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1.
Nutrients ; 13(8)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34444938

RESUMO

l-Arginine is an important nutrient in the infant diet that significantly regulates the maturation of the immune system in neonates, including the maturation of CD4+ T cells. The biological activities of CD4+ T cells differ substantially between neonates and adults, and these differences may be governed by epigenetic processes. Investigating these differences and the causative processes may help understand neonatal and developmental immunity. In this study, we compared the functional DNA methylation profiles in CD4+ T cells of neonates and adults, focusing on the role of l-arginine supplementation. Umbilical cord blood and adult CD4+ T cells were cultured with/without l-arginine treatment. By comparing DNA methylation in samples without l-arginine treatment, we found that CD4+ T cells of neonatal cord blood generally showed higher DNA methylation than those of adults (average CpG methylation percentage 0.6305 for neonate and 0.6254 for adult, t-test p-value < 0.0001), suggesting gene silencing in neonates. By examining DNA methylation patterns of CpG dinucleotides induced by l-arginine treatment, we found that more CpG dinucleotides were hypomethylated and more genes appeared to be activated in neonatal T-cells as compared with adult. Genes activated by l-arginine stimulation of cord blood samples were more enriched regarding immune-related pathways. CpG dinucleotides at IL-13 promoter regions were hypomethylated after l-arginine stimulation. Hypomethylated CpG dinucleotides corresponded to higher IL-13 gene expression and cytokine production. Thus, DNA methylation partially accounts for the mechanism underlying differential immune function in neonates. Modulatory effects of l-arginine on DNA methylation are gene-specific. Nutritional intervention is a potential strategy to modulate immune function of neonates.


Assuntos
Arginina/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Imunidade/efeitos dos fármacos , Adulto , Ilhas de CpG , Suplementos Nutricionais , Epigênese Genética , Sangue Fetal/metabolismo , Expressão Gênica , Humanos , Imunidade/genética , Recém-Nascido , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Regiões Promotoras Genéticas
2.
Int J Mol Sci ; 22(16)2021 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-34445126

RESUMO

Experimental and clinical studies have suggested that several neurological disorders are associated with the occurrence of central nervous system neuroinflammation. Metaxalone is an FDA-approved muscle relaxant that has been reported to inhibit monoamine oxidase A (MAO-A). The aim of this study was to investigate whether metaxalone might exert antioxidant and anti-inflammatory effects in HMC3 microglial cells. An inflammatory phenotype was induced in HMC3 microglial cells through stimulation with interleukin-1ß (IL-1ß). Control cells and IL-1ß-stimulated cells were subsequently treated with metaxalone (10, 20, and 40 µM) for six hours. IL-1ß stimulated the release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), but reduced the anti-inflammatory cytokine interleukin-13 (IL-13). The upstream signal consisted of an increased priming of nuclear factor-kB (NF-kB), blunted peroxisome proliferator-activated receptor gamma (PPARγ), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression. IL-1ß also augmented MAO-A expression/activity and malondialdehyde levels and decreased Nrf2 mRNA expression and protein levels. Metaxalone decreased MAO-A activity and expression, reduced NF-kB, TNF-α, and IL-6, enhanced IL-13, and also increased PPARγ, PGC-1α, and Nrf2 expression. The present experimental study suggests that metaxalone has potential for the treatment of several neurological disorders associated with neuroinflammation.


Assuntos
Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Microglia/efeitos dos fármacos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Oxazolidinonas/farmacologia , Anti-Inflamatórios , Linhagem Celular , Humanos , Inflamação/metabolismo , Interleucina-13/metabolismo , Interleucina-6/metabolismo , Microglia/metabolismo , PPAR gama/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
3.
Molecules ; 26(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34361744

RESUMO

Korean red pine (Pinus densiflora) belongs to the Genus Pinus, and its bark contains a great amount of naturally occurring phenolic compounds. Until now, few studies have been conducted to assess the neuroprotective effects of Pinus densiflora bark extract against brain ischemic injury. The aim of this study was to investigate the neuroprotective effects of pre-treatment with the extract in the hippocampus following 5-min transient forebrain ischemia in gerbils. Furthermore, this study examined the anti-inflammatory effect as a neuroprotective mechanism of the extract. Pinus densiflora bark was extracted by pure water (100 °C), and this extract was quantitatively analyzed and contained abundant polyphenols, flavonoids, and proanthocyanidins. The extract (25, 50, and 100 mg/kg) was orally administered once a day for seven days before the ischemia. In the gerbil hippocampus, death of the pyramidal neurons was found in the subfield cornu ammonis 1 (CA1) five days after the ischemia. This death was significantly attenuated by pre-treatment with 100 mg/kg, not 25 or 50 mg/kg, of the extract. The treatment with 100 mg/kg of the extract markedly inhibited the activation of microglia (microgliosis) and significantly decreased the expression of pro-inflammatory cytokines (interleukin 1ß and tumor necrosis factor α). In addition, the treatment significantly increased anti-inflammatory cytokines (interleukin 4 and interleukin 13). Taken together, this study clearly indicates that pre-treatment with 100 mg/kg of Pinus densiflora bark extract in gerbils can exert neuroprotection against brain ischemic injury by the attenuation of neuroinflammatory responses.


