0). Inflammatory macrophages (M1) were made by activating M0 macrophages with LPS/IFN-γ. These M1 macrophages were treated with oxidized low-density lipoprotein (ox-LDL) to create the high-lipid group, of which some macrophages were further treated with GMSC-Exos for 24 h to form the GMSC-Exos group. Supernatants were collected, and total RNA were extracted for downstream analysis. The expression of surface markers in macrophages were analyzed by flow cytometry. The lipid accumulation level was assessed by oil red O staining. RESULTS: Exosomes were successfully isolated from GMSC medium. The GMSC-Exos group showed lower Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and cluster of differentiation 86 (CD86) expression levels than the high-lipid group, and the highest levels of Interleukin-10 (IL-10) among all groups. The GMSC-Exos group showed significant reductions in TNF-α levels than the high-lipid group, and significant escalations in IL-10 levels than the other two groups. Oil red o Staining showed that lipid accumulation in macrophages was inhibited in the GMSC-Exos group. CONCLUSIONS: GMSC-Exos reduce the release level and expression of inflammatory factors, inhibit lipid accumulation, and promote the polarization of pro-inflammatory macrophages into anti-inflammatory phenotype in a high-lipid microenvironment.


Assuntos
Exossomos , Macrófagos/imunologia , Células-Tronco Mesenquimais , Adolescente , Adulto , Antígeno B7-2/imunologia , Diferenciação Celular , Gengiva/citologia , Humanos , Inflamação/imunologia , Interleucina-10/imunologia , Lipídeos , Fenótipo , Células THP-1 , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
15.
Int J Infect Dis ; 104: 725-731, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33556615

RESUMO

OBJECTIVES: The genetic diversity of Mycobacterium tuberculosis complex (MTBC) influences the immune response of the host, which may affect the immunodiagnostic tests and biomarker assessment studies used for tuberculosis (TB). This study aimed to determine whether the mycobacterial-antigen-stimulated cytokine responses vary with the genotype of the MTBC infecting the patient. METHODS: Eighty-one patients with confirmed active pulmonary TB were recruited, and MTBC clinical strains were isolated from their sputum for bacterial lineage single-nucleotide polymorphism typing. Whole blood was drawn from the patients to measure the purified protein derivative (PPD)-stimulated cytokine responses (GM-CSF, IFN-γ, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, TNF-α, IFN-α, IL-12, eotaxin, IL-13, IL-15, IL-17, MIP1-α, MIP1-ß, MCP1, IL1RA, IP10, IL2R, MIG) with the Luminex multiplex immunoassay. RESULTS: Of the 24 cytokines studied, three were produced differentially in whole blood dependent on the infecting lineage of MTBC. Decreased production of IL-17 was observed in patients infected with modern lineages compared with patients infected with ancestral lineages (P < 0.01), and production of IFN-γ and IL-2 was significantly decreased in patients infected with lineage 4 strains compared with patients infected with lineage 3 strains (P < 0.05). CONCLUSION: MTBC strains belonging to lineage 4 induced a decreased whole-blood PPD-stimulated pro-inflammatory cytokine response.


Assuntos
Citocinas/imunologia , Mycobacterium tuberculosis/genética , Tuberculina/imunologia , Tuberculose/imunologia , Adulto , Biomarcadores/sangue , Citocinas/sangue , Testes Diagnósticos de Rotina , Feminino , Humanos , Imunoensaio , Interleucinas/sangue , Interleucinas/imunologia , Masculino , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/imunologia , Tuberculose/sangue , Tuberculose/diagnóstico , Tuberculose/microbiologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
16.
PLoS Negl Trop Dis ; 15(2): e0009126, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33524030

