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1.
J Clin Exp Hematop ; 61(3): 145-151, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34334531

RESUMO

We established an IL-2 and IL-4 (IL2/4) - dependent adult T-cell leukemia/lymphoma (ATLL) cell line (YG-PLL) by adding poly-L-lysine (PLL) to the culture medium. YG-PLL originates from lymphoma cells and contains a defective HTLV-I proviral genome. Although YG-PLL cannot survive without IL-2/4, the follicular dendritic cell (FDC)-like cell line HK expressing OX40-ligand gene (OX40L+HK) inhibited their death in the presence of soluble neutral polymers. After the prevention of cell death, YG-PLL proliferated on OX40L+HK without IL2/4 in the presence of two kinds of positively or negatively charged polymers. In particular, dermatan sulfate and poly-L-histidine supported growth for more than 4 months. Therefore, the original lymphoma cells proliferated transiently in the presence of IL2/4, and their growth arrest was inhibited by the addition of PLL. Furthermore, YG-PLL lost IL2/4 dependency by the following 3-step procedure: preculture with IL2/4 and neutral polymers, 3-day culture with neutral polymer on OX40L+HK to inhibit cell death, and co-culture with OX40L+HK in the presence of the positively and negatively charged polymers. The extracellular environment made by soluble polymers plays a role in the growth of ATLL in vitro.


Assuntos
Linhagem Celular Tumoral , Dermatan Sulfato/farmacologia , Histidina/farmacologia , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Leucemia-Linfoma de Células T do Adulto/etiologia , Leucemia-Linfoma de Células T do Adulto/metabolismo , Ligante OX40/metabolismo , Células Dendríticas Foliculares/imunologia , Células Dendríticas Foliculares/metabolismo , Expressão Gênica , Humanos , Leucemia-Linfoma de Células T do Adulto/patologia , Ligante OX40/genética
2.
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
3.
Biomed Res Int ; 2021: 3725316, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34414234

RESUMO

Dexmedetomidine is an α2 adrenergic receptor agonist that has been reported to modulate the polarization of CD4+ T cells. However, the underlying mechanisms by which dexmedetomidine induces T-helper 1 (Th1) cell differentiation remain poorly understood. The aim of this study was to explore the potential mechanisms through which dexmedetomidine can induce Th1 cell differentiation. Purified CD4+ T cells were stimulated with anti-CD3/anti-CD28 and then treated with dexmedetomidine. Flow cytometry analysis was adopted to measure the concentration of Th1 cells. Enzyme-linked immunosorbent assay (ELISA) and real-time quantitative polymerase chain reaction (qPCR) were performed to detect protein levels and mRNA expression, respectively, of IFN-γ and IL-4. Western blotting was used to determine the phosphorylation of signal transducer and activator of transcription 1 (STAT1) and T-bet expression. The Th1 cell subset and IFN-γ levels were elevated in the dexmedetomidine-induced CD4+ T cells. Dexmedetomidine enhanced the phosphorylation of STAT1 and the expression of T-bet in the CD4+ T cells. Atipamezole (an α2 adrenergic antagonist) and fludarabine (a STAT1 inhibitor) reversed the dexmedetomidine-induced Th1 cell differentiation. These results suggested that dexmedetomidine induced Th1 cell differentiation via the STAT1-T-bet signaling pathway.


Assuntos
Linfócitos T CD4-Positivos/citologia , Dexmedetomidina/farmacologia , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Th1/citologia , Animais , Anticorpos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas com Domínio T/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo
4.
Int J Mol Sci ; 22(15)2021 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-34360687