Assuntos
Anti-Inflamatórios/farmacologia , Isquemia Encefálica/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pinus/química , Prosencéfalo/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Flavonoides/química , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Gerbillinae , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação , Interleucina-13/agonistas , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/agonistas , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/química , Casca de Planta/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Polifenóis/química , Polifenóis/farmacologia , Proantocianidinas/química , Proantocianidinas/farmacologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Células Piramidais/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
Biomolecules ; 11(8)2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34439751

RESUMO

Periostin is known to be a useful biomarker for various diseases. In this article, we focus on allergic diseases and pulmonary fibrosis, for which we and others are now developing detection systems for periostin as a biomarker. Biomarker-based precision medicine in the management of type 2 inflammation and fibrotic diseases since heterogeneity is of utmost importance. Periostin expression is induced by type 2 cytokines (interleukin-4/-13) or transforming growth factor-ß, and plays a vital role in the pathogenesis of allergic inflammation or interstitial lung disease, respectively, andits serum levels are correlated disease severity, prognosis and responsiveness to the treatment. We first summarise the importance of type 2 biomarker and then describe the pathological role of periostin in the development and progression of type 2 allergic inflammation and pulmonary fibrosis. In addition, then, we summarise the recent development of assay methods for periostin detection, and analyse the diseases in which periostin concentration is elevated in serum and local biological fluids and its usefulness as a biomarker. Furthermore, we describe recent findings of periostin as a biomarker in the use of biologics or anti-fibrotic therapy. Finally, we describe the factors that influence the change in periostin concentration under the healthy conditions.


Assuntos
Biomarcadores/metabolismo , Moléculas de Adesão Celular/química , Inflamação/metabolismo , Fibrose Pulmonar/metabolismo , Doença Crônica , Citocinas/metabolismo , Eosinofilia/metabolismo , Fibrose/patologia , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Fibrose Pulmonar Idiopática/patologia , Imunoglobulina E/química , Inflamação/patologia , Interleucina-13/metabolismo , Pulmão/metabolismo , Medicina de Precisão , Prognóstico , Fibrose Pulmonar/patologia , Rinite/metabolismo , Sinusite/metabolismo , Fator de Crescimento Transformador beta/metabolismo
5.
Front Immunol ; 12: 650779, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34194428

RESUMO

Listeria monocytogenes (L.m) is efficiently controlled by several cells of the innate immunity, including the Mast Cell (MC). MC is activated by L.m inducing its degranulation, cytokine production and microbicidal mechanisms. TLR2 is required for the optimal control of L.m infection by different cells of the immune system. However, little is known about the MC receptors involved in recognizing this bacterium and whether these interactions mediate MC activation. In this study, we analyzed whether TLR2 is involved in mediating different MC activation responses during L.m infection. We found that despite MC were infected with L.m, they were able to clear the bacterial load. In addition, MC degranulated and produced ROS, TNF-α, IL-1ß, IL-6, IL-13 and MCP-1 in response to bacterial infection. Interestingly, L.m induced the activation of signaling proteins: ERK, p38 and NF-κB. When TLR2 was blocked, L.m endocytosis, bactericidal activity, ROS production and mast cell degranulation were not affected. Interestingly, only IL-6 and IL-13 production were affected when TLR2 was inhibited in response to L.m infection. Furthermore, p38 activation depended on TLR2, but not ERK or NF-κB activation. These results indicate that TLR2 mediates only some MC activation pathways during L.m infection, mainly those related to IL-6 and IL-13 production.


Assuntos
Interleucina-13/imunologia , Interleucina-6/imunologia , Listeria monocytogenes/imunologia , Mastócitos/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Degranulação Celular/imunologia , Degranulação Celular/fisiologia , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Ativação Enzimática/imunologia , Interações Hospedeiro-Patógeno/imunologia , Interleucina-13/metabolismo , Interleucina-6/metabolismo , Listeria monocytogenes/fisiologia , Mastócitos/microbiologia , Mastócitos/fisiologia , Camundongos Endogâmicos C57BL , NF-kappa B/imunologia , NF-kappa B/metabolismo , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Receptor 2 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
6.
Anticancer Res ; 41(7): 3471-3480, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230142

