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1.
Biomed Pharmacother ; 138: 111535, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34311533

RESUMO

Dysregulation of intestinal immune response plays a critical role in the pathogenesis of Inflammatory Bowel Disease (IBD). Mastiha's anti-inflammatory properties are well established. Our aim was to investigate Mastiha's regulatory effect on IL-17A serum levels in IBD patients. Alterations of the faecal metabolome as a functional readout of microbial activity were explored. A randomized, double-blind, placebo-controlled, parallel-group design was applied for a total of 3 months in active and 6 months in inactive IBD patients. Serum IL-17A increased significantly in Mastiha group (p = 0.006), and the mean change differed significantly between Mastiha and placebo (p = 0.003) even after adjusting for age, sex and BMI (p = 0.001) in inactive patients. In inactive UC patients IL-17A decreased significantly only in placebo (p = 0.033). No significant differences were detected in active disease. Faecal metabolomics indicated that intervention with Mastiha influenced considerably the metabolic profile of IBD patients in remission exhibiting, in between others, increased levels of glycine and tryptophan. Glycine has been proposed to have a therapeutic effect against IBD, while tryptophan derivatives are involved in immunoregalutory mechanisms, such as the Th17 cells differentiation. Thus, it is quite possible that the immunoregulatory role of Mastiha in quiescent IBD involves the regulation of Th17 cells function and differentiation.


Assuntos
Anti-Inflamatórios/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fezes/química , Interleucina-17/sangue , Resina Mástique/uso terapêutico , Metaboloma , Metabolômica , Espectroscopia de Prótons por Ressonância Magnética , Adolescente , Adulto , Idoso , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/isolamento & purificação , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Método Duplo-Cego , Feminino , Grécia , Humanos , Masculino , Resina Mástique/efeitos adversos , Pessoa de Meia-Idade , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
2.
Lab Invest ; 101(9): 1176-1185, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34108631

RESUMO

Asthma is an allergic inflammatory lung disease affecting nearly 300 million people worldwide. To better understand asthma, new regulators must be identified. We conducted a study to investigate the effect and mechanisms of action of surfactant protein A (SPA) in OVA-induced asthmatic mice. Treatment with SPA delayed the onset of asthma, decreased its severity, as well as notably suppressed pro-inflammatory cytokine production. Furthermore, SPA-treated mice possessed more leukocytes; more CD4+ T cells infiltrated the spleen in the SPA-treated mice than in the control mice, and there were decreased percentages of Th1 and Th17 cells in vivo. In addition, expression levels of the T-bet (Th1 transcription factor) and RORγt (Th17 transcription factor) genes were significantly downregulated by SPA treatment. Moreover, SPA reduced the production and mRNA expression of pro-inflammatory cytokine mRNAs in activated T cells in vivo. Mechanistically, SPA could inhibit STAT1/4 and STAT3 phosphorylation, resulting in the differentiation of Th1 and suppression of Th17 cells, respectively. In the presence of CD3/CD28 expression, STAT1/4 and STAT3 were activated but suppressed by SPA, which was responsible for the augmentation of Th1 and Th17 differentiation. This result showed that SPA can effectively modulate the JAK/STAT pathway by suppressing Th1 and Th17 differentiation, thus preventing asthma. The present study reveals the novel immunomodulatory activity of SPA and highlights the importance of further investigating the effects of SPA on asthma.


Assuntos
Asma/metabolismo , Proteína A Associada a Surfactante Pulmonar/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Asma/induzido quimicamente , Asma/fisiopatologia , Feminino , Janus Quinases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/efeitos adversos , Fatores de Transcrição STAT/metabolismo , Células Th1/metabolismo , Células Th17/metabolismo
3.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34070011

RESUMO

Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.


