Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 300
Filtrar
1.
Mol Med Rep ; 20(3): 2381-2388, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31322198

RESUMO

The phagocytosis of apoptotic cells by alveolar epithelial cells helps to eliminate airway inflammation. Insulin­like growth factor 1 (IGF­1) regulates cell metabolism and proliferation, and promotes cell survival, while it may also promote the proliferation and differentiation of alveolar epithelial cells during the repair of lung injury. The present study investigated the effect of IGF­1 on the phagocytic activity of alveolar epithelial cells, a nonprofessional phagocyte. IGF­1 was elevated in lung tissue and bronchoalveolar lavage fluid obtained from mice with ovalbumin­induced asthma. IGF­1 was reduced by 50% in the lung tissue and by nearly 100% in the bronchoalveolar lavage fluid in asthmatic mice established by depletion of alveolar macrophages using 2­chloroadenosine. In addition, interleukin­33 induced IGF­1 production in primary alveolar macrophages. It was also observed that IGF­1 inhibited the phagocytosis of fluorescent microspheres and apoptotic cells by MLE­12 alveolar epithelial cells. Antibody blocking of IGF­1 enhanced the phagocytosis of fluorescent microspheres and apoptotic cells, and significantly reduced inflammatory cell infiltration in airway and perivascular tissues. The elevated IGF­1 level in the lungs of asthma model mice was mainly produced in alveolar macrophages. Taken together, the current study demonstrated that IGF­1 inhibited phagocytosis by alveolar epithelial cells, and that IGF­1 blockade enhanced the phagocytic activity and alleviated airway inflammation. These results support the potential use of IGF­1 as a target in the treatment of asthma.


Assuntos
Células Epiteliais Alveolares/imunologia , Asma/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Fagocitose , Células Epiteliais Alveolares/patologia , Animais , Apoptose , Asma/complicações , Asma/patologia , Células Cultivadas , Feminino , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Fator de Crescimento Insulin-Like I/análise , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C
2.
World J Gastroenterol ; 25(23): 2924-2934, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-31249450

RESUMO

BACKGROUND: The digestive tract is the maximal immunizing tissue in the body, and mucosal integrity and functional status of the gut is very important to maintain a healthy organism. Severe infection is one of the most common causes of gastrointestinal dysfunction, and the pathogenesis is closely related to endotoxemia and intestinal barrier injury. Bifidobacterium is one of the main probiotics in the human body that is involved in digestion, absorption, metabolism, nutrition, and immunity. Bifidobacterium plays an important role in maintaining the intestinal mucosal barrier integrity. This study investigated the protective mechanism of Bifidobacterium during ileal injury in rats. AIM: To investigate the effects of Bifidobacterium on cytokine-induced neutrophil chemoattractant (CINC) and insulin-like growth factor 1 (IGF-1) in the ileum of rats with endotoxin injury. METHODS: Preweaning rats were randomly divided into three groups: Control (group C), model (group E) and treatment (group T). Group E was intraperitoneally injected with lipopolysaccharide (LPS) to create an animal model of intestinal injury. Group T was intragastrically administered Bifidobacterium suspension 7 d before LPS. Group C was intraperitoneally injected with normal saline. The rats were killed at 2, 6 or 12 h after LPS or physiological saline injection to collect ileal tissue samples. The expression of ileal CINC mRNA was evaluated by reverse transcription-polymerase chain reaction (RT-PCR), and expression of ileal IGF-1 protein and mRNA was detected by immunohistochemistry and RT-PCR, respectively. RESULTS: The ileum of rats in Group C did not express CINC mRNA, ileums from Group E expressed high levels, which was then significantly decreased in Group T (F = 23.947, P < 0.05). There was no significant difference in CINC mRNA expression at different times (F = 0.665, P > 0.05). There was a high level of IGF-1 brown granules in ileal crypts and epithelial cells in Group C, sparse staining in Group E, and dark, dense brown staining in Group T. There was a significant difference between Groups C and E and Groups E and T (P < 0.05). There was no significant difference in IGF-1 protein expression at different times (F = 1.269, P > 0.05). IGF-1 mRNA expression was significantly different among the three groups (P < 0.05), though not at different times (F = 0.086, P > 0.05). CONCLUSION: Expression of CINC mRNA increased in the ileum of preweaning rats with endotoxin injury, and exogenous administration of Bifidobacterium reduced CINC mRNA expression. IGF-1 protein and mRNA expression decreased in the ileum of preweaning rats with endotoxin injury, and exogenous administration of Bifidobacterium prevented the decrease in IGF-1 expression. Bifidobacterium may increase IGF-1 expression and enhance intestinal immune barrier function in rats with endotoxin injury.