RESUMO

BACKGROUND/AIM: Pseudomonas exotoxin (PE) is one of the most widely used toxins in the construction of therapeutic fusion proteins in pre-clinical studies followed by phase trials. In principle, PE acts by blocking protein synthesis through catalyzing the inactivation of elongation factor-2 (EF-2). The interleukin-13 fused PE (IL13-PE) cytotoxin was previously designed to target GBM cells. In this study, the cytotoxic effects of IL13-PE were evaluated in 5 different types of cancers and the therapeutic effects were further analyzed in a lung cancer cell line, NCI-H460. Conceptually, in another lung cancer cell line (A549), IL13Rα2 was overexpressed by lentiviruses (A549-IL13Rα2) and evaluated for cytotoxic efficacy of IL13-PE. MATERIALS AND METHODS: The expression profile of IL13Rα2 in different cancer cell lines was determined by RT-PCR. Secretable toxin fusion was expressed in the toxin resistant HEK-293T cell line (293T-TxR) by using a plasmid coding for IL13-PE and IRES-GFP (LV-IL13-PE-IRES/GFP). Next, the cells were shown to produce and secrete functional IL13-PE by dot blot analysis, followed by cell viability assays and cell death analysis. RESULTS: Upon treatment with IL13-PE, a significant decrease in cell viability was selectively demonstrated in cancer cells with cognate receptor expression. IL13-PE treatment increased the apoptotic/necrotic cell populations in the NCI-H460 cell line. CONCLUSION: Our results demonstrate that IL13-PE can be a therapeutic target for tumors bearing mostly IL13Rα2 positive cell populations. Our findings also suggest a cell-based delivery option for the recombinant toxins in the treatment of different cancers which can provide a solution for the clinical use of toxin therapy.


Assuntos
Exotoxinas/farmacologia , Imunotoxinas/farmacologia , Neoplasias/tratamento farmacológico , Pseudomonas/metabolismo , Células A549 , Antineoplásicos/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Interleucina-13/metabolismo , Neoplasias/metabolismo , Proteínas Recombinantes de Fusão/farmacologia
7.
Am J Physiol Heart Circ Physiol ; 321(2): H309-H317, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34170196

RESUMO

Pulmonary hypertension (PH) observed during respiratory syncytial virus (RSV) bronchiolitis is associated with morbidity and mortality, especially in children with congenital heart disease. Yet, the pathophysiological mechanisms of RSV-associated PH remain unclear. Therefore, this study aimed to investigate the pathophysiological mechanism of RSV-associated PH. We used a translational mouse model of RSV-associated PH, in which wild-type (WT) and suppression of tumorigenicity 2 (ST2) knockout neonatal mice were infected with RSV at 5 days old and reinfected 4 wk later. The development of PH in WT mice following RSV reinfection was evidenced by elevated right ventricle systolic pressure, shortened pulmonary artery acceleration time (PAT), and decreased PAT/ejection time (ET) ratio. It coincided with the augmentation of periostin and IL-13 expression and increased arginase bioactivity by both arginase 1 and 2 as well as induction of nitric oxide synthase (NOS) uncoupling. Absence of ST2 signaling prevented RSV-reinfected mice from developing PH by suppressing NOS uncoupling. In summary, ST2 signaling was involved in the development of RSV-associated PH. ST2 signaling inhibition may be a novel therapeutic target for RSV-associated PH.NEW & NOTEWORTHY We report that the pathogenic role of ST2-mediated type 2 immunity and mechanisms contribute to RSV-associated pulmonary hypertension. Inhibiting ST2 signaling may be a novel therapeutic target for this condition.


Assuntos
Bronquiolite Viral/genética , Hipertensão Pulmonar/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Pulmão/metabolismo , Infecções por Vírus Respiratório Sincicial/genética , Animais , Animais Recém-Nascidos , Arginase/genética , Arginase/metabolismo , Bronquiolite Viral/complicações , Bronquiolite Viral/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/metabolismo , Interleucina-13/genética , Interleucina-13/metabolismo , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Reinfecção , Infecções por Vírus Respiratório Sincicial/complicações , Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sinciciais Respiratórios
8.
Biomed Pharmacother ; 140: 111746, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34062412