RESUMO

In the intestine, the innate immune system excludes harmful substances and invading microorganisms. Tuft cells are taste-like chemosensory cells found in the intestinal epithelium involved in the activation of group 2 innate lymphoid cells (ILC2). Although tuft cells in other tissues secrete the neurotransmitter acetylcholine (ACh), their function in the gut remains poorly understood. In this study, we investigated changes in the expression of genes and cell differentiation of the intestinal epithelium by stimulation with interleukin-4 (IL-4) or IL-13 in macaque intestinal organoids. Transcriptome analysis showed that tuft cell marker genes were highly expressed in the IL-4- and IL-13-treated groups compared with the control, and the gene expression of choline acetyltransferase (ChAT), a synthesis enzyme of ACh, was upregulated in IL-4- and IL-13-treated groups. ACh accumulation was observed in IL-4-induced organoids using high-performance liquid chromatography-mass spectrometry (HPLC/MS), and ACh strongly released granules from Paneth cells. This study is the first to demonstrate ACh upregulation by IL-4 induction in primates, suggesting that IL-4 plays a role in Paneth cell granule secretion via paracrine stimulation.


Assuntos
Acetilcolina/metabolismo , Diferenciação Celular , Interleucina-4/farmacologia , Intestinos/fisiologia , Organoides/metabolismo , Animais , Perfilação da Expressão Gênica , Interleucina-4/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Macaca fuscata/fisiologia , Macaca mulatta/metabolismo , Macaca mulatta/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Organoides/efeitos dos fármacos , Organoides/fisiologia
5.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445510

RESUMO

Microglia are resident immune cells of the central nervous system that act as brain-specific macrophages and are also known to regulate the innate immune functions of astrocytes through secretory molecules. This communication plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia could crosstalk to induce microglial polarization and proliferation, which can be further regulated under a microenvironment mimicking that of brain stroke. Microglia in a mixed glial culture showed increased survival and proliferation and were altered to M2 microglia; CD11b-GFAP+ astrocytes resulted in an approximately tenfold increase in microglial cell proliferation after the reconstitution of astrocytes. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced them to become CCR7+ M1 microglia, which have a phenotype that could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and substance P. In addition, the astrocytes in the microglial co-culture showed an A2 phenotype; they could be activated to A1 astrocytes by TNF-α and IFN-γ under the stroke-mimicking condition. Altogether, astrocytes in the mixed glial culture stimulated the proliferation of the microglia and M2 polarization, possibly through the acquisition of the A2 phenotype; both could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimicking environment. This study demonstrated that microglia and astrocytes could be polarized to M2 microglia and A2 astrocytes, respectively, through crosstalk in vitro and provides a system with which to explore how microglia and astrocytes may behave in the inflammatory disease milieu after in vivo transplantation.


Assuntos
Astrócitos/citologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Macrófagos/citologia , Microglia/citologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Comunicação Celular , Polaridade Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Ratos
6.
Nat Commun ; 12(1): 4623, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330904

RESUMO

Visceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. Here, we report that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat. Mice lacking functional beige fat exhibit accelerated cognitive dysfunction and microglial activation with dietary obesity. Subcutaneous fat transplantation also protects against chronic obesity in wildtype mice via beige fat-dependent mechanisms. Beige adipocytes restore hippocampal synaptic plasticity following transplantation, and these effects require the anti-inflammatory cytokine interleukin-4 (IL4). After observing beige fat-mediated induction of IL4 in meningeal T-cells, we investigated the contributions of peripheral lymphocytes in donor fat. There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.


Assuntos
Adipócitos Bege/metabolismo , Tecido Adiposo Bege/metabolismo , Adiposidade , Obesidade/metabolismo , Gordura Subcutânea/metabolismo , Adipócitos Bege/citologia , Animais , Anti-Inflamatórios/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Humanos , Interleucina-4/metabolismo , Camundongos Obesos , Plasticidade Neuronal/fisiologia , Fármacos Neuroprotetores/metabolismo , Obesidade/etiologia , Obesidade/fisiopatologia , Gordura Subcutânea/transplante , Linfócitos T/metabolismo
7.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299012