Assuntos
Dopamina/imunologia , Esclerose Múltipla/tratamento farmacológico , Receptores Dopaminérgicos/efeitos dos fármacos , Animais , Dopamina/fisiologia , Dopaminérgicos/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/fisiopatologia , Humanos , Camundongos , Modelos Imunológicos , Modelos Neurológicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/fisiopatologia , Neuroimunomodulação/efeitos dos fármacos , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Receptores Dopaminérgicos/imunologia , Receptores Dopaminérgicos/fisiologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
4.
Molecules ; 26(11)2021 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071080

RESUMO

The main purpose of this study was to investigate whether the blockade of the interaction between the receptor activator of nuclear factor-κB (NF-ĸB) ligand (RANKL) and its receptor RANK as well as the blockade of NF-κB inhibitor kinase (IKK) and of NF-κB translocation have the potential to suppress the pathogenesis of allergic asthma by inhibition and/or enhancement of the production by CD4+ and CD8+ T cells of important cytokines promoting (i.e., IL-4 and IL-17) and/or inhibiting (i.e., IL-10 and TGF-ß), respectively, the development of allergic asthma. Studies using ovalbumin(OVA)-immunized mice have demonstrated that all the tested therapeutic strategies prevented the OVA-induced increase in the absolute number of IL-4- and IL-17-producing CD4+ T cells (i.e., Th2 and Th17 cells, respectively) indirectly, i.e., through the inhibition of the clonal expansion of these cells in the mediastinal lymph nodes. Additionally, the blockade of NF-κB translocation and RANKL/RANK interaction, but not IKK, prevented the OVA-induced increase in the percentage of IL-4-, IL-10- and IL-17-producing CD4+ T cells. These latter results strongly suggest that both therapeutic strategies can directly decrease IL-4 and IL-17 production by Th2 and Th17 cells, respectively. This action may constitute an important mechanism underlying the anti-asthmatic effect induced by the blockade of NF-κB translocation and of RANKL/RANK interaction. Thus, in this context, both these therapeutic strategies seem to have an advantage over the blockade of IKK. None of the tested therapeutic strategies increased both the absolute number and frequency of IL-10- and TGF-ß-producing Treg cells, and hence they lacked the potential to inhibit the development of the disease via this mechanism.


Assuntos
Asma/imunologia , Asma/metabolismo , Animais , Asma/fisiopatologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Hipersensibilidade/fisiopatologia , Imunoglobulina E/imunologia , Interleucina-17/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos
5.
J Neuroimmunol ; 356: 577583, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33940233

RESUMO

Sphingosine-1-phosphate receptor 1 (S1P1) plays an important role in autoimmune disease. Here, we evaluated whether ponesimod, an S1P1 modulator, affects inflammation in experimental autoimmune encephalomyelitis (EAE) and investigated Th1/Th2/Th17/Treg cell subsets. Ponesimod treatment ameliorated EAE and alleviated inflammatory infiltration. Compared with untreated EAE, ponesimod-treated mice had lower Th1 and Th17 cell numbers and higher Treg cell numbers; their IFN-γ, T-bet, IL-17, and RORγt levels as well as their pmTOR/mTOR ratio were diminished, while their TGF-ß and Foxp3 levels were enhanced. These results suggest that ponesimod modulates the Th1/Th17/Treg balance and regulates the mTOR pathway.


Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Tiazóis/uso terapêutico , Animais , Feminino , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Linfócitos T Reguladores/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Tiazóis/farmacologia
6.
J Neuroimmunol ; 356: 577608, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34000471

RESUMO

Fluoxetine is a selective serotonin reuptake inhibitor, which also has an immunomodulatory effect. We investigated the effects of fluoxetine and serotonin (5-HT) on the pro-inflammatory Th17- and Th1-cells in 30 patients with relapsing-remitting MS and 20 healthy subjects. Fluoxetine and 5-HT suppressed IL-17, IFN-γ and GM-CSF production by stimulated СD4+ T-cells in both groups. Blockade of 5-HT2B-receptors decreased the inhibitory effect of fluoxetine on cytokine production in MS patients. Finally, 5-HT2B-receptor activation inhibits IL-17, IFN-γ and GM-CSF production in both groups. These data suggest an anti-inflammatory role for fluoxetine in MS, which could be mediated by the activation of 5-HT2B-receptors.