RESUMO

BACKGROUND/AIMS: Asthma is a common chronic respiratory disease. It has been reported that Pingchuan formula (PCF) can control asthma attacks by reducing airway inflammation, muscle spasm and mucus secretion. However, PCF's mechanism for reducing airway mucus hypersecretion remains unclear. This study aimed to investigate the effect of PCF on airway mucus secretion in asthmatic mice and to explore changes in the PNEC-GABA-IL13-Muc5ac axis. METHODS: Male Babl/c mice were used to establish the asthma model via sensitisation with OVA. Mice were randomly divided into Normal, OVA, DEX, and PCF groups. After treatment, lung histopathology was observed with H&E and PAS staining. BALF levels of IL-5 and IL-13 were detected using ELISA. The levels of mRNA and protein expression for GAD1, GABAARß1, GABAARα1 and Muc5ac in the lung tissue were measured by RT-PCR and Western blot assays. PNECs were observed with AgNOR staining. RESULTS: PCF treatment effectively reduced goblet cell (P < 0.01) and PNEC (P < 0.05) proliferation, lung tissue inflammation and airway mucus hypersecretion. In addition, PCF also markedly downregulated mRNA and protein expression of GAD1, GABAARß1, GABAARα1 and Muc5ac (P < 0.05, compared with OVA), thus inhibiting the GABA-IL-13 pathway in the lung tissue of asthmatic mice. CONCLUSION: These findings suggest that PCF controls asthma attacks by reducing airway inflammation and mucus hypersecretion via the PNEC-GABA-IL13-Muc5ac axis.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Animais , Antiasmáticos/farmacologia , Asma/imunologia , Asma/metabolismo , Asma/patologia , Líquido da Lavagem Broncoalveolar/imunologia , Proliferação de Células/efeitos dos fármacos , Citocinas/imunologia , Medicamentos de Ervas Chinesas/farmacologia , Células Caliciformes/efeitos dos fármacos , Interleucina-13/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos Endogâmicos BALB C , Mucina-5AC/metabolismo , Muco/metabolismo , Células Neuroendócrinas/efeitos dos fármacos , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo
9.
J Clin Invest ; 131(12)2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33956668

RESUMO

Severe asthma remains challenging to manage and has limited treatment options. We have previously shown that targeting smooth muscle integrin α5ß1 interaction with fibronectin can mitigate the effects of airway hyperresponsiveness by impairing force transmission. In this study, we show that another member of the integrin superfamily, integrin α2ß1, is present in airway smooth muscle and capable of regulating force transmission via cellular tethering to the matrix protein collagen I and, to a lesser degree, laminin-111. The addition of an inhibitor of integrin α2ß1 impaired IL-13-enhanced contraction in mouse tracheal rings and human bronchial rings and abrogated the exaggerated bronchoconstriction induced by allergen sensitization and challenge. We confirmed that this effect was not due to alterations in classic intracellular myosin light chain phosphorylation regulating muscle shortening. Although IL-13 did not affect surface expression of α2ß1, it did increase α2ß1-mediated adhesion and the level of expression of an activation-specific epitope on the ß1 subunit. We developed a method to simultaneously quantify airway narrowing and muscle shortening using 2-photon microscopy and demonstrated that inhibition of α2ß1 mitigated IL-13-enhanced airway narrowing without altering muscle shortening by impairing the tethering of muscle to the surrounding matrix. Our data identified cell matrix tethering as an attractive therapeutic target to mitigate the severity of airway contraction in asthma.


Assuntos
Asma/metabolismo , Colágeno Tipo I/metabolismo , Integrina alfa2beta1/metabolismo , Traqueia/metabolismo , Animais , Asma/patologia , Linhagem Celular , Constrição Patológica/metabolismo , Humanos , Interleucina-13/metabolismo , Camundongos
10.
Immunology ; 164(2): 292-304, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33999409

RESUMO

Allergic diseases are caused by dysregulated Th2 immune responses involving multiple effector cells including basophils. Short chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, exert immunomodulatory functions via activation of its receptors GPR41 and GPR43, and inhibition of the histone deacetylases (HDACs) activity. In allergic diseases, SCFAs suppress the activity of mast cells, eosinophils and type 2 innate lymphoid cells (ILC2) but enhance the function of Th2 cells. Here, we aimed to elucidate the function of SCFAs on human basophils. Human basophils were purified from healthy donors by flow cytometric sorting. The surface proteins, apoptosis and degranulation of basophils were analyzed by flow cytometric analysis. The mRNA expression was assayed using real-time PCR. Interleukin 4 (IL-4) and IL-13 were measured by ELISA. Histone acetylation was examined by western blot. GPR41 was expressed by basophils and was enhanced by IL-3. Acetate induced intracellular calcium influx in basophils which was suppressed by blocking GPR41. Propionate and butyrate, but not acetate, induced the expression of CD69 and IL-13. In addition, propionate and butyrate enhanced IgE-mediated basophil degranulation but inhibited basophil survival and IL-4 secretion. Propionate and butyrate induced histone acetylation of basophils and suppression of HDACs activity mimicked the effects of propionate and butyrate on human basophils. Our findings demonstrate that propionate and butyrate may play a complex role in regulating basophil apoptosis, activation and degranulation via inhibiting HDACs activity. The in vivo effects of SCFAs on the regulation of basophil-associated allergic diseases need to be further explored.