RESUMO

Atopic dermatitis (AD) represents a severe global burden on physical, physiological and mental health. Innate immune cell basophils are essential for provoking allergic inflammation in AD. However, the roles of novel immunoregulatory cytokine IL-37 in basophils remain elusive. We employed in vitro co-culture of human basophils and human keratinocyte HaCaT cells and an in vivo MC903-induced AD murine model to investigate the anti-inflammatory mechanism of IL-37. In the in vitro model, IL-37b significantly decreased Der p1-induced thymic stromal lymphopoietin (TSLP) overexpression in HaCaT cells and decreased the expression of TSLP receptor as well as basophil activation marker CD203c on basophils. IL-37 could also reduce Th2 cytokine IL-4 release from TSLP-primed basophils ex vivo. In the in vivo model, alternative depletion of basophils ameliorated AD symptoms and significantly lowered the Th2 cell and eosinophil populations in the ear and spleen of the mice. Blocking TSLP alleviated the AD-like symptoms and reduced the infiltration of basophils in the spleen. In CRISPR/Cas9 human IL-37b knock-in mice or mice with direct treatment by human IL-37b antibody, AD symptoms including ear swelling and itching were significantly alleviated upon MC903 challenge. Notably, IL-37b presence significantly reduced the basophil infiltration in ear lesions. In summary, IL-37b could regulate the TSLP-mediated activation of basophils and reduce the release of IL-4. The results, therefore, suggest that IL-37 may target TSLP-primed basophils to alleviate AD.


Assuntos
Basófilos/imunologia , Citocinas/metabolismo , Dermatite Atópica/metabolismo , Interleucina-1/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Basófilos/efeitos dos fármacos , Linhagem Celular , Técnicas de Cocultura , Citocinas/antagonistas & inibidores , Citocinas/farmacologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Regulação para Baixo , Orelha/patologia , Eosinófilos/metabolismo , Técnicas de Introdução de Genes , Humanos , Interleucina-1/genética , Interleucina-1/farmacologia , Interleucina-1/uso terapêutico , Interleucina-4/metabolismo , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Baço/imunologia , Baço/metabolismo , Células Th2/imunologia , Regulação para Cima
8.
Front Immunol ; 12: 611673, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220793

RESUMO

In tuberculosis, T cell-mediated immunity is extensively studied whilst B cells received limited attention in human and mice. Of interest, Mycobacterium tuberculosis (Mtb) does increase IL-4 Receptor-alpha (IL4Rα) expression in murine B cells. To better understand the role of IL4Rα signalling in B cells, we compared wild type mice with B cell-specific IL4Rα deficient mice (mb1creIL-4Rα-/lox mice). Chronic Mtb aerosol infection in mb1creIL-4Rα-/lox mice reduced lung and spleen bacterial burdens, compared to littermate (IL-4Rα-/lox) control animals. Consequently, lung pathology, inflammation and inducible nitric oxide synthase (iNOS) expression were reduced in the lungs of mb1creIL-4Rα-/lox mice, which was also accompanied by increased lung IgA and decreased IgG1 levels. Furthermore, intratracheal adoptive transfer of wild-type B cells into B cell-specific IL4Rα deficient mice reversed the protective phenotype. Moreover, constitutively mCherry expressing Mtb showed decreased association with B cells from mb1creIL-4Rα-/lox mice ex vivo. In addition, supernatants from Mtb-exposed B cells of mb1creIL-4Rα-/lox mice also increased the ability of macrophages to produce nitric oxide, IL-1ß, IL-6 and TNF. Together, this demonstrates that IL-4-responsive B cells are detrimental during the chronic phase of tuberculosis in mice with perturbed antibody profiles, inflammatory cytokines and tnf and stat1 levels in the lungs.


Assuntos
Linfócitos B/imunologia , Imunoglobulina A/metabolismo , Interleucina-4/metabolismo , Pulmão/metabolismo , Macrófagos/patologia , Mycobacterium tuberculosis/fisiologia , Tuberculose/imunologia , Animais , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Superfície Celular/genética , Transdução de Sinais
9.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069564

