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1.
Radiat Res ; 192(4): 367-379, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31373871

RESUMO

Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive complication of therapeutic irradiation of the thorax. It has been suggested that senescence of type II pneumocytes (AECIIs), an alveolar stem cell, plays a role in the development of RIPF through loss of replicative reserve and via senescent AECII-driven release of proinflammatory and profibrotic cytokines. Within this context, we hypothesized that arachidonate 12-lipoxygenase (12-LOX) is a critical mediator of AECII senescence and RIPF. Treatment of wild-type AECIIs with 12S-hydroxyeicosateraenoic acid (12S-HETE), a downstream product of 12-LOX, was sufficient to induce senescence in a NADPH oxidase 4 (NOX4)-dependent manner. Mice deficient in 12-LOX exhibited reduced AECII senescence, pulmonary collagen accumulation and accumulation of alternatively activated (M2) macrophages after thoracic irradiation (5 × 6 Gy) compared to wild-type mice. Conditioned media from irradiated or 12S-HETE-treated primary pneumocytes contained elevated levels of IL-4 and IL-13 compared to untreated pneumocytes. Primary macrophages treated with conditioned media from irradiated AECII demonstrated preferential M2 type polarization when AECIIs were derived from wild-type mice compared to 12-LOX-deficient mice. Together, these data identified 12-LOX as a critical component of RIPF and a therapeutic target for radiation-induced lung injury.


Assuntos
Células Epiteliais Alveolares/patologia , Araquidonato 12-Lipoxigenase/metabolismo , Senescência Celular/efeitos da radiação , Macrófagos/efeitos da radiação , Pneumonite por Radiação/enzimologia , Células Epiteliais Alveolares/efeitos da radiação , Animais , Araquidonato 12-Lipoxigenase/genética , Feminino , Regulação Enzimológica da Expressão Gênica/efeitos da radiação , Interleucina-13/biossíntese , Interleucina-4/biossíntese , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pneumonite por Radiação/genética , Pneumonite por Radiação/imunologia , Pneumonite por Radiação/patologia
2.
Mol Med Rep ; 20(4): 3256-3264, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432141

RESUMO

Preeclampsia (PE) is a serious pregnancy­specific pathologic complication, and represents a primary cause of mother and fetus mortality. Abnormally expressed microRNAs (miRNAs) serve important regulatory roles in the development of PE. At present, the pathogenesis and molecular mechanism of PE remain unclear. The aim of the present study was to investigate the potential functions of miRNA (miR)­320a in the human extravillous trophoblast cell line HTR­8/SVneo and to identify the molecular mechanisms underlying miR­320a function. Reverse transcription­quantitative PCR was used in the present study to detect the levels of miR­320a in the placentas of 57 pregnant patients with PE and 57 healthy pregnant patients. The effects of miR­320a overexpression on the proliferation and invasion of HTR­8/SVneo cells were determined using MTT and Transwell invasion assays. Western blot analysis and dual luciferase reporter assay were used to identify the genes targeted by miR­320a. The present results suggested that miR­320a expression level was decreased in placentas of patients with PE and the expression level of miR­320a was found to be associated with the pathogenesis of PE (P<0.05). Overexpression of miR­320a using miR­320a mimics significantly inhibited cell proliferation and invasion in HTR­8/SVneo cells in vitro (P<0.05). Furthermore, interleukin (IL)­4 was identified to be a direct target gene of miR­320a. miR­320a could repress IL­4 expression by binding to its 3' untranslated region (P<0.05). Mechanistic studies suggested that IL­4 was a functional target gene of miR­320a, and miR­320a upregulation inhibited the proliferation and invasion of HTR­8/SVneo cells by directly targeting IL­4 (P<0.05). Collectively, to the best of our knowledge, the present study is the first to suggest that miR­320a may be a downregulated miRNA during PE, and IL­4 may act as a functional target gene of miR­320a. The present study suggested that miR­320a upregulation was involved in the development of PE by inhibiting the proliferation and invasion of trophoblast cells by targeting IL­4, indicating that the miR­320a/IL­4 pathway may represent a novel therapeutic target for PE treatment.