Assuntos
Apoptose/efeitos dos fármacos , Basófilos/efeitos dos fármacos , Butiratos/farmacologia , Histonas/metabolismo , Interleucina-13/metabolismo , Propionatos/farmacologia , Apoptose/imunologia , Basófilos/imunologia , Basófilos/metabolismo , Células Cultivadas , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Ácidos Graxos Voláteis , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Humanos , Hipersensibilidade/imunologia , Hipersensibilidade/metabolismo , Imunidade Inata/efeitos dos fármacos , Imunidade Inata/imunologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo
11.
J Mater Chem B ; 9(12): 2909-2917, 2021 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-33885646

RESUMO

Macrophages are essential in innate immunity and are involved in a variety of biological functions. Due to high plasticity, macrophages are polarized in different phenotypes depending on different microenvironments to perform specific functions. Although many studies have focused on macrophage polarization, few have explored the polarization characteristics of macrophages at the subcellular level, even at nanoscale resolution. Here, we utilize AFM-based infrared spectroscopy (AFM-IR) to investigate the influence of an inducer on the expressed proteins of M1/M2 macrophages (induced by LPS and IL-13, respectively). The results from AFM-IR combined with principal component analysis revealed that the characteristic proteins within M1 contain about 35% antiparallel ß-sheets (due to the high expression of TNF-α), while the proteins within M2 are made up of approximately 38.8% α-helices. The corresponding nanoscale chemical mapping demonstrates a remarkably heterogeneous distribution of expressed proteins inside single macrophages. Beside the biochemical properties, the biomechanical properties of macrophages were found to be softened in response to the polarization process.


Assuntos
Interleucina-13/genética , Lipopolissacarídeos/genética , Macrófagos/metabolismo , Fator de Necrose Tumoral alfa/genética , Animais , Fenômenos Biomecânicos , Microambiente Celular , Regulação da Expressão Gênica , Interleucina-13/metabolismo , Lipopolissacarídeos/metabolismo , Ativação de Macrófagos , Macrófagos/ultraestrutura , Camundongos , Microscopia de Força Atômica , Fenótipo , Análise de Componente Principal , Conformação Proteica , Células RAW 264.7 , Espectrofotometria Infravermelho , Fator de Necrose Tumoral alfa/metabolismo
12.
Front Immunol ; 12: 635531, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763079

RESUMO

Interleukin-2 (IL-2) expands the depleted T regulatory (Treg) cell population, and it has emerged as a potential therapy in systemic lupus erythematosus (SLE). However, IL-2 administration may involve the risk of expanding unwanted pro-inflammatory cells. We herein studied the effects of IL-2 on pro-inflammatory cytokine production by CD4+ and CD8+ T cells in parallel with Treg development following CD3/CD28 co-stimulation. While Treg cells are depleted in SLE patients, their CD4+ T cells were poised to receive and activate IL-2 signaling as evidenced by upregulation of CD25 and enhanced IL-2-incued STAT5 phosphorylation during Treg differentiation. In patients with SLE, however, IL-2 also expanded CD8+ T cells capable of producing interleukin-5, interkeukin-13 (IL-13), and interferon-γ (IFN-γ) that occurred with enhanced expression of GATA-3 and phosphorylation of STAT6 but not STAT5. Our data pinpoint a safety signal for systemic administration of IL-2 and challenges a long-held conceptual platform of type 1 and 2 cytokine antagonism by newly documenting the IL-2-dependent development of IL-13 and IFN-γ double-positive (IL-13+IFNγ+) CD8+ T cells in SLE.


Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Fator de Transcrição GATA3/metabolismo , Interferon gama/metabolismo , Interleucina-13/metabolismo , Interleucina-2/farmacologia , Lúpus Eritematoso Sistêmico/imunologia , Ativação Linfocitária/efeitos dos fármacos , Fator de Transcrição STAT6/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Feminino , Humanos , Interleucina-2/toxicidade , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Fosforilação , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
13.
Int J Mol Med ; 47(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33655321

RESUMO

Fine particulate matter (PM2.5) with an average aerodynamic diameter of <2.5 µm can cause severe lung injury. Oxidative stress and inflammation are considered the main outcomes of PM2.5 exposure. Curcumin is a well­known antioxidant; however, its effect on PM2.5­induced oxidative injury in airway epithelial cells remains unclear. In the present study, it was demonstrated that pre­treatment with curcumin significantly reduced the PM2.5­induced apoptosis of BEAS­2B human bronchial epithelial cells by decreasing the level of intercellular reactive oxygen species. Western blot analysis revealed that curcumin increased the expression of nuclear factor erythroid 2­related factor 2 (NRF2) and regulated the transcription of downstream genes, particularly those encoding antioxidant enzymes. Moreover, curcumin reduced the PM2.5­induced expression and production of inflammatory factors, and induced the expression of the anti­inflammatory factors, interleukin (IL)­5 and IL­13. Taken together, the present study demonstrates that curcumin protects BEAS­2B cells against PM2.5­induced oxidative damage and inflammation, and prevents cell apoptosis by increasing the activation of NRF2­related pathways. It is thus suggested that curcumin may be a potential compound for use in the prevention of PM2.5­induced tissue injury.