RESUMO

In the follicular lymphoma (FL) microenvironment, CXCR5+ICOS+PD1+BCL6+ follicular helper T (Tfh) cells, which closely correlate with FL B cells in neoplastic follicles, play a major role in supporting FL. Interleukin-4 secreted by Tfh cells triggers the upregulation of the lymphocyte chemoattractant CXCL12 in stromal cell precursors, in particular by fibroblastic reticular cells (FRCs). In turn, mesenchymal stem cells (MSCs) can be committed to FRC differentiation in the bone marrow and lymph nodes involved by FL. Noteworthy, MSCs can promote the differentiation of Tfh cells into highly immunosuppressive T-follicular regulatory cells. The tumor suppressor HVEM is highly mutated in FL cells, and its deficiency increases Tfh cell frequency. In contrast, PI3Kδ inhibition impedes the recruitment of Tfh/regulatory T cells and impairs the proliferation of follicular dendritic cells (FDCs) and FDC-induced angiogenesis. Since TIGIT ligands are expressed by FDCs, the immune checkpoint receptor TIGIT plays an important role in tumor-infiltrating T cells. Thus, TIGIT blockade might invigorate cytotoxic T cells in the FL microenvironment. Given their potential to simultaneously reduce the neoplastic B cells, Tfh, and TFR cells could also reinforce the effects of the cytotoxic T cells. This combinatory strategy should be explored as a treatment option to tackle FL.


Assuntos
Linfoma Folicular/imunologia , Células T Auxiliares Foliculares/imunologia , Microambiente Tumoral/fisiologia , Linfócitos B/imunologia , Diferenciação Celular/fisiologia , Quimiocina CXCL12/metabolismo , Humanos , Interleucina-4/imunologia , Interleucina-4/metabolismo , Linfoma de Células B/patologia , Linfoma Folicular/metabolismo , Linfoma Folicular/fisiopatologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Receptores Imunológicos/metabolismo , Células Estromais/patologia , Células T Auxiliares Foliculares/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia
10.
Int Immunopharmacol ; 97: 107828, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34091116

RESUMO

In various pathological conditions, cellular immunity plays an important role in immune responses. Amongimmunecells, T lymphocytes pdomotecellular and humoralresponses as well as innate immunity. Therefore, careful investigation of these cells has a significant impact on accurate knowledge in COVID-19diseasepathogenesis. In current research, the frequency and function of various T lymphocytes involved in immune responses examined in SARS-CoV-2 patients with various disease severity compared to normal subjects. In order to make an accurate comparison among patients with various disease severity, this study was performed on asymptomatic recovered cases (n = 20), ICU hospitalized patients (n = 30), non-ICU hospitalized patients (n = 30), and normal subjects (n = 20). To precisely evaluate T cells activity following purification, their cytokine secretion activity was examined. Similarly, immediately after purification of Treg cells, their inhibitory activity on T cells was investigated. The results showed that COVID-19 patients with severe disease (ICU hospitalized patients) not only had a remarkable increase in Th1 and Th17 but also a considerable decrease in Th2 and Treg cells. More importantly, as the IL-17 and IFN-γ secretion was sharply increased in severe disease, the secretion of IL-10 and IL-4 was decreased. Furthermore, the inhibitory activity of Treg cells was reduced in severe disease patients in comparison to other groups. In severe COVID-19 disease, current findings indicate when the inflammatory arm of cellular immunity is significantly increased, a considerable reduction in anti-inflammatory and regulatory arm occurred.


Assuntos
COVID-19/sangue , COVID-19/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia , Adulto , Idoso , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Voluntários Saudáveis , Humanos , Imunidade Celular , Inflamação/metabolismo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Adulto Jovem
11.
Toxicol Lett ; 349: 145-154, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34126182