Assuntos
Bifidobacterium longum subspecies infantis , Quimiocina CXCL1/metabolismo , Ileíte/terapia , Fator de Crescimento Insulin-Like I/metabolismo , Probióticos/administração & dosagem , Animais , Quimiocina CXCL1/imunologia , Modelos Animais de Doenças , Endotoxinas/toxicidade , Humanos , Ileíte/induzido quimicamente , Ileíte/patologia , Íleo/efeitos dos fármacos , Íleo/imunologia , Íleo/patologia , Fator de Crescimento Insulin-Like I/imunologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
3.
Nat Commun ; 10(1): 1364, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30910999

RESUMO

The mechanisms linking muscle injury and regeneration are not fully understood. Here we report an unexpected role for ZEB1 regulating inflammatory and repair responses in dystrophic and acutely injured muscles. ZEB1 is upregulated in the undamaged and regenerating myofibers of injured muscles. Compared to wild-type counterparts, Zeb1-deficient injured muscles exhibit enhanced damage that corresponds with a retarded p38-MAPK-dependent transition of their macrophages towards an anti-inflammatory phenotype. Zeb1-deficient injured muscles also display a delayed and poorer regeneration that is accounted by the retarded anti-inflammatory macrophage transition and their intrinsically deficient muscle satellite cells (MuSCs). Macrophages in Zeb1-deficient injured muscles show lower phosphorylation of p38 and its forced activation reverts the enhanced muscle damage and poorer regeneration. MuSCs require ZEB1 to maintain their quiescence, prevent their premature activation following injury, and drive efficient regeneration in dystrophic muscles. These data indicate that ZEB1 protects muscle from damage and is required for its regeneration.


Assuntos
Músculo Esquelético/metabolismo , Distrofias Musculares/genética , RNA Mensageiro/genética , Regeneração/genética , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Animais , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Cromonas/farmacologia , Modelos Animais de Doenças , Flavonoides/farmacologia , Regulação da Expressão Gênica , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/imunologia , Laminina/genética , Laminina/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Morfolinas/farmacologia , Músculo Esquelético/imunologia , Músculo Esquelético/lesões , Distrofias Musculares/imunologia , Distrofias Musculares/patologia , Fenótipo , Fosforilação , RNA Mensageiro/imunologia , Regeneração/imunologia , Células Satélites de Músculo Esquelético/imunologia , Células Satélites de Músculo Esquelético/metabolismo , Células Satélites de Músculo Esquelético/patologia , Transdução de Sinais , Homeobox 1 de Ligação a E-box em Dedo de Zinco/deficiência , Homeobox 1 de Ligação a E-box em Dedo de Zinco/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
4.
Neuropsychobiology ; 77(1): 49-56, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30336492