Assuntos
Antioxidantes/farmacologia , Curcumina/farmacologia , Lesão Pulmonar/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Material Particulado/toxicidade , Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Humanos , Inflamação/prevenção & controle , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Lesão Pulmonar/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo
14.
Allergol Immunopathol (Madr) ; 49(2): 208-216, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33641310

RESUMO

Asthma is a heterogeneous disease with ranging etiology and severity. Asthma is a disease of chronic inflammation of the airways, with clinical symptoms of wheezing, breathlessness, cough, and chest tightness manifested as chronic fixed or variable airflow obstruction and airway hyperresponsiveness that predispose the airway epithelium to repeated injury, repair, and regeneration. In recent years, innate lymphoid cells (ILC1, ILC2, and ILC3) have been discovered. The predominant ILC type found in the lung tissue is group 2 innate lymphoid cells (ILC2s). Upon damage to the airway epithelium mediating the release of epithelial cytokines (TSLP, IL-33, and IL-25) ensued the activation of ILC2 in an antigen-independent manner. Activated ILC2 produces a significant amount of type 2 cytokines (IL-4, IL-5, IL-9, and IL-13), altogether contributing to type 2 inflammation in the airways. ILC2s are mediators of type 2 immunity for many type 2 inflammatory diseases such as asthma, since ILC2s were reported to play an important role in asthma pathogenesis. Here we discuss the role of ILC2 in the development of asthma and ILC2 effector cytokines (IL-4, IL-5, and IL-13) contributing to airway epithelial structural changes.


Assuntos
Asma/imunologia , Imunidade Inata , Pulmão/patologia , Linfócitos/imunologia , Mucosa Respiratória/patologia , Animais , Asma/patologia , Modelos Animais de Doenças , Humanos , Inflamação/imunologia , Inflamação/patologia , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Interleucina-9/metabolismo , Pulmão/imunologia , Linfócitos/metabolismo , Camundongos , Mucosa Respiratória/imunologia , Índice de Gravidade de Doença , Transdução de Sinais/imunologia
15.
Immunology ; 163(2): 220-235, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33512727

RESUMO

Eosinophils are a common clinical feature associated with chronic allergic diseases, and elemental diets, systemic steroids, anti-IL-5 and anti-IL-13 treatment have shown some therapeutic promise. Herein, we present evidence that pre- and post-intraperitoneal administration of tacrolimus (FK506) is very effective in reducing CCR3/Siglec-F+ eosinophils in Aspergillus-challenged asthma and EoE, CD2-IL-5 induced global eosinophilia, and DOX regulated IL-13-induced asthma. We used flow cytometry and anti-major basic protein (MBP) immunostaining to examine eosinophils in the spleen, bone marrow, BALF, lung, oesophagus and intestine. Additionally, we also performed ELISA and Western blot analyses to show that tacrolimus treatment also reduces the levels of eosinophil-specific cytokines IL-4, IL-5, IL-13 and TGF-ß, eosinophil-specific chemokines Eotaxin-1 and Eotaxin-2, and progenitors of target RCAN1 mRNA and protein levels. Additionally, the current investigations also show that the TGF-ß-mediated oesophageal and lung fibrosis is also reduced in Aspergillus-challenged, CD2-IL-5 transgenic and DOX-responsive IL-13 mice. Mechanistically, we show that tacrolimus in vitro treatment inhibited bone marrow-derived eosinophil proliferation and viability by promoting eosinophil apoptosis that may be associated with downregulation of RCAN1. Taken together, we provide in vivo and in vitro evidence that tacrolimus ameliorates eosinophil levels and associated pathogenesis in allergen-, IL-5- and IL-13-induced EoE, EG and asthma pathogenesis. Considering tacrolimus side-effects and reactivity to several other drugs, we propose the topical use of tacrolimus for paediatric and low-dose oral for adult patients as a novel therapeutic strategy for the clinical trial to reduce mucosal eosinophilia first in steroid-refractory or elemental diet non-responsive adult EoE, EG and asthma patients.