Assuntos
Fluoxetina/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Receptor 5-HT2B de Serotonina/metabolismo , Inibidores de Captação de Serotonina/uso terapêutico , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Adulto , Feminino , Fluoxetina/farmacologia , Humanos , Masculino , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Receptor 5-HT2B de Serotonina/imunologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Adulto Jovem
7.
Front Immunol ; 12: 569287, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841390

RESUMO

Bullous pemphigoid (BP) is a prototypic autoimmune disorder of the elderly, characterized by serum IgG autoantibodies, namely anti-BP180 and anti-BP230, directed against components of the basal membrane zone that lead to sub-epidermal loss of adhesion. Pruritus may be indicative of a pre-clinical stage of BP, since a subset of these patients shows serum IgG autoantibodies against BP230 and/or BP180 while chronic pruritus is increasingly common in the elderly population and is associated with a variety of dermatoses. Clinical and experimental evidence further suggests that pruritus of the elderly may be linked to autoimmunity with loss of self-tolerance against cutaneous autoantigens. Thus, the objective of this study was to determine autoreactive T cell responses against BP180 in elderly patients in comparison to patients with BP. A total of 22 elderly patients with pruritic disorders, 34 patients with bullous or non-bullous BP and 34 age-matched healthy controls were included in this study. The level of anti-BP180 and anti-BP230 IgG serum autoantibodies, Bullous Pemphigoid Disease Area Index (BPDAI), and pruritus severity were assessed for all patients and controls. For characterization of the autoreactive T cell response, peripheral blood mononuclear cells were stimulated ex vivo with recombinant BP180 proteins (NH2- and COOH-terminal domains) and the frequencies of BP180-specific T cells producing interferon-γ, interleukin (IL)-5 or IL-17 were subsequently determined by ELISpot assay. Patients with BP showed a mixed Th1/Th2 response against BP180 while autoreactive Th1 cells were identified in a minor subset of elderly patients with pruritic disorders. Furthermore, our T cell characterization revealed that therapeutic application of topical clobetasol propionate ointment in BP patients significantly reduced peripheral blood BP180-specific T cells, along with clinically improved symptoms, strongly suggesting a systemic immunosuppressive effect of this treatment.


Assuntos
Autoimunidade/imunologia , Penfigoide Bolhoso/imunologia , Prurido/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Idoso , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Clobetasol/uso terapêutico , Estudos de Coortes , Citocinas/imunologia , Citocinas/metabolismo , Distonina/imunologia , ELISPOT , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Colágenos não Fibrilares/imunologia , Pomadas , Penfigoide Bolhoso/complicações , Penfigoide Bolhoso/tratamento farmacológico , Prurido/complicações , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
8.
Chem Biol Interact ; 341: 109451, 2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-33798506

RESUMO

The pathogenesis of rheumatoid arthritis (RA) is characterized by synoviocyte hyperplasia and proinflammatory cytokine secretion, as well as the destruction of cartilage and bone. Glaucocalyxin A (GLA) is an alkaloid derived from a Chinese medicinal plant that exhibits anti-inflammatory, anti-tumor and neuroprotective properties. We investigated the effects of GLA on RA-fibroblast-like synoviocytes (FLS cells), and collagen-induced arthritis (CIA), and further explored the underlying mechanisms. GLA inhibited TNF-a-induced RA-FLS proliferation, increased apoptotic ratios and upregulated levels of caspase-3, cleaved PARP, and Bax. GLA also inhibited the expression of IL-10, IL-1ß, and IL-6 in vitro. Levels of p-STAT3 were downregulated in a dose-dependent manner. Over-expression of STAT3 partly neutralized the GLA-mediated elevation of caspase-3 and cleaved PARP levels as well as the downregulation of IL-10, IL-1B and IL-6 expression levels. This suggests that GLA inactivated the STAT3 pathway. Furthermore, the production of inflammatory cytokines in RA-FLS and a CIA rat model were inhibited effectively by GLA. Taken together, our data suggest that GLA is a potential long-term therapeutic agent for patients with RA.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Diterpenos do Tipo Caurano/farmacologia , Fator de Transcrição STAT3/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apoptose/efeitos dos fármacos , Artrite Experimental/tratamento farmacológico , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos Endogâmicos DBA , Ratos Wistar , Fator de Transcrição STAT3/genética , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Sinoviócitos/patologia , Células Th17/efeitos dos fármacos , Células Th17/fisiologia , Fator de Necrose Tumoral alfa/farmacologia
9.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924467