RESUMO

Cutaneous eruptions caused by the combination of Chinese and Western medicine have attracted widespread attention; however, the underlying mechanism remains unclear. This study aimed to evaluate the potential mechanism of cutaneous eruptions in vivo and in vitro using the combination of Shuanghuanglian injection powder (SHL) and aspirin (ASA) as an example. ASA and SHL co-administration induced inflammatory responses in HaCat cells, as evidenced by marked increases in the expression of IL-4 and TNF-α, and the level of apoptosis. Additionally, histopathological investigation of mice skin tissues showed local inflammatory cell infiltration. Western boltting was used to detect the effects of ASA on desmoglein-1 (DSG1) expression; we found that DSG1 expression was down-regulated in vivo and in vitro. Finally, the key components of SHL were administered to HaCat cells with down-regulated DSG1; it was seen that neochlorogenic acid and rutin have a significant effect on HaCat cell apoptosis. These results demonstrate that DSG1 deficiency is a potential cause of cutaneous eruptions caused by the combination of SHL and ASA, and neochlorogenic acid and rutin are the main allergenic components. This study provides a new research strategy for the safety evaluation of integrated traditional Chinese and Western medicine.


Assuntos
Apoptose/efeitos dos fármacos , Aspirina/toxicidade , Desmogleína 1/antagonistas & inibidores , Erupção por Droga/etiologia , Medicamentos de Ervas Chinesas/toxicidade , Queratinócitos/efeitos dos fármacos , Animais , Ácido Clorogênico/análogos & derivados , Ácido Clorogênico/toxicidade , Desmogleína 1/metabolismo , Erupção por Droga/metabolismo , Erupção por Droga/patologia , Feminino , Células HaCaT , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-4/metabolismo , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos Endogâmicos ICR , Ácido Quínico/análogos & derivados , Ácido Quínico/toxicidade , Rutina/toxicidade , Fator de Necrose Tumoral alfa/metabolismo
12.
Cell Death Dis ; 12(6): 501, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34006836

RESUMO

Regulatory T cells play a crucial role in orchestrating immune response and maintaining immune tolerance, and the expression of the Foxp3 gene is indispensable to the differentiation of regulatory T cells. IL-4 shows strong inhibitory effects on Foxp3 expression and regulatory T cells differentiation, but the detailed mechanisms are still unclear. Here, we revealed that epigenetic modulations are key to this process. Specifically, the inhibition was found to be STAT6 dependent, and HDAC9 was involved with the process of histone deacetylation at the Foxp3 locus, subsequently decreasing chromatin accessibility and Foxp3 gene transcription. Pan-histone deacetylation inhibitors, especially sodium butyrate, notably abolished the inhibitory effects of IL-4 and ameliorated allergic airway inflammation in mouse models. Our research provides important mechanistic insights into how IL-4 inhibits regulatory T cells differentiation and suggests the therapeutic potential of the sodium butyrate in allergic airway disease.


Assuntos
Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Interleucina-4/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Linfócitos T Reguladores/citologia , Animais , Diferenciação Celular/fisiologia , Epigênese Genética , Feminino , Humanos , Camundongos , Linfócitos T Reguladores/imunologia
13.
Arch Biochem Biophys ; 706: 108918, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-33992596

RESUMO

Tripartite motif-containing 21 (TRIM21) has been confirmed to mediate the production of inflammatory mediators via NF-κB signaling. However, the function of TRIM21 in microglia-mediated neuroinflammation remains unclear. This study aimed to explore the effect of TRIM21 on LPS-activated BV2 microglia and its underlying mechanism. BV2 cells exposed to lipopolysaccharide (LPS) were used to simulated neuroinflammation in vitro. Loss-of-function and gain-of-function of TRIM21 in BV2 cells were used to assess the effect of TRIM21 on LPS-induced neuroinflammation. BV2 microglia and HT22 cells co-culture system were used to investigate whether TRIM21 regulated neuronal inflammation-mediated neuronal death. TRIM21 knockdown triggered the polarization of BV2 cells from M1 to M2 phenotype. Knockdown of TRIM21 reduced the secretion of TNF-α, IL-6, and IL-1ß, while increased the content of IL-4 in LPS-treated cells. Knockdown of TRIM21 inhibited the expression of p65 and the binding activity of NF-κB-DNA. Additionally, TRIM21 siRNA eliminated the increase in NLRP3 and cleaved caspase-1 proteins expression and caspase-1 activity induced by LPS. TRIM21 knockdown could resist cytotoxicity induced by activated microglia, including increasing the viability of co-cultured HT22 cells and reducing the emancipation of LDH. Moreover, the increased apoptosis and caspase-3 activity of HT22 neurons induced by activated BV2 cells were blocked by TRIM21 siRNA. Blocking of NF-κB abolished the effect of TRIM21 in promoting the expression of M1 phenotype marker genes. Similarly, the blockade of NF-κB pathway eliminated the promotion of TRIM21 on neurotoxicity induced by neuroinflammation. TRIM21 knockdown suppressed the M1 phenotype polarization of microglia and neuroinflammation-mediated neuronal damage via NF-κB/NLRP3 inflammasome pathway, which suggested that TRIM21 might be a potential therapeutic target for the therapy of central nervous system diseases.