Assuntos
Movimento Celular , Interleucina-4/biossíntese , MicroRNAs/biossíntese , Pré-Eclâmpsia/metabolismo , Trofoblastos/metabolismo , Regulação para Cima , Adulto , Proliferação de Células , Feminino , Humanos , Pré-Eclâmpsia/patologia , Gravidez , Trofoblastos/patologia
3.
PLoS One ; 14(6): e0218827, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237933

RESUMO

Size and composition of γδ T cell populations change dramatically with tissue location, during development, and in disease. Given the functional differentiation of γδ T cell subsets, such shifts might alter the impact of γδ T cells on the immune system. To test this concept, and to determine if γδ T cells can affect other immune cells prior to an immune response, we examined non-immunized mice derived from strains with different genetically induced deficiencies in γδ T cells, for secondary changes in their immune system. We previously saw extensive changes in pre-immune antibodies and B cell populations. Here, we report effects on αß T cells. Similarly to the B cells, αß T cells evidently experience the influence of γδ T cells at late stages of their pre-immune differentiation, as single-positive heat stable antigen-low thymocytes. Changes in these and in mature αß T cells were most prominent with memory-phenotype cells, including both CD8+ and CD4+ populations. As previously observed with B cells, most of the effects on αß T cells were dependent on IL-4. Unexpectedly, IL-4 seemed to be produced mainly by αß T cells in the non-immunized mice, albeit strongly regulated by γδ T cells. Similarly to our findings with B cells, changes of αß T cells were less pronounced in mice lacking all γδ T cells than in mice lacking only some, suggesting that the composition of the γδ T cell population determines the nature of the γδ-influence on the other pre-immune lymphocytes.


Assuntos
Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Feminino , Memória Imunológica , Interleucina-4/biossíntese , Linfopenia/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/deficiência , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Baço/imunologia
4.
Skin Pharmacol Physiol ; 32(4): 192-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31096247

RESUMO

BACKGROUND: Atopic diseases constitute a major health challenge for industrialized countries, and elevated levels of interleukin 4 (IL-4) frequently characterize these disorders. Previous in vitroanalyses have indicated that IL-4 strongly upregulates the expression of IL-4-sensitive genes in human monocytes. OBJECTIVE: To explore whether similar expression alterations may contribute to the pathomechanisms of atopic diseases in vivo we carried out a small-scale case-control clinical study (n = 43), in which we quantified the plasma levels of IgE and IL-4 as well as the expression of selected IL-4-sensitive genes in blood leukocytes. METHODS: 34 allergic patients suffering from allergic rhinitis (n = 11), atopic eczema (n = 11) and allergic asthma (n = 12) as well as 9 healthy control individuals were recruited. IgE and IL-4 plasma levels were determined by ELISA, and the expression of selected IL-4-sensitive gene products in blood leukocytes was quantified by qRT-PCR. In addition, the fatty acid oxygenase activity of isolated monocytes was measured by RP-HPLC analysis of the arachidonic acid oxygenation products (ex vivo activity assays). RESULTS: We found that plasma levels of IgE and IL-4 were significantly elevated in atopic patients but the degree of elevation was not sufficient to upregulate the expression of the selected IL-4-sensitive genes in circulating leukocytes. Moreover, the arachidonic acid oxygenase activity of blood monocytes was not significantly altered in atopic patients. CONCLUSION: Our data suggest that the IL-4 plasma levels of atopic patients are not high enough to impact the expression of IL-4-sensitive genes.


Assuntos
Hipersensibilidade Imediata/sangue , Hipersensibilidade Imediata/genética , Imunoglobulina E/biossíntese , Interleucina-4/biossíntese , Leucócitos/fisiologia , Adulto , Asma/sangue , Asma/genética , Estudos de Casos e Controles , Dermatite Atópica/sangue , Dermatite Atópica/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxigenases/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Rinite Alérgica/sangue , Rinite Alérgica/genética , Regulação para Cima
5.
Scand J Immunol ; 90(2): e12775, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069827