RESUMO

Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H2O2) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H2O2. All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Flavonoides/uso terapêutico , Animais , Antioxidantes/metabolismo , Bovinos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas , Colágeno Tipo II , Citocinas/sangue , Citocinas/metabolismo , Feminino , Flavonoides/farmacologia , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Mediadores da Inflamação/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Malondialdeído/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Superóxido Dismutase/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
10.
Cell Death Dis ; 12(3): 280, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723242

RESUMO

Regulatory T-cell (Treg)/T-helper 17 (Th17) cell balance plays an important role in the progression of rheumatoid arthritis (RA). Our study explored the protective effect of protectin DX (PDX), which restored Treg/Th17 cell balance in RA, and the role of the nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome pathway in this process. Using mass spectrometry, we discovered that level of PDX decreased in active-RA patients and increased in inactive-RA patients compared with HCs, and serum PDX was a potential biomarker in RA activity detection (area under the curve [AUC] = 0.86). In addition, a collagen-induced arthritis (CIA) mice model was constructed and PDX obviously delayed RA progression in the CIA model, upregulating Tregs and anti-inflammatory cytokines while downregulating Th17 cells and pro-inflammatory cytokines. Moreover, NLRP3 knockout and rescue experiments demonstrated that NLRP3 participated in PDX-mediated Treg/Th17 cell balance restoration, joint injury amelioration and inflammatory-response attenuation using Nlrp3-/- mice. Furthermore, microarray and verified experiments confirmed that PDX reduced NLRP3 expression via miRNA-20a (miR-20a). In summary, we confirmed for the first time that PDX could effectively ameliorate CIA progression by restoring Treg/Th17 cell balance, which was mediated by inhibition of the NLRP3 inflammasome pathway via miR-20a.


Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/farmacologia , Inflamassomos/antagonistas & inibidores , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Estudos de Casos e Controles , Citocinas/metabolismo , Ácidos Docosa-Hexaenoicos/sangue , Humanos , Inflamassomos/genética , Inflamassomos/metabolismo , Mediadores da Inflamação/metabolismo , Camundongos Endogâmicos DBA , Camundongos Knockout , MicroRNAs/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/imunologia , Células Th17/metabolismo
11.
Front Immunol ; 12: 625667, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777008

RESUMO

During the last decade, immune checkpoint inhibition (ICI) has become a pillar of cancer therapy. Antibodies targeting CTLA-4 or PD-1/PD-L1 have been approved in several malignancies, with thousands of clinical trials currently underway. While the majority of cancer immunotherapies have traditionally focused on enhancing cytotoxic responses by CD8+ or NK cells, there are clear evidences that CD4+ T cell responses can modulate the immune response against tumors and influence the efficacy of ICI therapy. CD4+ T cells can differentiate into several subsets of helper T cells (Th) or regulatory T cells (Treg), with a wide range of effector and/or regulatory functions. Importantly, different Th subsets may have different and sometimes contrasting roles in the clinical response to ICI therapy, which in addition may vary depending on the organ and tumor niche. In this review, we discuss recent evidence that highlights how ICI therapy impacts Th1, Th9, and Th17 cells and vice versa. These data might be important designing better interventions that unleash the full potential of immune response against cancer.


Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Fenótipo , Células Th1/imunologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Resultado do Tratamento , Microambiente Tumoral
12.
Theranostics ; 11(9): 4531-4548, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754076