Assuntos
Inflamassomos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Neurônios/efeitos dos fármacos , Ribonucleoproteínas/genética , Fator de Transcrição RelA/genética , Animais , Caspase 1/genética , Caspase 1/metabolismo , Diferenciação Celular , Linhagem Celular , Técnicas de Cocultura , Cultura em Câmaras de Difusão , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Inflamassomos/genética , Inflamassomos/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Microglia/citologia , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neurônios/citologia , Neurônios/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ribonucleoproteínas/antagonistas & inibidores , Ribonucleoproteínas/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Nat Commun ; 12(1): 3010, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021148

RESUMO

Resident memory T cells (TRM) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, TRM are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7+ T cells secreting IL-10. In convalescent patients, lung-TRM are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting TRM cells as important for future protection against SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , Memória Imunológica/imunologia , Pulmão/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Apoptose/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , COVID-19/virologia , Movimento Celular/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Pulmão/virologia , SARS-CoV-2/fisiologia , Linfócitos T/metabolismo
15.
Anim Sci J ; 92(1): e13550, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33899985

RESUMO

This research aimed to determine whether the astragalus polysaccharide (AP) can improve the production performance and gut microbiota in Chongren hens.120 Chongren hens (240-d old) were randomly allocated into 4 treatments with 30 hens and fed with a control basal diet (CON) or CON supplemented with the different levels of AP (100, 200, and 400 mg/kg) for 56 d. The egg production and feed conversion ratio were decreased (p < .05) with the levels of AP. The yolk weight, yolk color, eggshell thickness, eggshell redness index and egg shell yellowness were increased (p < .05). AP supplementation increased CAT and T-AOC and SOD, and decreased MDA (p < .05). Supplementation of AP decreased IL-2, IL-6 and TNF-α levels (p < .05), but increased the IL-4 level in the liver (p < .05). The villus heights of duodenum, jejunum ileum, the crypt depth and V/C in the jejunum were increased (p < .05). Dietary supplementation of 200 mg/kg AP increased (P relative abundances of Firmicutes and Lactobacteriaceae in the cecum of Chongren hens. In conclusion, addition of AP improved the production performance, egg quality, antioxidant function, and intestinal morphology in hens, which might be associated with the gut microbiota.


Assuntos
Astrágalo (Planta)/química , Galinhas/microbiologia , Galinhas/fisiologia , Dieta/veterinária , Suplementos Nutricionais , Ovos , Qualidade dos Alimentos , Microbioma Gastrointestinal/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Polissacarídeos/farmacologia , Animais , Antioxidantes , Galinhas/sangue , Feminino , Mediadores da Inflamação/sangue , Interleucina-2/sangue , Interleucina-4/metabolismo , Interleucina-6/sangue , Jejuno/efeitos dos fármacos , Fígado/metabolismo , Polissacarídeos/isolamento & purificação , Fator de Necrose Tumoral alfa/sangue
16.
J Immunol Methods ; 494: 113055, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33857474