RESUMO

Invariant NKT (iNKT) cells express markers of both T and NK cells and may produce various cytokines to regulate liver immunity. However, the role of iNKT cells in the progression of HBV-relative liver cirrhosis (HBV-LC) is incompletely understood. Here, we investigated the impact of peripheral iNKT cells on a cohort of patients with HBV-LC. The frequency, number, activation status, apoptosis and proliferation ability of peripheral iNKT cells were detected with flow cytometry. The impact of peripheral iNKT cells on the proliferation of hepatocyte cell line (MIHA) and activation of hepatic stellate cell line (LX-2) was detected with flow cytometry and PCR. In HBV-LC patients, the frequency and absolute number of peripheral iNKT cells significantly reduced, but the expression levels of CD25, interleukin (IL)-4, IL-13 and interferon (IFN)-γ increased. No difference was observed in the proliferation and apoptosis of circulating iNKT cells between patients and healthy controls (HCs). CXCR6 (CD186), known to be closely associated with iNKT cells migration from the periphery to the liver, was highly expressed on peripheral iNKT cells in HBV-LC patients. Furthermore, peripheral iNKT cells had a profound impact on MIHA cell proliferation and LX-2 cell activation through IL-4 or IL-13. Our data suggest that in HBV-LC patients, highly activated peripheral iNKT cells may migrate to the liver and affect hepatocyte cell line (MIHA) proliferation and hepatic stellate cell line (LX-2) activation through the expression of type 2 cytokines, which may result in excessive healing and contributing to the progression of fibrosis toward cirrhosis in liver.


Assuntos
Células Estreladas do Fígado/metabolismo , Hepatite B Crônica/patologia , Hepatócitos/metabolismo , Cirrose Hepática/patologia , Fígado/patologia , Células T Matadoras Naturais/imunologia , Adulto , Idoso , Apoptose/fisiologia , Linhagem Celular , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Progressão da Doença , Feminino , Vírus da Hepatite B/imunologia , Humanos , Interferon gama/biossíntese , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Interleucina-4/biossíntese , Fígado/citologia , Fígado/virologia , Cirrose Hepática/virologia , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR6/metabolismo
6.
Psychopharmacology (Berl) ; 236(10): 2959-2973, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30963194

RESUMO

RATIONALE: Converging evidence suggests that neuroimmunity plays an important role in the pathophysiology of anxiety. Interleukin (IL)-4 is a key cytokine regulating neuroimmune functions in the central nervous system. More efficient anxiolytics with neuro-immune mechanisms are urgently needed. OBJECTIVE: To determine whether 3'-deoxyadenosine (3'-dA) exerts an anxiolytic effect and to examine the role of IL-4 in the anxiolytic effect of 3'-dA in mice. METHODS: We investigated the effects of 3'-dA on anxiety-like behaviors using elevated plus maze (EPM) or light-dark box (LDB) tests after 45 min or 5 days of treatment. Expression of IL-4, IL-10, IL-1ß, TNF-α, and IL-6 in the prefrontal cortex (PFC) was detected by Western blot and/or double immunostaining. Intracerebroventricular injection of RIL-4Rα (an IL-4-specific inhibitor) and intraperitoneal injection of 3'-dA or imipramine were co-administered, followed by EPM test. RESULTS: 3'-dA exhibited a stronger and faster anxiolytic effect than imipramine in behavioral tests. Furthermore, 3'-dA enhanced IL-4 expression after 45 min or 5 days, TNF-α and IL-1ß expression decreased significantly after a 5-day treatment with 3'-dA, and IL-10 expression increased after a 5-day treatment with 3'-dA or imipramine in the PFC. IL-4 was expressed in neurons and in some astrocytes and microglia. IL-4 expression showed a strong positive correlation with reduced anxiety behaviors. RIL-4Rα completely blocked the anxiolytic effects induced by 3'-dA and imipramine. CONCLUSIONS: This study identifies a novel and common anxiolytic IL-4 signaling pathway and provides an innovative drug with a novel neuro-immune mechanism for treating anxiety disorder.


Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Desoxiadenosinas/uso terapêutico , Interleucina-4/biossíntese , Transdução de Sinais/efeitos dos fármacos , Animais , Ansiolíticos/farmacologia , Ansiedade/psicologia , Desoxiadenosinas/farmacologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Transdução de Sinais/fisiologia
8.
Int J Mol Sci ; 20(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669479