RESUMO

Background: Peroxisome proliferator-activated receptor gamma (PPARγ) has the ability to counter Th17 responses, but the full mechanisms remain elusive. Herein, we aimed to elucidate this process in view of cellular metabolism, especially glutaminolysis. Methods: MTT, CCK-8, Annexin V-FITC/PI staining or trypan blue exclusion assays were used to analyze cytotoxicity. Flow cytometry and Q-PCR assays were applied to determine Th17 responses. The detection of metabolite levels using commercial kits and rate-limiting enzyme expression using western blotting assays was performed to illustrate the metabolic activity. ChIP assays were used to examine H3K4me3 modifications. Mouse models of dextran sulfate sodium (DSS)-induced colitis and house dust mite (HDM)/lipopolysaccharide (LPS)-induced asthma were established to confirm the mechanisms studied in vitro. Results: The PPARγ agonists rosiglitazone and pioglitazone blocked glutaminolysis but not glycolysis under Th17-skewing conditions, as indicated by the detection of intracellular lactate and α-KG and the fluorescence ratios of BCECF-AM. The PPARγ agonists prevented the utilization of glutamine and thus directly limited Th17 responses even when Foxp3 was deficient. The mechanisms were ascribed to restricted conversion of glutamine to glutamate by reducing the expression of the rate-limiting enzyme GLS1, which was confirmed by GLS1 overexpression. Replenishment of α-KG and 2-HG but not succinate weakened the effects of PPARγ agonists, and α-KG-promoted Th17 responses were dampened by siIDH1/2. Inhibition of KDM5 but not KDM4/6 restrained the inhibitory effect of PPARγ agonists on IL-17A expression, and the H3K4me3 level in the promoter and CNS2 region of the il-17 gene locus down-regulated by PPARγ agonists was rescued by 2-HG and GLS1 overexpression. However, the limitation of PPARγ agonists on the mRNA expression of RORγt was unable to be stopped by 2-HG but was attributed to GSH/ROS signals subsequent to GLS1. The exact role of PPARγ was proved by GW9662 or PPARγ knockout, and the mechanisms for PPARγ-inhibited Th17 responses were further confirmed by GLS1 overexpression in vivo. Conclusion: PPARγ agonists repressed Th17 responses by counteracting GLS1-mediated glutaminolysis/2-HG/H3K4me3 and GSH/ROS signals, which is beneficial for Th17 cell-related immune dysregulation.


Assuntos
Glutaminase/metabolismo , Glutamina/metabolismo , Glutationa/metabolismo , Histonas/metabolismo , PPAR gama/agonistas , Espécies Reativas de Oxigênio/metabolismo , Células Th17/efeitos dos fármacos , Animais , Colite/tratamento farmacológico , Colite/metabolismo , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pioglitazona/farmacologia , RNA Mensageiro/metabolismo , Rosiglitazona/farmacologia , Células Th17/metabolismo
13.
Front Immunol ; 12: 614320, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708208

RESUMO

Heat shock proteins (Hsp) are constitutive and stress-induced molecules which have been reported to impact innate and adaptive immune responses. Here, we evaluated the role of Hsp70 as a treatment target in the imiquimod-induced, psoriasis-like skin inflammation mouse model and related in vitro assays. We found that immunization of mice with Hsp70 resulted in decreased clinical and histological disease severity associated with expansion of T cells in favor of regulatory subtypes (CD4+FoxP3+/CD4+CD25+ cells). Similarly, anti-Hsp70 antibody treatment led to lowered disease activity associated with down-regulation of pro-inflammatory Th17 cells. A direct stimulating action of Hsp70 on regulatory T cells and its anti-proliferative effects on keratinocytes were confirmed in cell culture experiments. Our observations suggest that Hsp70 may be a promising therapeutic target in psoriasis and potentially other autoimmune dermatoses.


Assuntos
Anticorpos/imunologia , Dermatite/etiologia , Dermatite/metabolismo , Suscetibilidade a Doenças , Proteínas de Choque Térmico HSP70/imunologia , Animais , Anticorpos/farmacologia , Biomarcadores , Biópsia , Citocinas/metabolismo , Dermatite/diagnóstico , Dermatite/tratamento farmacológico , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Feminino , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/genética , Imunização , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Proteínas Recombinantes , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
14.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669855

RESUMO

Colitis is a multifactorial disorder that mostly occurs in the gastrointestinal tract. Despite improvements in mucosal inflammation research, little is known regarding the small bioactive molecules that are beneficial for regulating T cells and colon cell activity. 6,7,4'-trihydroxyflavanone (THF) is a flavanone that possesses anti-osteoclastogenesis activity and exerts protective effects against methamphetamine-induced immunotoxicity. Whether THF mitigates intestinal inflammation by regulating T cells and colon cell activity remains unknown. In the present study, Jurkat and HT-29 cells were used for in vitro experiments, and dextran sulfate sodium (DSS)-induced colitis model in mice was used for in vivo experiment. We observed that THF did not have a negative effect on the viability of Jurkat and HT-29 cells. Quantitative PCR and Western blot analysis revealed that THF regulates the activity of Jurkat cells and HT-29 cells via the NFκB and MAPK pathways under stimulated conditions. In the DSS-induced colitis model, oral administration of THF attenuated the manifestations of DSS-induced colitis, including a reduction in body weight, shrinkage of the colon, and enhanced expression of pro-inflammatory cytokines in the colon and mesenteric lymph nodes. These data suggest that THF alleviates DSS-induced colitis by modulating the activity of T cells and colon cells in vivo.