RESUMO

AIMS: The aim of this study was to evaluate serum levels of the antineuronal antibodies anti-N-methyl-D-aspartate receptor (NMDAR) and anti-glutamic acid decarboxylase (GAD), and insulin-like growth factor 1 (IGF-1), in patients with bipolar disorder (BD), during manic and depressive episodes and in remission compared to euthymic patients receiving long-term lithium therapy. METHODS: Serum levels of anti-NMDAR and anti-GAD 450/620 antibodies, as well as IGF-1, were measured using the ELISA method in 19 manic and 17 depressed patients both in an acute episode and in remission after the episode. All of the subjects were under pharmacological treatment. The control group included 18 euthymic BD patients receiving lithium for 9-44 years (mean 22 ± 11) in whom a single measurement was performed. RESULTS: Serum levels of anti-NMDAR antibodies were higher in acute manic episodes than in lithium-treated patients. Serum levels of anti-GAD 450/620 antibodies were higher in acute manic and depressive episodes compared to remission after the respective episode. Their values in both acute manic and depressive episodes were higher than those in lithium-treated patients. Serum levels of IGF-1 were higher in acute manic episodes and in remission after mania than in lithium-treated patients. CONCLUSION: Higher levels of anti-NMDAR and anti-GAD antibodies during episodes may point to an abnormality in the glutamatergic system in BD. Increased levels of IGF-1 during an acute manic episode and in remission after mania may constitute a compensatory mechanism against excitotoxicity. Lower levels of anti-NMDAR, anti-GAD antibodies, and IGF-1 during long-term lithium treatment may reflect normalization of this processes, contributing to mood stabilization.


Assuntos
Autoanticorpos/sangue , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/imunologia , Glutamato Descarboxilase/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Adulto , Transtorno Bipolar/sangue , Transtorno Bipolar/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão
5.
Front Immunol ; 9: 2785, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30546365

RESUMO

Ginsenosides are the principal active components of ginseng and are considered attractive candidates for combination cancer therapy because they can kill tumors and have favorable safety profiles. However, the overall benefit of ginsenosides remains unclear, particularly in cancer immunosurveillance, considering the controversial results showing repression or promotion of immune responses. Here we identify a potentiating role of ginsenoside F1 (G-F1) in cancer surveillance by natural killer (NK) cells. Among 15 different ginsenosides, G-F1 most potently enhanced NK cell cytotoxicity in response to diverse activating receptors and cancer cells. G-F1 also improved cancer surveillance in mouse models of lymphoma clearance and metastatic melanoma that rely on NK cell activity. G-F1-treated NK cells exhibited elevated cytotoxic potential such as upregulation of cytotoxic mediators and of activation signals upon stimulation. NK cell potentiation by G-F1 was antagonized by insulin-like growth factor (IGF)-1 blockade and recapitulated by IGF-1 treatment, suggesting the involvement of IGF-1. Thus, our results suggest that G-F1 enhances NK cell function and may have chemotherapeutic potential in NK cell-based immunotherapy. We anticipate our results to be a starting point for further comprehensive studies of ginsenosides in the immune cells mediating cancer surveillance and the development of putative therapeutics.


Assuntos
Ginsenosídeos/farmacologia , Imunidade Celular/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/imunologia , Células Matadoras Naturais , Linfoma , Neoplasias Experimentais , Animais , Humanos , Imunoterapia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Linfoma/imunologia , Linfoma/patologia , Linfoma/terapia , Camundongos , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/terapia
6.
Front Immunol ; 9: 2175, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30333823