RESUMO

Trophoblast expressing paternal HLA-C resembles a semiallograft, and could be rejected by maternal T cells. IL-22 seems to be involved in allograft rejection and thus could be responsible for miscarriages. We examined the role of decidual IL-22-producing CD4+ T on human pregnancy. In those experiencing successful pregnancy and those experiencing unexplained recurrent abortion (URA), the levels of IL-22 produced by decidual CD4+ T cells are higher than those of peripheral blood T cells. We found a correlation of IL-22 and IL-4 produced by decidual CD4+ T cells in those experiencing successful pregnancy, not in those experiencing URA. The correlation of IL-22 and IL-4 was also found in the serum of successful pregnancy. A prevalence of CD4+ T cells producing IL-22 and IL-4 (Th17/Th2/IL-22+, Th17/Th0/IL-22+, Th17/Th2/IL-22+, and Th0/IL-22+ cells) was observed in decidua of those experiencing successful pregnancy, whereas Th17/Th1/IL-22+ cells, which do not produce IL-4, are prevalent in those experiencing URA. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells are exclusively present at the embryo implantation site where IL-4, GATA-3, IL-17A, ROR-C, IL-22, and AHR mRNA are expressed. T-bet and IFN-γ mRNA are found away from the implantation site. There is no pathogenic role of IL-22 when IL-4 is also produced by decidual CD4+ cells. Th17/Th2/IL-22+ and Th17/Th0/IL-22+ cells seem to be crucial for embryo implantation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Decídua/fisiologia , Interleucina-4/biossíntese , Interleucinas/biossíntese , Subpopulações de Linfócitos T/metabolismo , Aborto Habitual/etiologia , Aborto Habitual/metabolismo , Biomarcadores , Linfócitos T CD4-Positivos/imunologia , Citocinas/biossíntese , Citocinas/sangue , Feminino , Humanos , Interleucina-4/sangue , Interleucinas/sangue , Modelos Biológicos , Gravidez , Resultado da Gravidez , Gravidez Ectópica/etiologia , Gravidez Ectópica/metabolismo , Subpopulações de Linfócitos T/imunologia
9.
Int Arch Allergy Immunol ; 178(3): 238-247, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30699406

RESUMO

BACKGROUND: Transient receptor potential ankyrin 1 (TRPA1) is an ion channel known to mediate nociception and neurogenic inflammation, and to be activated by reactive oxygen and nitrogen species (ROS and RNS) produced at the sites of inflammation. Because neurogenic inflammation as well as the release of ROS and RNS are typical features of early stages of allergic responses, we hypothesized that TRPA1 may be involved in triggering and/or amplifying allergic inflammation. OBJECTIVE: This study aims at exploring the role of TRPA1 ion channel in acute ovalbumin-induced allergic inflammation in applicable murine models. METHODS: The effects of pharmacological blockade and genetic deletion of TRPA1 in ovalbumin-induced allergic conjunctivitis and acute paw inflammation were studied in mice sensitized to ovalbumin. RESULTS: Ovalbumin-induced allergic conjunctivitis was milder in TRPA1-deficient mice and alleviated in wild-type mice treated with the TRPA1 antagonist TCS 5861528. Subcutaneous challenge with ovalbumin caused a significant paw edema and interleukin (IL)-4 production in sensitized mice; these responses were attenuated in animals treated with the TRPA1 antagonist and in TRPA1-deficient mice. Interestingly, blockade of the major secondary effector of TRPA1, substance P, also resulted in attenuated ovalbumin-induced paw edema and IL-4 production. However, the splenocytes' responses to ovalbumin were similar in cells from wild-type and TRPA1-deficient mice sensitized to ovalbumin. CONCLUSION: These results introduce a novel concept that TRPA1 mediates early events in allergic inflammation, but does not seem to affect allergic sensitization, and could therefore be a novel drug target to treat conditions associated with allergic inflammation.


Assuntos
Conjuntivite Alérgica/etiologia , Ovalbumina/imunologia , Canal de Cátion TRPA1/fisiologia , Animais , Conjuntivite Alérgica/imunologia , Modelos Animais de Doenças , Eosinófilos/fisiologia , Interleucina-13/biossíntese , Interleucina-4/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Canal de Cátion TRPA1/antagonistas & inibidores
10.
Am J Physiol Renal Physiol ; 316(4): F682-F692, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30623726