Assuntos
Colite/induzido quimicamente , Colite/tratamento farmacológico , Colo/imunologia , Colo/patologia , Flavanonas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Linfócitos T/imunologia , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Colite/imunologia , Citocinas/metabolismo , Sulfato de Dextrana , Modelos Animais de Doenças , Feminino , Flavanonas/administração & dosagem , Flavanonas/química , Flavanonas/farmacologia , Células HT29 , Humanos , Inflamação/patologia , Intestinos/patologia , Células Jurkat , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Substâncias Protetoras/farmacologia , Linfócitos T/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fator de Transcrição RelA/metabolismo
15.
Food Funct ; 12(7): 3191-3205, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33735338

RESUMO

Fructooligosaccharides (FOS) can change gut microbiota composition and play a protective role in food allergy (FA). Furthermore, the protective mechanism of FOS against FA is unclear. In this study, intestinal flora and tryptophan (Trp) metabolites were investigated in a mouse model with FA supplemented with FOS. Meanwhile, we injected aryl hydrocarbon receptor antagonists (AhR-A) into a mouse model of FA supplemented with FOS to investigate whether T helper cell (Th) 17/regulatory T (Treg) cell balance was affected. Our research studies showed that dietary intake of FOS provided moderate protection from the intestinal inflammation induced by ovalbumin (OVA). This protective effect disappeared in AhR-A mice. The OVA mice manifestations had significantly lower bacterial richness, when compared to the normal control (NC) mice. Among fecal bacteria, the abundance of Akkermansiaceae (family level) and Verrucomicrobia (phylum level) increased and Ruminococcacere (phylum level) decreased in the feces of allergic mice. These changes were reversed by FOS treatment. FOS modulated the gut microbiome profiles that were altered in OVA mice, which showed an increase in the abundance of Ruminococcacere (phylum level) and a decrease in the abundance of Akkermansiaceae (family level) and Verrucomicrobia (phylum level). Liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of Trp metabolites showed significant reductions in the level of kynurenine (kyn) in the serum of OVA mice, as compared to NC and FOS mice. Conversely, the levels of Trp and 5-hydroxytryptamine (5-HT) were significantly increased in OVA mice. Correlation analysis revealed a negative relationship between the relative abundance of Verrucomicrobiae (class level) and Akkermansiaceae (family level) with kyn, and a positive relationship with 5-HT. FOS significantly reduced interleukin-17A (IL-17A) and retinoic acid-associated nuclear orphan receptor-γt (RORγt) in FOS mice but not in AhR-A mice. FOS increased the level of interleukin-10 (IL-10) and Forkhead box P3 (Foxp3) in FOS mice but not in AhR-A mice. These findings suggest that FOS ameliorates allergic symptoms and impacts Th17/Treg balance in mice by modulating the gut microbiota composition and Trp metabolites. FOS may serve as an effective tool for the treatment of FA by regulating immune and gut microbiota.


Assuntos
Hipersensibilidade Alimentar/prevenção & controle , Oligossacarídeos/administração & dosagem , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oligossacarídeos/farmacologia , Ovalbumina , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Triptofano/metabolismo
16.
Life Sci ; 276: 119395, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33781828