RESUMO

To develop a suitable and effective vaccine against Staphylococcus aureus (S. aureus), we selected the Hla-MntC-SACOL0723 (HMS) recombinant protein with two different formulations of alum and Monophosphoryl lipid A (MPL) adjuvants. In this study, we aimed to evaluate the potentials of alum and MPL adjuvants in stimulating the immune response of HMS vaccine candidate against S. aureus. To evaluate the type of induced immune response, anti-HMS total IgG, IgG1, IgG2a, and IFN-γ, IL-2, IL-4, and IL-17 cytokines were determined after vaccination of mice with HMS-alum, HMS-MPL candidates. Mice were challenged with Methicillin-resistant Staphylococcus aureus (MRSA) was isolated from pressure sores and evaluated for bacterial load in the kidney homogenates and survival rate. It was observed that total IgG and isotypes (IgG1 and IgG2a), IL-4, and IL-17 were significantly increased in the group that received HMS-alum vaccine compared with the group that received HMS-MPL formulation. On the other hand, the levels of IFN-γ and IL-2 cytokines in the group that received HMS-MPL were higher than the group that received HMS-alum formulation. Bacterial load in the mice who received HMS protein formulated with alum adjuvant was reduced more than the mice who received HMS protein formulated with MPL adjuvant. Histopathological analysis showed more pathological changes in kidney tissues of the group received of HMS-MPL compared with the HMS-alum formulation. The survival rate was equal in both groups of immunized with HMS-alum and HMS-MPL formulations. Finally, it could be concluded that both adjuvants of alum and MPL are suitable immune response enhancers to HMS vaccine candidate.


Assuntos
Rim/patologia , Staphylococcus aureus Resistente à Meticilina/fisiologia , Proteínas Periplásmicas de Ligação/genética , Sepse/imunologia , Infecções Estafilocócicas/imunologia , Vacinas Antiestafilocócicas/imunologia , Staphylococcus aureus/fisiologia , Compostos de Alúmen , Animais , Feminino , Antígenos HLA/genética , Imunoglobulina G/metabolismo , Interleucina-17/metabolismo , Interleucina-4/metabolismo , Lipídeo A/análogos & derivados , Lipídeo A/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Recombinantes de Fusão/genética , Sepse/prevenção & controle , Regulação para Cima
17.
Molecules ; 26(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916154

RESUMO

Plants of the genus Wikstroemia are used in Chinese traditional medicine to treat inflammatory diseases, such as arthritis, bronchitis, and pneumonia. The present study was designed to determine whether Wikstroemia ganpi (Siebold and Zucc.) Maxim. offers a potential means of treating 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis (AD) in mice. Symptoms such as redness, edema, and keratinization in AD mice induced by DNCB were alleviated by the co-application of an ethanolic extract of W. ganpi for 2 weeks. The severity of skin barrier function damage was evaluated by measuring TEWL (transepidermal water loss). TEWLs of DNCB sensitized mouse dorsal skin were reduced by the application of a W. ganpi ethanolic extract, and skin hydration was increased. In addition, the infiltration of inflammatory cells into the dermis was significantly reduced, as were blood levels of IgE and IL-4, which play an important role in the expression of AD. The results of this experiment suggest that W. ganpi is a potential therapeutic agent for AD.


Assuntos
Dermatite Atópica/etiologia , Dermatite Atópica/metabolismo , Dinitroclorobenzeno/efeitos adversos , Medicamentos de Ervas Chinesas/farmacologia , Interleucina-4/metabolismo , Extratos Vegetais/farmacologia , Animais , Biópsia , Cromatografia Líquida de Alta Pressão , Citocinas/genética , Citocinas/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/química , Feminino , Expressão Gênica , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Camundongos , Camundongos Pelados , Estrutura Molecular , Extratos Vegetais/química , Resultado do Tratamento
18.
Elife ; 102021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33720008

RESUMO

Atherosclerosis is a disease of chronic inflammation. We investigated the roles of the cytokines IL-4 and IL-13, the classical activators of STAT6, in the resolution of atherosclerosis inflammation. Using Il4-/-Il13-/- mice, resolution was impaired, and in control mice, in both progressing and resolving plaques, levels of IL-4 were stably low and IL-13 was undetectable. This suggested that IL-4 is required for atherosclerosis resolution, but collaborates with other factors. We had observed increased Wnt signaling in macrophages in resolving plaques, and human genetic data from others showed that a loss-of-function Wnt mutation was associated with premature atherosclerosis. We now find an inverse association between activation of Wnt signaling and disease severity in mice and humans. Wnt enhanced the expression of inflammation resolving factors after treatment with plaque-relevant low concentrations of IL-4. Mechanistically, activation of the Wnt pathway following lipid lowering potentiates IL-4 responsiveness in macrophages via a PGE2/STAT3 axis.