RESUMO

Chronic inflammation and prostate fibrosis have been identified as contributors to lower urinary tract symptoms (LUTS) pathophysiology in humans. It has been shown that transurethral infection of an Escherichia coli strain named CP1, which was isolated from a patient with chronic prostatitis, can lead to the develop of differential chronic inflammation and pain in certain mouse strains. Therefore, we hypothesized that differential inflammation would influence fibrotic response in the prostate. This study showed that while prostatic infection by CP1 causes the development of chronic tactile allodynia in NOD/ShiltJ (NOD) but not C57BL/6 (B6) mice, both mice developed evidence of prostate inflammation, prostate fibrosis, and urinary dysfunction. Fibrosis was confirmed by the upregulation of fibrosis-associated messenger RNAs (mRNAs), α-smooth muscle actin immunohistochemistry, and collagen staining with picrosirius red. These findings were mainly focused on the dorsolateral lobes of the prostate. Both mouse strains also developed smaller, more frequent voiding patterns postinfection, examined via cystometry. B6 mice responded to CP1 infection with type 2 cytokines (IL-4 and IL-13), while NOD mice did not, which may explain the differing tactile allodynia responses and level of collagen deposition. When mice lacking signal transducer and activator of transcription 6 (STAT6), a transcription factor known to be important for the production and signaling of IL-4 and IL-13, were infected with CP1, fibrosis was attenuated. This study provides a potential model for studying the development of infection-induced prostatic fibrosis and LUTS. This study also demonstrates that CP1-induced prostate fibrosis has a STAT6-dependent mechanism in B6 mice.


Assuntos
Citocinas , Infecções por Escherichia coli/patologia , Sintomas do Trato Urinário Inferior/patologia , Escherichia coli Uropatogênica , Animais , Infecções por Escherichia coli/fisiopatologia , Fibrose , Hiperalgesia/etiologia , Interleucina-13/biossíntese , Interleucina-4/biossíntese , Sintomas do Trato Urinário Inferior/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Medição da Dor , Próstata/patologia , Fator de Transcrição STAT6/metabolismo , Transdução de Sinais
11.
BMC Immunol ; 20(1): 3, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30630412

RESUMO

BACKGROUND: T cell activation induces ER stress and upregulates Inositol Requiring Enzyme 1 alpha (IRE1α), an activator of the unfolded protein response (UPR) pathway. Inhibition of IRE1α RNase activity in activated CD4+ splenocytes from naïve mice, via treatment of the cells with the commercially available drug 4µ8c upon activation, results in the reduction of the secretion of proteins IL-5, IL-4, and IL-13. Prior to this work, it was unknown if 4µ8c could inhibit TH2 cytokines in established TH2 cells, cells that are crucial in promoting disease in severe asthma. RESULTS: Treatment of a mouse T helper (TH)2 cell line and differentiated human TH2 cells with 4µ8c resulted in inhibition of IL-5, but not IL-4, as measured by ELISA. The reduced cytokine expression was not due to differences in mRNA stability or mRNA levels; it appears to be due to a defect in secretion, as the cells produce cytokines IL-5 as measured by flow cytometry and western blot. CONCLUSION: These data suggest that the inhibition of IL-5 was due to post-translational processes. IL-5 promotes chronic, inflammatory asthma, and 4µ8c blocks its expression in T cells in vitro. Future studies will determine if 4µ8c treatment can ameliorate the effects of the cytokine IL-5 in a disease model.


Assuntos
Himecromona/análogos & derivados , Interleucina-4/biossíntese , Interleucina-5/biossíntese , Células Th2/efeitos dos fármacos , Células Th2/metabolismo , Animais , Diferenciação Celular/imunologia , Linhagem Celular , Citocinas/metabolismo , Endorribonucleases/antagonistas & inibidores , Humanos , Himecromona/farmacologia , Camundongos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Processamento Pós-Transcricional do RNA , Células Th2/citologia
12.
J Biol Chem ; 294(1): 290-298, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30404921