RESUMO

The increasing use of immunosuppressants in areas where visceral leishmaniasis (VL) is endemic has increased the number of people susceptible to developing more severe forms of the disease. Few studies have examined the quality of the immune response in immunosuppressed patients or experimental animals with VL. The present work characterises the parasite load developed in, and immune response to, Leishmania infantum-induced VL in C57BL/6 mice that, prior to and during infection, received immunosuppressant treatment with methylprednisolone (MPDN), anti-tumour necrosis factor (anti-TNF) antibodies, or methotrexate (MTX). The latter two treatments induced a significant reduction in the number of CD4+ T lymphocytes over the infection period. The anti-TNF treatment was also associated with a higher parasite load in the liver and a lower parasite load in the spleen. This, plus a possibly treatment-induced reduction in the number of cytokine-producing Th1 cells in the spleen, indicates the development of more severe VL. Interestingly, the MPDN and (especially) MTX treatments provoked a greater presence of soluble Leishmania antigen-specific multi-cytokine-producing T cells in the spleen and a lower liver parasite load than in control animals. These results highlight the need to better understand how immunosuppressant treatments might influence the severity of VL in human patients.


Assuntos
Imunidade , Imunossupressores , Leishmaniose Visceral/imunologia , Carga Parasitária , Animais , Antígenos de Protozoários/imunologia , Linfócitos T CD4-Positivos , Citocinas/imunologia , Feminino , Humanos , Imunidade Celular , Imunoglobulina G , Leishmania infantum/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/imunologia , Linfócitos T , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfa/imunologia
17.
Chem Biodivers ; 18(2): e2000956, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33533162

RESUMO

The marine fungus, Aspergillus flavipes (MTCC 5220), was isolated from the pneumatophore of a mangrove plant Acanthus ilicifolius found in Goa, India. The crude extract of A. flavipes was found to show anti-inflammatory activity. It blocked interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production in lipopolysaccharide (LPS)-activated THP-1 cells with IC50 of 2.69±0.5 µM and 6.64±0.4 µM, respectively. The chemical investigation led to the isolation of optically inactive 4ß-[(1E)-propen-1-yl]cyclopentane-1ß,2ß-diol (1) along with a new optically active diastereoisomeric compound, 4ß-[(1E)-propen-1-yl]cyclopentane-1ß,2α-diol (2). In addition, the fungus also produced known compounds (+)-terrein (3), butyrolactone I (4) and butyrolactone II (5) in high yields. Among these, (+)-terrein (3) exhibited IL-6 and TNF-α inhibition activity with IC50 of 8.5±0.68 µM and 15.76±0.18 µM, respectively, while butyrolactone I (4) exhibited IC50 of 12.03±0.85 µM (IL-6) and 43.29±0.76 µM (TNF-α) inhibition activity with low toxicity to host cells in LPS stimulated THP-1 cells. This is the first report of the isolation and characterization of 4ß-[(1E)-propen-1-yl]cyclopentane-1ß,2α-diol (2). The structures of all the isolated compounds were elucidated on the basis of extensive detailed NMR spectroscopic data. Anti-inflammatory activity of the fungi A. flavipes is presented here for the first time, which was due to (+)-terrein and butyrolactone I, as the major constituents and they can be further explored in the therapeutic area.


Assuntos
Anti-Inflamatórios/química , Aspergillus/química , Produtos Biológicos/química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/química , 4-Butirolactona/farmacologia , Anti-Inflamatórios/farmacologia , Produtos Biológicos/farmacologia , Ciclopentanos/química , Ciclopentanos/farmacologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Lipopolissacarídeos/imunologia , Células THP-1 , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
18.
Int Immunopharmacol ; 93: 107418, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33540248

RESUMO

The tumor necrosis factor alpha (TNF-α)/nuclear factor-kappa B (NF-κB) signaling pathway plays a crucial role in the pathogenesis of inflammatory diseases. Several therapeutic monoclonal antibodies (mAbs) and biosimilars against TNF-α have been developed to treat patients who suffer from inflammatory diseases caused by disordered expression of TNF-α. Hence, quality control of biopharmaceuticals is crucial during research and development. The high-order structure of these complex molecules cannot be entirely identified by physiochemical attributes; however, they can be inferred by observing biological activities. Thus, we developed a U937-based bioassay to determine the biological activities of mAbs and biosimilars against TNF-α using a low-basal NF-κB-inducible lentiviral reporter gene. The reporter gene assay (RGA) can be induced with a high signal-to-noise ratio (SNR) in a short time by TNF-α. Validation of the RGA showed accuracy (% relative standard deviation [RSD] = 4.64%), linearity (r2 = 0.9856), and precision (Interday RSD = 4.6%, between analysts RSD = 3.51%) as well as reasonable specificity and robustness. The measured potency values of a biosimilar to adalimumab were between 90% and 110%. Results showed our RGA is suitable for mAb quality control and lot release, and for evaluation of the biological activity similarity of the biosimilar.