Assuntos
Aspergilose/imunologia , Aspergillus/fisiologia , Asma/tratamento farmacológico , Enterite/tratamento farmacológico , Eosinofilia/tratamento farmacológico , Eosinófilos/imunologia , Gastrite/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Imunossupressores/uso terapêutico , Interleucina-13/metabolismo , Interleucina-5/metabolismo , Pulmão/patologia , Mucosa Respiratória/imunologia , Tacrolimo/uso terapêutico , Alérgenos/imunologia , Animais , Apoptose , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Fibrose , Humanos , Interleucina-13/genética , Interleucina-5/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo
16.
J Cell Mol Med ; 25(4): 1949-1957, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33443817

RESUMO

Previous studies in Graves' orbitopathy (GO) patient-derived fibroblasts showed that inhibition of autophagy suppresses adipogenic differentiation. Autophagy activation is associated with inflammation, production of reactive oxygen species and fibrosis. Neferine is an alkaloid extracted from Nelumbo nucifera, which induces Nrf2 expression and inhibits autophagy. Here, we have elucidated the role of neferine on interleukin (IL)-13-induced autophagy using patient-derived orbital fibroblasts as an in vitro model of GO. GO patient-derived orbital fibroblasts were isolated and cultured to generate an in vitro model of GO. Autophagy was determined by Western blot detection of the markers such as Beclin-1, Atg-5 and LC3 and by immunofluorescence detection of autophagosome formation. Analysis of differentiation towards an adipogenic lineage was performed by Oil red O staining. The expression of inflammatory factors was detected by ELISA and semiquantitative RT-PCR. Neferine inhibited autophagy in GO orbital fibroblasts, as indicated by the suppression of IL-13-induced autophagosome formation, overexpression of autophagy markers, increased LC3-II/LC3-I levels and finally down-regulation of p62. Neferine suppressed IL-13-induced inflammation, ROS generation, fibrosis and adipogenic differentiation in GO patient-derived orbital fibroblasts. The anti-inflammatory, antioxidant and antiadipogenic effects of neferine were accompanied by the up-regulation of Nrf2. These results indicated that orbital tissue remodelling and inflammation in GO may be mediated by autophagy, and neferine suppressed autophagy-related inflammation and adipogenesis through a mechanism involving Nrf2.


Assuntos
Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Benzilisoquinolinas/farmacologia , Oftalmopatia de Graves/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Adipócitos/metabolismo , Benzilisoquinolinas/química , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Suscetibilidade a Doenças , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Oftalmopatia de Graves/etiologia , Humanos , Interleucina-13/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo
17.
Proc Natl Acad Sci U S A ; 118(2)2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33397719

RESUMO

Exaggerated airway hyperresponsiveness and inflammation are hallmarks of asthma, and lipopolysaccharide (LPS) exposure is linked to the severity of the disease and steroid resistance. To investigate the mechanisms underlying asthma exacerbation, we established a mouse model of LPS-induced steroid-resistant exacerbation on the background of house dust mite (HDM)-induced asthma to profile the immune cells in lung by using single-cell RNA deep sequencing. Twenty immune subsets were identified by their molecular and functional properties. Specific cell clusters of basophils, type 2 innate lymphoid cells (ILC2), and CD8+ memory T cells were the predominant sources of interleukin (IL)-4 and IL-13 transcripts whose expressions were dexamethasone resistant. Production of IL-13 by these cells was validated by IL-13-reporter mice. Neutralization of IL-13 abolished HDM/LPS-induced airway hyperresponsiveness, airway inflammation, and decreased mucus hypersecretion. Furthermore, using Ingenuity Pathway Analysis systems, we identified canonical pathways and upstream regulators that regulate the activation of basophils, ILC2, and CD8+ memory T cells. Our study provides mechanistic insights and an important reference resource for further understanding of the immune landscape during asthma exacerbation.


Assuntos
Asma/imunologia , Interleucina-13/metabolismo , Leucócitos/metabolismo , Pulmão/imunologia , Sistema Fagocitário Mononuclear/metabolismo , Transcriptoma , Animais , Progressão da Doença , Interleucina-4/metabolismo , Lipopolissacarídeos , Camundongos Endogâmicos BALB C , Pyroglyphidae/imunologia , Análise de Célula Única
18.
Int J Mol Sci ; 22(2)2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33450900

RESUMO

Interleukin (IL)-4 and -13 are structurally and functionally related cytokines sharing common receptor subunits. They regulate immune responses and, moreover, are involved in the pathogenesis of a variety of human neoplasms. Three different receptors have been described for IL-4, but only IL-4 receptor type II (IL-4Rα/IL-13Rα1) is expressed in solid tumors. While IL-13 can also bind to three different receptors, IL-13 receptor type I (IL-4Rα/IL-13Rα1/IL-13Rα2) and type II (IL-4Rα/IL-13Rα1) are expressed in solid tumors. After receptor binding, IL-4 and IL-13 can mediate tumor cell proliferation, survival, and metastasis in gastric or colon cancer. This review summarizes the results about the role of IL-4/IL-13 and their receptors in gastric and colon cancer.