RESUMO

High-throughput sequencing has revealed a tremendous complexity of cellular transcriptomes, which is partly due to the generation of multiple alternative transcripts from a single gene locus. Because alternative transcripts often have low abundance in bulk cells, the functions of most of these transcripts and their relationship with their canonical counterparts remain unclear. Here we applied single-cell RNA-Seq to analyze the transcriptome complexity of in vitro-differentiated, murine type 2 T helper (Th2) cells. We found that cytokine gene transcripts contribute most of the intercellular heterogeneity, with a group of universal cytokines, including interleukins 1a, 2, 3, and 16, being bimodally expressed. At the single-cell level, use of alternative promoters prevalently generated alternative transcripts. For instance, although undetectable in bulk cells, a noncoding RNA isoform of IL-4 (IL4nc), which was driven by an intronic promoter in the IL-4 locus, was predominantly expressed in a subset of Th2 cells. IL4nc displayed distinct temporal expression patterns compared with the canonical IL-4 mRNA and post-transcriptionally promoted the production of IL-4 protein in Th2 cells. In conclusion, our findings reveal a mechanism whereby minor noncanonical transcripts post-transcriptionally regulate expression of their cognate canonical genes.


Assuntos
Interleucina-4/biossíntese , RNA Mensageiro/biossíntese , RNA não Traduzido/biossíntese , Análise de Sequência de RNA , Células Th2/metabolismo , Transcrição Genética , Regulação para Cima , Animais , Linhagem Celular , Interleucina-4/genética , Camundongos , RNA Mensageiro/genética , RNA não Traduzido/genética , Células Th2/citologia
13.
Nat Microbiol ; 4(1): 62-70, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30420782

RESUMO

Streptococcus pneumoniae (the pneumococcus) is a major cause of mortality and morbidity globally, and the leading cause of death in children under 5 years old. The pneumococcal cytolysin pneumolysin (PLY) is a major virulence determinant known to induce pore-dependent pro-inflammatory responses. These inflammatory responses are driven by PLY-host cell membrane cholesterol interactions, but binding to a host cell receptor has not been previously demonstrated. Here, we discovered a receptor for PLY, whereby pro-inflammatory cytokine responses and Toll-like receptor signalling are inhibited following PLY binding to the mannose receptor C type 1 (MRC-1) in human dendritic cells and mouse alveolar macrophages. The cytokine suppressor SOCS1 is also upregulated. Moreover, PLY-MRC-1 interactions mediate pneumococcal internalization into non-lysosomal compartments and polarize naive T cells into an interferon-γlow, interleukin-4high and FoxP3+ immunoregulatory phenotype. In mice, PLY-expressing pneumococci colocalize with MRC-1 in alveolar macrophages, induce lower pro-inflammatory cytokine responses and reduce neutrophil infiltration compared with a PLY mutant. In vivo, reduced bacterial loads occur in the airways of MRC-1-deficient mice and in mice in which MRC-1 is inhibited using blocking antibodies. In conclusion, we show that pneumococci use PLY-MRC-1 interactions to downregulate inflammation and enhance bacterial survival in the airways. These findings have important implications for future vaccine design.


Assuntos
Células Dendríticas/imunologia , Macrófagos Alveolares/imunologia , Infecções Pneumocócicas/patologia , Receptores Imunológicos/metabolismo , Streptococcus pneumoniae/patogenicidade , Estreptolisinas/metabolismo , Animais , Carga Bacteriana , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Linhagem Celular , Fatores de Transcrição Forkhead/biossíntese , Humanos , Interferon gama/biossíntese , Interleucina-4/biossíntese , Camundongos , Infiltração de Neutrófilos/imunologia , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores Imunológicos/genética , Streptococcus pneumoniae/genética , Estreptolisinas/genética , Proteína 1 Supressora da Sinalização de Citocina/biossíntese , Linfócitos T/imunologia , Fatores de Virulência
14.
Sci Rep ; 8(1): 16904, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30442915

RESUMO

The origin of human T-cell responses against fungal pathogens early in life is not clearly understood. Here, we show that antifungal T-cell responses are vigorously initiated within the first years of life against lysates and peptides of Candida albicans or Aspergillus fumigatus, presented by autologous monocytes. The neonatal responding T-cell pool consists of 20 different TCR-Vß families, whereas infant and adult pools display dramatically less variability. Although we demonstrate no bias for anti-fungal IL-4 expression early in life, there was a strong bias for anti-fungal IL-17 production. Of note, only T-cells from neonates and infants show an immediate co-expression of multiple cytokines. In addition, only their T-cells co-express simultaneously transcription factors T-bet and RORγt in response to fungi and subsequently their target genes IL-17 and IFNγ. Thus, T-cells of neonates and infants are predetermined to respond quickly with high plasticity to fungal pathogens, which might give an excellent opportunity for therapeutic interventions.