Assuntos
Aterosclerose/terapia , Interleucina-4/administração & dosagem , Macrófagos/metabolismo , Via de Sinalização Wnt , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Interleucina-4/metabolismo , Masculino , Camundongos
19.
J Immunol ; 206(8): 1943-1956, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33762327

RESUMO

The concept of plasticity of neutrophils is highlighted by studies showing their ability to transdifferentiate into APCs. In this regard, transdifferentiated neutrophils were found at inflammatory sites of autoimmune arthritis (AIA). Exposure of neutrophils to inflammatory stimuli prolongs their survival, thereby favoring the acquisition of pathophysiologically relevant phenotypes and functions. By using microarrays, quantitative RT-PCR, and ELISAs, we showed that long-lived (LL) neutrophils obtained after 48 h of culture in the presence of GM-CSF, TNF, and IL-4 differentially expressed genes related to apoptosis, MHC class II, immune response, and inflammation. The expression of anti-inflammatory genes mainly of peptidase inhibitor families is upregulated in LL neutrophils. Among these, the PI3 gene encoding elafin was the most highly expressed. The de novo production of elafin by LL neutrophils depended on a synergism between GM-CSF and TNF via the activation and cooperativity of C/EBPß and NF-κB pathways, respectively. Elafin concentrations were higher in synovial fluids (SF) of patients with AIA than in SF of osteoarthritis. SF neutrophils produced more elafin than blood counterparts. These results are discussed with respect to implications of neutrophils in chronic inflammation and the potential influence of elafin in AIA.


Assuntos
Artrite/imunologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Elafina/metabolismo , Inflamação/imunologia , NF-kappa B/metabolismo , Neutrófilos/imunologia , Osteoartrite/imunologia , Autoimunidade , Células Cultivadas , Elafina/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Interleucina-4/metabolismo , Transdução de Sinais , Líquido Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Eur J Clin Microbiol Infect Dis ; 40(8): 1623-1631, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33666790

RESUMO

In this study, immunoregulation and desensitization therapies were jointly applied in the treatment of asthma, in which chitosan (CS) nanoparticles were used. BALB/c mice were selected and mouse models of asthma were constructed. Mice were divided into 7 groups. A double-chamber plethysmograph, MTT, hematoxylin-eosin staining, and ELISA were used. The expression levels of IL-4 and IL-5 in lung tissue cells were detected. CS-BCG-PSN-OVA sustained-release vaccines significantly alleviated airway hyperresponsiveness (AHR) in asthmatic mice. The numbers of total lymphocytes and eosinophils in BALF were remarkably reduced. The expression levels of IL-4 and IL-5 in lung tissue cells of the treatment groups were dramatically decreased. CS-BCG-PSN-OVA was found in vitro to be able to inhibit OVA-induced T-cell proliferation and upregulate the proportion of CD4+CD25+Foxp3+ T cells. CS-BCG-PSN-OVA sustained-release vaccine could significantly attenuate AHR and airway inflammation in asthmatic mice. Thus, it has a promising application prospect for the treatment of bronchial asthma.


Assuntos
Asma/tratamento farmacológico , Vacina BCG/administração & dosagem , Nanopartículas , Ácidos Nucleicos/administração & dosagem , Animais , Linfócitos T CD4-Positivos/imunologia , Quitosana , Liberação Controlada de Fármacos , Feminino , Inflamação , Interleucina-4/metabolismo , Interleucina-5/metabolismo , Pulmão/patologia , Camundongos Endogâmicos BALB C , Ovalbumina , Polissacarídeos
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