RESUMO

The precise impact of the somatotrope axis upon the immune system is still highly debated. We have previously shown that mice with generalized ablation of growth hormone (GH) releasing hormone (GHRH) gene (Ghrh -/-) have normal thymus and T-cell development, but present a marked spleen atrophy and B-cell lymphopenia. Therefore, in this paper we have investigated vaccinal and anti-infectious responses of Ghrh -/- mice against S. pneumoniae, a pathogen carrying T-independent antigens. Ghrh -/- mice were unable to trigger production of specific IgM after vaccination with either native pneumococcal polysaccharides (PPS, PPV23) or protein-PPS conjugate (PCV13). GH supplementation of Ghrh -/- mice restored IgM response to PPV23 vaccine but not to PCV13 suggesting that GH could exert a specific impact on the spleen marginal zone that is strongly implicated in T-independent response against pneumococcal polysaccharides. As expected, after administration of low dose of S. pneumoniae, wild type (WT) completely cleared bacteria after 24 h. In marked contrast, Ghrh -/- mice exhibited a dramatic susceptibility to S. pneumoniae infection with a time-dependent increase in lung bacterial load and a lethal bacteraemia already after 24 h. Lungs of infected Ghrh -/- mice were massively infiltrated by inflammatory macrophages and neutrophils, while lung B cells were markedly decreased. The inflammatory transcripts signature was significantly elevated in Ghrh -/- mice. In this animal model, the somatotrope GHRH/GH/IGF1 axis plays a vital and unsuspected role in vaccine and immunological defense against S. pneumoniae.


Assuntos
Linfócitos B/imunologia , Hormônio Liberador de Hormônio do Crescimento/imunologia , Hormônio do Crescimento/deficiência , Vacinas Pneumocócicas/imunologia , Transdução de Sinais/imunologia , Streptococcus pneumoniae/imunologia , Animais , Linfócitos B/patologia , Hormônio do Crescimento/imunologia , Hormônio Liberador de Hormônio do Crescimento/genética , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/imunologia , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Knockout , Transdução de Sinais/genética
7.
Cancer Cell ; 34(3): 439-452.e6, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30205046

RESUMO

Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Células HEK293 , Humanos , Imunidade Inata/efeitos dos fármacos , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Fatores de Transcrição
8.
Int J Mol Sci ; 19(9)2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30134574

RESUMO

A common feature of the aging process is a decline in immune system performance. Extensive research has sought to elucidate how changes in adaptive immunity contribute to aging and to provide evidence showing that changes in innate immunity have an important role in the overall decline of net immune function. Drosophila is an emerging model used to address questions related to immunosenescence via research that integrates its capacity for genetic dissection of aging with groundbreaking molecular biology related to innate immunity. Herein, we review information on the immunosenescence of Drosophila and suggest its possible mechanisms that involve changes in insulin/IGF(insulin-like growth factor)-1 signaling, hormones such as juvenile hormone and 20-hydroxyecdysone, and feedback system degeneration. Lastly, the emerging role of microbiota on the regulation of immunity and aging in Drosophila is discussed.


Assuntos
Envelhecimento/imunologia , Proteínas de Drosophila/imunologia , Drosophila melanogaster/imunologia , Imunossenescência/genética , Fator de Crescimento Insulin-Like I/imunologia , Insulina/imunologia , Envelhecimento/genética , Animais , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/microbiologia , Ecdisterona/imunologia , Ecdisterona/metabolismo , Retroalimentação Fisiológica , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Imunidade Inata , Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Hormônios Juvenis/imunologia , Hormônios Juvenis/metabolismo , Modelos Biológicos , Transdução de Sinais
9.
Am J Physiol Endocrinol Metab ; 315(4): E638-E649, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29783855

RESUMO

It is well known that insulin-like growth factor 1 (IGF1) acts as a trophic factor in small intestine under both physiological and pathophysiological conditions. However, it still lacks direct in vivo evidence of the functions of intestinal epithelial cell (IEC)-specific IGF1 under both normal and pathological conditions. Using IEC-specific IGF1-knockout (cKO) mice and Lgr5-eGFP-CreERT mice, we demonstrate that IEC-specific IGF1 can enhance nutrient uptake, reduce protein catabolism and energy consumption, and promote the proliferation and expansion of intestinal epithelial cells, including intestinal epithelial stem cells and intestinal secretory cells. Next, we showed that IEC-specific IGF1 renders IECs resistant to irradiation and promotes epithelial regeneration. Strikingly, transcriptome profiling assay revealed that many differentially expressed genes involved in the differentiation and maturation of lymphoid lineages were significantly suppressed in the cKO mice as compared with the control mice. We demonstrated that deletion of IGF1 in IECs enhances bacterial translocation to the mesenteric lymph nodes and liver. Furthermore, high-throughput sequencing of 16S ribosomal RNA genes of gut microbiota revealed that IEC-specific IGF1 loss profoundly affected the gut microbial composition at various levels of classification. Therefore, our findings shed light on the in vivo roles of IEC-specific IGF1 in intestinal homeostasis, epithelial regeneration, and immunity, broadening our current insights on IGF1 functions.