RESUMO

AIMS: STAT3 signaling is critical for Th17 development that plays an important role in multiple sclerosis pathogenesis. To evaluate the anti-inflammatory and regulatory T cells effects of JAK1/2 and STAT3 inhibition, we assessed the JAK 1/2 inhibitor ruxolitinib effects on Th17 cell/Tregs balance. MAIN METHODS: Ruxolitinib was administered to experimental autoimmune encephalomyelitis (EAE) mice via oral gavage, and its effects were assessed. The expression of pro-inflammatory and anti-inflammatory cytokines, including IL-17A and IL-10, were analyzed by real-time PCR. The frequency of Th17 cells and Tregs were evaluated by flow cytometry. KEY FINDING: Ruxolitinib ameliorated the EAE severity and decreased the proportion of Th17 cells and inflammatory markers levels. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine were increased in ruxolitinib-treated mice. Furthermore, ruxolitinib markedly decreased the expression of Th17 related transcription factor, RORÉ£t, whereas FOXP3 expression associated with Treg differentiation was increased. SIGNIFICANCE: Our results show that ruxolitinib may be a promising therapeutic strategy for multiple sclerosis.


Assuntos
Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Pirazóis/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
17.
J Immunol ; 206(6): 1127-1139, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33558372

RESUMO

T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared with healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism promote allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with Alternaria alternata extract displayed genetic signatures for elevated oxidative and glucose metabolism by single-cell RNA sequencing. This result was most pronounced when protein levels were measured in IL-17-producing cells and was recapitulated when airway inflammation was induced with house dust mite plus LPS, a model that led to abundant IL-4- and IL-17-producing T cells. Importantly, inhibitors of the glucose transporter 1 or glutaminase in vivo attenuated house dust mite + LPS eosinophilia, T cell cytokine production, and airway hyperresponsiveness as well as augmented the immunosuppressive properties of dexamethasone. These data show that T cells induce markers to support metabolism in vivo in airway inflammation and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.


Assuntos
Asma/tratamento farmacológico , Dexametasona/farmacologia , Transportador de Glucose Tipo 1/antagonistas & inibidores , Glutaminase/antagonistas & inibidores , Imunossupressores/farmacologia , Adulto , Alternaria/imunologia , Animais , Asma/sangue , Asma/imunologia , Biomarcadores/análise , Biomarcadores/metabolismo , Glicemia/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Estudos de Casos e Controles , Células Cultivadas , Dexametasona/uso terapêutico , Modelos Animais de Doenças , Sinergismo Farmacológico , Feminino , Transportador de Glucose Tipo 1/metabolismo , Glutaminase/metabolismo , Glutamina/metabolismo , Voluntários Saudáveis , Humanos , Imunossupressores/uso terapêutico , Pulmão/citologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Cultura Primária de Células , Pyroglyphidae/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/imunologia , Células Th2/metabolismo , Adulto Jovem
18.
Biomed Pharmacother ; 137: 111346, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33556876

RESUMO

Abnormal T helper 17 (Th17) responses promote inflammation and cause inflammatory diseases. Natural components that modulate Th17 functions can be effective for the amelioration of inflammatory diseases. Procyanidin B2 3,3''-di-O-gallate (PCB2DG) contained in grape seeds markedly suppressed interleukin (IL)-17 production from spleen cells but not CD4+ T cells. The aim of this study was to elucidate the mechanisms by which PCB2DG suppresses IL-17. Our results showed that PCB2DG suppressed the production of IL-17, tumor necrosis factor (TNF)-α, IL-1ß, and IL-6 with the suppression of transcription factors expression. In addition, we revealed that TNF-α and IL-1ß were required to induce IL-17 production in this experimental condition, and PCB2DG suppressed these cytokines from dendritic cells (DCs). Furthermore, CD4-DC co-culture experiments showed that the production of IL-17, TNF-α, and IL-1ß was markedly inhibited in co-cultures of PCB2DG-pretreated CD4+ T cells and DCs. These results suggested that PCB2DG first modulated TNF-α production by CD4+ T cells and then suppressed IL-1ß secretion from DCs, resulting in decreased IL-17 production. Thus, PCB2DG can control the cytokine network associated with Th17 cells, providing a novel mechanism underlying the immunosuppressive effects of polyphenols.