Assuntos
Neoplasias do Colo/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Receptores de Interleucina-13/metabolismo , Receptores de Interleucina-4/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Neoplasias do Colo/etiologia , Neoplasias do Colo/patologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Humanos , Interleucina-13/genética , Interleucina-4/genética , Polimorfismo de Nucleotídeo Único , Ligação Proteica , Receptores de Interleucina-13/genética , Receptores de Interleucina-4/genética , Transdução de Sinais , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia
19.
Laryngoscope ; 131(3): E800-E806, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32621541

RESUMO

OBJECTIVES: To investigate the clinical, laboratory, radiological, histopathological, and immunohistochemical features, and the expression of allergy-related cytokines in eosinophilic sialodochitis (ES). METHODS: Thirty-eight patients diagnosed with chronic obstructive sialadenitis (COS) who had undergone glandular excision or incisional biopsy were enrolled. Seventeen patients with comorbid atopic disease and increased ductal tissue eosinophils comprised the ES group, while 21 patients comprised the COS group. The clinicopathological features and allergy-related cytokine expression were compared between groups. RESULTS: The ES group frequently involved multiple, bilateral major salivary glands, and the number of glands was significantly greater than the COS group (2.8 ± 1.1 vs. 1.2 ± 0.4, P < .001). Serum immunoglobulin (Ig) E was elevated in 91% of patients in ES group (419 ± 357 kU/L) and peripheral blood eosinophil was significantly greater compared with the COS group (7.6% ± 4.6% vs. 2.5% ± 1.4%, P < .001). Histologically, eosinophil infiltration in ES group was observed around the main and interlobular ducts (50 ± 39/high power field [HPF]). Follicular hyperplasia (76%), epithelial mucous metaplasia (82%), and mucus plugs with eosinophils (41%) were observed. IgE-positive cell count was 20.7 ± 18.3/HPF and tryptase-positive mast cell count was 23.5 ± 15.1/HPF, which was significantly greater than the respective cell counts in COS group, which mainly infiltrated around the ducts. The levels of interleukin-4, interleukin-13, and eotaxin in tissue were significantly greater in ES than the COS group. CONCLUSIONS: The clinicopathological characteristics of ES are significantly different from COS and ES might have an allergy-related pathogenesis. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E800-E806, 2021.


Assuntos
Eosinofilia/imunologia , Hipersensibilidade/imunologia , Sialadenite/imunologia , Adolescente , Adulto , Contagem de Células Sanguíneas , Quimiocinas CC/metabolismo , Doença Crônica , Eosinofilia/patologia , Feminino , Humanos , Hipersensibilidade/patologia , Imunoglobulina E/sangue , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Masculino , Pessoa de Meia-Idade , Glândulas Salivares/imunologia , Glândulas Salivares/patologia , Sialadenite/patologia , Triptases/sangue , Adulto Jovem
20.
Am J Respir Cell Mol Biol ; 64(1): 50-58, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33026825

RESUMO

TMEM16A is a Ca2+-activated chloride channel that was shown to enhance production and secretion of mucus in inflamed airways. It is, however, not clear whether TMEM16A directly supports mucus production, or whether mucin and TMEM16A are upregulated independently during inflammatory airway diseases such as asthma and cystic fibrosis (CF). We examined this question using BCi-NS1 cells, a human airway basal cell line that maintains multipotent differentiation capacity, and the two human airway epithelial cell lines, Calu-3 and CFBE. The data demonstrate that exposure of airway epithelial cells to IL-8 and IL-13, two cytokines known to be enhanced in CF and asthma, respectively, leads to an increase in mucus production. Expression of MUC5AC was fully dependent on expression of TMEM16A, as shown by siRNA knockdown of TMEM16A. In addition, different inhibitors of TMEM16A attenuated IL-13-induced mucus production. Interestingly, in CFBE cells expressing F508 delCFTR, IL-13 was unable to upregulate membrane expression of TMEM16A or Ca2+-activated whole cell currents. The regulator of TMEM16A, CLCA1, strongly augmented both Ca2+- and cAMP-activated Cl- currents in cells expressing wtCFTR but failed to augment membrane expression of TMEM16A in F508 delCFTR-expressing CFBE cells. The data confirm the functional relationship between CFTR and TMEM16A and suggest an impaired upregulation of TMEM16A by IL-13 or CLCA1 in cells expressing the most frequent CF-causing mutation F508 delCFTR.


Assuntos
Anoctamina-1/metabolismo , Células Epiteliais/metabolismo , Muco/metabolismo , Proteínas de Neoplasias/metabolismo , Mucosa Respiratória/metabolismo , Cálcio/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Canais de Cloreto/metabolismo , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células HEK293 , Células HT29 , Humanos , Interleucina-13/metabolismo , RNA Interferente Pequeno/metabolismo , Regulação para Cima/fisiologia
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