Assuntos
Aspergillus fumigatus/imunologia , Candida albicans/imunologia , Crescimento e Desenvolvimento/imunologia , Linfócitos T/imunologia , Fatores Etários , Biomarcadores/metabolismo , Diferenciação Celular/imunologia , Proliferação de Células , Criança , Pré-Escolar , Humanos , Lactente , Recém-Nascido , Interleucina-17/biossíntese , Interleucina-4/biossíntese , Ativação Linfocitária/imunologia , Linfócitos T/citologia , Linfócitos T/microbiologia , Células Th1/imunologia , Regulação para Cima
15.
J Nat Prod ; 81(11): 2590-2594, 2018 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-30417645

RESUMO

The inhibitory activities of the antimycin-class antibiotics UK-2A, antimycin A, and splenocin B against the production of anti-inflammatory cytokine IL-4, which is related to IgE-mediated allergic responses in rat basophilic leukemia (RBL-2H3) cells, were evaluated. Although antimycin A and splenocin B showed cytotoxicity at concentrations at which IL-4 release from the cells was restricted, UK-2A was found to restrict IL-4 release without cytotoxicity. Three UK-2A analogues (4-6) were then synthesized and assessed. Compound 5 restricted IL-4 release dose-dependently without cytotoxicity, and its effect was more potent than that of UK-2A.


Assuntos
Antibacterianos/farmacologia , Mediadores da Inflamação/metabolismo , Interleucina-4/biossíntese , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Lactonas/farmacologia , Piridinas/farmacologia , Ratos
16.
J Immunol ; 201(10): 2910-2922, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30291167

RESUMO

Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-ß and is associated with TGF-ß-dependent in vivo expansion of Foxp3+ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-ß-dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-ß secretion, TGF-ß-dependent expansion of Foxp3+ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-ß. In contrast, TGF-ß is not necessary for GATA3 expression by Foxp3+ Tregs or by Foxp3- CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4-mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-ß generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Interleucina-4/biossíntese , Infecções por Strongylida/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/biossíntese , Animais , Transplante de Medula Óssea , Linfócitos T CD4-Positivos/imunologia , Fator de Transcrição GATA3/imunologia , Fator de Transcrição GATA3/metabolismo , Interleucina-4/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nematospiroides dubius , Fator de Crescimento Transformador beta/imunologia
17.
Clin Exp Immunol ; 194(1): 17-26, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30260469

RESUMO

Vitamin D receptor (VDR) mediates various biochemical activities between the cytoplasm and the nucleus in the cell. The nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) protein is involved in the T helper type 2 (Th2) response. This study tests a hypothesis that VDR interacts with NLRP3 to restrict the Th2-biased response. In this study, VDR-/- mice and WT (WT) mice were used. Th2 cell differentiation between VDR-/- mice and WT mice was observed. We observed that CD4+ T cell activation was higher in VDR-/- mice. The VDR-/-CD4+ T cells were prone to Th2 polarization. VDR-/- mice produced more immunoglobulin (Ig)E. VDR bound NLRP3 to prevent Th2 differentiation by restricting IL4 gene transcription. Th2 biased inflammation spontaneously developed in the intestine of VDR-/- mice. In conclusion, VDR binds NLRP3 to restrict IL4 gene transcription and prevent biased Th2 polarization.


Assuntos
Hipersensibilidade Alimentar/imunologia , Interleucina-4/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Calcitriol/metabolismo , Células Th2/imunologia , Adulto , Animais , Células Cultivadas , Feminino , Hipersensibilidade Alimentar/genética , Humanos , Interleucina-4/biossíntese , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores de Calcitriol/genética
18.
Clin Exp Immunol ; 194(3): 400-413, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30105843