Assuntos
Biflavonoides/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Catequina/farmacologia , Citocinas/biossíntese , Células Dendríticas/efeitos dos fármacos , Imunossupressores/farmacologia , Interleucina-17/biossíntese , Proantocianidinas/farmacologia , Baço/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Células Dendríticas/metabolismo , Interleucina-17/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Baço/metabolismo , Células Th17/efeitos dos fármacos , Fatores de Transcrição/antagonistas & inibidores
19.
Mol Immunol ; 132: 30-40, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33540227

RESUMO

Psoriasis is a refractory inflammatory skin disease affecting 2 %-3 % of the world population, characterized by the infiltration and hyper-proliferation of inflammatory cells and aberrant differentiation of keratinocytes. Targeting the IL-23/ Th17 axis has been well recognized as a promising therapeutic strategy, as the IL-23/ Th17 signal plays a vital role in the pathology of psoriasis. Three pentacyclic triterpene compounds isolated from loquat leaves have been reported with significant inhibitory effects on RORγt transcription activity and Th17 cell differentiation, and excellent performance in preventing lupus nephritis pathogenesis. However, the potential effects of these pentacyclic triterpene compounds on psoriasis remain unknown. In this study, we demonstrated the potent therapeutic effects of these pentacyclic triterpene compounds on psoriasis. These three pentacyclic triterpene compounds significantly alleviated skin inflammation as well as aberrant keratinocyte proliferation in an imiquimod-induced mouse psoriasis model. These compounds also inhibited the infiltration of immune cells and the level of pro-inflammatory cytokine in the dermis, as well as the cells number and changed the cytokine profiling expression of Th17 cells. These compounds could reduce the amount of CD4+ and CD8+ T cells in local lymph node, but not in spleen, which is different from hydrocortisone, the positive control treatment. These results suggest better performance of these compounds than steroids on treating psoriasis with less side effects on the integrated immune system. In summary, our findings uncover the potent therapeutic effects of pentacyclic triterpene compounds on psoriasis, providing potential candidate compounds for drug development.


Assuntos
Eriobotrya/química , Hiperplasia/tratamento farmacológico , Inflamação/tratamento farmacológico , Triterpenos Pentacíclicos/uso terapêutico , Folhas de Planta/química , Psoríase/tratamento farmacológico , Células Th17/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/patologia , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Imiquimode/toxicidade , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/metabolismo , Triterpenos Pentacíclicos/farmacologia , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Células Th17/imunologia , Células Th17/metabolismo
20.
Phytomedicine ; 84: 153519, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33640781

RESUMO

BACKGROUND: Gegen Qinlian decoction (GQ) is a traditional Chinese herbal prescription that has been widely used for the treatment of bacterial dysentery and enteric typhoid fever. Recently, GQ has been clinically reported to be a potential candidate for the treatment of ulcerative colitis (UC). However, the immunoregulatory function of GQ in the treatment of UC has not been fully elucidated. PURPOSE: This study focused on the role of immune imbalance in the pathogenesis of UC and the immunomodulatory effect of GQ in the treatment of UC. METHODS: The UC model was established by treating female mice with 3.0% dextran sulfate sodium (DSS) for 7 days, and GQ was orally administered at dosages of 1.5 and 7.5 g/kg/day. Inflammatory factors were detected by ELISA and qRT-PCR. Treg and Th17 cell dysregulation was analyzed by qRT-PCR, immunohistochemistry and flow cytometry. Proteins related to IL-6/JAK2/STAT3 signaling were detected by western blotting. RESULTS: GQ significantly alleviated the symptoms of UC mice and suppressed the activity of myeloperoxidase (MPO). Furthermore, the production of proinflammatory factors, such as IL-1ß, TNF-α and IL-6, was dramatically reduced after GQ administration. Furthermore, GQ improved the infiltration of Treg and Th17 cells into the colons and decreased the expression of inflammatory factors, such as TGF-ß1 and IL-17. The frequencies of Treg and Th17 cells in the Peyer's patches and spleen were reduced by GQ administration; however, GQ had no significant regulatory effect on normal mice. The western blotting results showed that GQ markedly suppressed the phosphorylation of JAK2 and STAT3 and decreased the transcription function of phosphorylated STAT3. CONCLUSIONS: Taken together, these results indicated that GQ alleviated DSS-induced UC by suppressing IL-6/JAK2/STAT3 signaling to restore Treg and Th17 cell homeostasis in colonic tissue.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana/toxicidade , Medicamentos de Ervas Chinesas/química , Feminino , Homeostase/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Interleucina-17/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Nódulos Linfáticos Agregados/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
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