Assuntos
Anticorpos Monoclonais/farmacologia , Bioensaio/métodos , Medicamentos Biossimilares/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Medicamentos Biossimilares/metabolismo , Genes Reporter/genética , Humanos , Lentivirus/genética , Camundongos , NF-kappa B/metabolismo , Controle de Qualidade , Fator de Necrose Tumoral alfa/imunologia , Células U937
19.
J Sci Food Agric ; 101(3): 863-870, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33433910

RESUMO

BACKGROUND: Protecting the intestinal mucosa from being destroyed helps reduce the inflammation caused by acute pancreatitis (AP). In this study, whether okra pectin (OP) could attenuate the inflammation of AP through protecting the intestinal barrier was investigated. RESULTS: OP was obtained from crude okra pectin (COP) through the purification by DEAE cellulose 52 column. Supplementation with OP or COP in advance reduced the severity of AP, as revealed by lower serum amylase and lipase levels, abated pancreatic edema, attenuated myeloperoxidase activity and pancreas histology. OP or COP inhibited the production of pancreatic proinflammatory cytokines, including tumor necrosis factor-α and interleukin-6. In addition, the upregulation of AP-related proteins including ZO-1, occludin, the antibacterial peptide-defensin-1 (DEFB1) and cathelicidin-related antimicrobial peptide (CRAMP), as well as the histological examination of colon injuries, demonstrated that OP or COP provision could effectively maintain intestinal barrier function. Ultimately, dietary OP or COP supplementation could inhibit AP-induced intestinal inflammation. For the above, the effect of OP was better than COP. CONCLUSION: Dietary OP supplementation could be considered as a preventive method that effectively interferes with intestinal damage and attenuates inflammatory responses trigged by AP. © 2020 Society of Chemical Industry.


Assuntos
Abelmoschus/química , Ceruletídeo/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Pancreatite/tratamento farmacológico , Pectinas/administração & dosagem , Extratos Vegetais/administração & dosagem , Animais , Citocinas/genética , Citocinas/imunologia , Frutas/química , Humanos , Mucosa Intestinal/imunologia , Masculino , Camundongos , Ocludina/genética , Ocludina/imunologia , Pancreatite/induzido quimicamente , Pancreatite/genética , Pancreatite/imunologia , Pectinas/química , Extratos Vegetais/química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteína da Zônula de Oclusão-1/genética , Proteína da Zônula de Oclusão-1/imunologia
20.
Carbohydr Polym ; 256: 117514, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33483035

RESUMO

The physicochemical properties, structural features and structure-immunomodulatory activity relationship of pectic polysaccharides from the white asparagus (Asparagus officinalis L.) skin were systematically studied. Using sequential ethanol precipitation, five sub-fractions namely WASP-40, WASP-50, WASP-60, WASP-70 and WASP-80 with distinct degree of esterification (DE) and molecular weight (Mw) were obtained. The Mw and DE values were decreased with the increase of the ethanol concentrations. Structurally, although 4-α-D-GalpA was the dominant sugar residue in all fractions, the molar ratios were decreased, whereas other sugar residues including arabinose- and mannose-based sugar residues overall increased with the increase of ethanol concentration. In addition, the effects of sub-fractions on the RAW 264.7 cells indicated that pectic polysaccharides with the higher DE value showed a stronger immunomodulatory activity. Moreover, the structure-activity relationship was also discussed in this study, which extends the value-added application of asparagus and its processing by-products.


Assuntos
Asparagus (Planta)/química , Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/química , Fagocitose/efeitos dos fármacos , Polissacarídeos/química , Animais , Arabinose/isolamento & purificação , Sequência de Carboidratos , Proliferação de Células/efeitos dos fármacos , Fracionamento Químico/métodos , Ésteres/química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Manose/isolamento & purificação , Camundongos , Peso Molecular , Extratos Vegetais/química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Células RAW 264.7 , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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