RESUMO

Inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease (CD), is a chronic autoimmune disease. Parasitic infections and their products have been shown to have protective effects on autoimmune diseases, including IBD. In this experiment, 96 male BALB/c mice aged 6-8 weeks were divided randomly into two large groups: prevention and therapy. The changes in the various indicators of colitis were detected to demonstrate that Trichinella spiralis serine protease inhibitors can relieve the inflammatory severity of 2,4,6-trinitrobenzenesulphonic acid solution (TNBS)-induced colitis and to explore possible immunological mechanisms. Results showed that the disease activity index (DAI) score, myeloperoxidase (MPO) activity, macroscopic and microscopic damage degrees of colon all decreased significantly, interferon (IFN)-γ expression decreased, interleukin (IL)-4 expression increased, nuclear factor kappa B (NF)-κB expression decreased and the percentage of CD4+ CD25+ forkhead box protein 3 (FoxP3+ ) regulatory T cells (Treg ) cells in the spleen. MLN increased significantly compared to the phosphate-buffered saline (PBS)/2,4,6-trinitrobenzenesulphonic acid solution (TNB) group. We found the same results with the T. spiralis Kazal-type serine protease inhibitors (TsKaSPI)+TNBS and TsAdSPI+TNBS groups in the large prevention group and the large therapy group, compared to the TNBS+PBS group with the TNBS+TsKaSPI and TNBS+TsAdSPI groups. Immunization with TsKaSPI and TsAdSPI on the CD models showed an intervention effect, possibly because TsKaSPI and TsAdSPI induced a T helper type 2 (Th2)-type immune response and balanced the TNBS-induced Th1-type immune response.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/uso terapêutico , Inibidores de Serino Proteinase/uso terapêutico , Linfócitos T Reguladores/imunologia , Trichinella spiralis/efeitos dos fármacos , Animais , Colite Ulcerativa/induzido quimicamente , Colo/metabolismo , Colo/patologia , Modelos Animais de Doenças , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/genética , Interferon gama/biossíntese , Interleucina-4/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo , Linfócitos T Reguladores/citologia , Células Th2/imunologia , Fator de Transcrição RelA/biossíntese , Trichinella spiralis/enzimologia , Ácido Trinitrobenzenossulfônico/toxicidade
19.
Eur J Immunol ; 48(9): 1588-1591, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30007005

RESUMO

Dimethyl fumarate (DMF) promotes an IL-17Alow IFN-γlow IL-4+ CD4+ T cell phenotype. Adoptive transfer of in vitro DMF-treated myelin peptide-reactive IL-17Alow IFN-γlow IL-4+ CD4+ T cells prior to immunization for EAE reduces the severity of encephalomyelitis. This beneficial effect of transferred DMF-treated CD4+ T cells requires an early in vivo recall.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Fumarato de Dimetilo/farmacologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Imunossupressores/farmacologia , Interferon gama/imunologia , Interleucina-4/imunologia , Células Th17/imunologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/transplante , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Interleucina-4/biossíntese , Camundongos , Células Th1/imunologia , Células Th2/imunologia
20.
Nature ; 559(7715): 627-631, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30022164

RESUMO

The thymus is responsible for generating a diverse yet self-tolerant pool of T cells1. Although the thymic medulla consists mostly of developing and mature AIRE+ epithelial cells, recent evidence has suggested that there is far greater heterogeneity among medullary thymic epithelial cells than was previously thought2. Here we describe in detail an epithelial subset that is remarkably similar to peripheral tuft cells that are found at mucosal barriers3. Similar to the periphery, thymic tuft cells express the canonical taste transduction pathway and IL-25. However, they are unique in their spatial association with cornified aggregates, ability to present antigens and expression of a broad diversity of taste receptors. Some thymic tuft cells pass through an Aire-expressing stage and depend on a known AIRE-binding partner, HIPK2, for their development. Notably, the taste chemosensory protein TRPM5 is required for their thymic function through which they support the development and polarization of thymic invariant natural killer T cells and act to establish a medullary microenvironment that is enriched in the type 2 cytokine, IL-4. These findings indicate that there is a compartmentalized medullary environment in which differentiation of a minor and highly specialized epithelial subset has a non-redundant role in shaping thymic function.


Assuntos
Células Epiteliais/citologia , Células Epiteliais/metabolismo , Interleucina-4/metabolismo , Timócitos/citologia , Timo/citologia , Timo/metabolismo , Animais , Microambiente Celular , Feminino , Humanos , Tolerância Imunológica/imunologia , Interleucina-4/biossíntese , Interleucinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Proteínas Serina-Treonina Quinases/metabolismo , Canais de Cátion TRPM/metabolismo , Timócitos/metabolismo , Timo/anatomia & histologia , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética
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