Assuntos
Proliferação de Células/genética , Células Epiteliais/citologia , Imunidade nas Mucosas/genética , Fator de Crescimento Insulin-Like I/genética , Mucosa Intestinal/imunologia , Regeneração/genética , Células-Tronco/citologia , Animais , Translocação Bacteriana/genética , Linhagem da Célula , Metabolismo Energético/genética , Células Epiteliais/fisiologia , Microbioma Gastrointestinal/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Homeostase , Imunidade nas Mucosas/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/fisiologia , Absorção Intestinal/genética , Mucosa Intestinal/citologia , Fígado/microbiologia , Linfonodos/microbiologia , Linfócitos/citologia , Mesentério , Camundongos , Camundongos Knockout , Nutrientes/metabolismo , Proteínas/metabolismo , RNA Ribossômico 16S , Tolerância a Radiação/genética
10.
Front Immunol ; 9: 240, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29483920

RESUMO

Dendritic epidermal T cells (DETCs) and dermal Vγ4 T cells engage in wound re-epithelialization and skin inflammation. However, it remains unknown whether a functional link between Vγ4 T cell pro-inflammation and DETC pro-healing exists to affect the outcome of skin wound closure. Here, we revealed that Vγ4 T cell-derived IL-17A inhibited IGF-1 production by DETCs to delay skin wound healing. Epidermal IL-1ß and IL-23 were required for Vγ4 T cells to suppress IGF-1 production by DETCs after skin injury. Moreover, we clarified that IL-1ß rather than IL-23 played a more important role in inhibiting IGF-1 production by DETCs in an NF-κB-dependent manner. Together, these findings suggested a mechanistic link between Vγ4 T cell-derived IL-17A, epidermal IL-1ß/IL-23, DETC-derived IGF-1, and wound-healing responses in the skin.


Assuntos
Interleucina-17/imunologia , Células de Langerhans/imunologia , Pele/lesões , Linfócitos T/imunologia , Cicatrização/imunologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Humanos , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/metabolismo , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Queratinócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Pele/citologia , Pele/imunologia , Linfócitos T/metabolismo
11.
Mol Med Rep ; 17(3): 4681-4687, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29344668

RESUMO

Human umbilical cord mesenchymal stem cells (hUCMSCs) are able to secrete growth factors, such as hepatocyte growth factor, vascular endothelial growth factor and insulin­like growth factor­1 (IGF­1). The secretion of these growth factors by transplanted hUCMSCs have been identified to stimulate the growth of the host cells in the target organs or tissues. The aim of the present study was to investigate the effect of autocrine IGF­1 on cell viability of hUCMSCs. The expression levels of IGF­1 and the IGF­1 receptor (IGF­1R) in hUCMSCs were identified using immunocytochemistry staining. In order to block autocrine IGF­1, hUCMSCs were treated with 5 µg/ml αIR­3, a specific IGF­1R antibody, for 24 h. The cells cultured in medium without αIR­3 were used as the control group. Cell viability, apoptosis, cell cycle and the proliferation­associated proteins were quantified using an MTT assay, flow cytometry and western blotting. The findings of the present study revealed that IGF­1 and IGF­1R were positively expressed in hUCMSCs. Treatment with αIR­3 significantly reduced cell viability and increased apoptosis of hUCMSCs (P<0.01). Cell cycle analysis indicated that the number of cells in the G2/M phase was reduced in the αIR­3­treated group compared with the control group. Western blotting revealed that the expression levels of phosphorylated (p)­protein kinase B (Akt), p­glycogen synthase kinase 3ß (GSK­3ß), p­p70 S6 kinase and cyclin D1 were markedly reduced and p21 expression was markedly increased in the αIR­3­treated group as compared with the control group (P<0.05). However, no significant difference was identified in the p­extracellular­signal regulated kinase 1/2 expression when the αIR­3 treatment group was compared with the control group. (P>0.05). The findings of the present study suggested that the autocrine IGF­1 from hUCMSCs may be capable of influencing cell viability of hUCMSCs, which may be associated with activation of Akt/GSK­3ß signaling pathway.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Anticorpos/imunologia , Anticorpos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Fator de Crescimento Insulin-Like I/imunologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptor IGF Tipo 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cordão Umbilical/citologia
12.
Oncogene ; 37(15): 2022-2036, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29367764

RESUMO

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.


Assuntos
Anticorpos Neutralizantes/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/administração & dosagem , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Anticorpos Monoclonais Humanizados , Anticorpos Neutralizantes/administração & dosagem , Neoplasias da Mama/patologia , Células Cultivadas , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Feminino , Humanos , Fator de Crescimento Insulin-Like I/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Receptor IGF Tipo 1/imunologia , Resultado do Tratamento
13.
Autoimmunity ; 51(8): 399-407, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30604632

RESUMO

The signaling pathways of interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1) play an important role in the progression of lung cancer, and this study aimed to explore whether they can synergistically promote the progression of non-small cell lung cancer (NSCLC). We found that IL-6, glycoprotein 130 (GP130), IGF-1 and IGF-1R were highly expressed in NSCLC (p = .000), and there was the correlation between GP130, IGF-1, and IGF-1R (p < .01). The overall survival of patients with the co-expression of GP130 and IGF-1R was significantly shorter (p = .0360). Co-stimulation of IL-6 and IGF-1 resulted in significantly enhanced in cell proliferation, (p < .05), invasion (p < .05), cycle (p < .05), apoptosis (p < .05), and the expression of signal molecules (GP130, IGF-1R, p-AKT, and p-ERK1/2) (all p < .05) in NSCLC cells. This experiment revealed that IL-6 and IGF-1 can synergistically promote the progression of NSCLC. The high expression of GP130 and IGF-1R is an independent risk factor for poor prognosis patients, and it is helpful to find a more accurate target for targeted therapy in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-6/metabolismo , Neoplasias Pulmonares/patologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Movimento Celular/imunologia , Proliferação de Células , Receptor gp130 de Citocina/imunologia , Receptor gp130 de Citocina/metabolismo , Progressão da Doença , Humanos , Fator de Crescimento Insulin-Like I/imunologia , Interleucina-6/imunologia , Pulmão/imunologia , Pulmão/patologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Prognóstico , Receptores de Somatomedina/imunologia , Receptores de Somatomedina/metabolismo , Análise de Sobrevida
14.
J Biomed Mater Res A ; 105(11): 3069-3076, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28782174

RESUMO

The modulation of macrophage phenotype from pro-inflammatory (M1) to tissue healing (M2) via exogenous addition of interleukin-4 (IL-4) facilitates osteogenesis; however, the molecular mediators underlying this phenomenon remain unknown. This study characterizes the IL-4-dependent paracrine crosstalk between macrophages and osteoprogenitors and its effect on osteogenesis in vitro. Primary murine M1 were co-cultured with MC3T3 cells (M1-MC3T3) in both transwell plates and direct co-cultures. To modulate M1 to M2, M1-MC3T3 were treated with IL-4 (20 ng/mL) at day 3 after seeding (M1 + IL-4-MC3T3). Selected molecular targets were assessed at days 3 and 6 after seeding at protein and mRNA levels. Mineralization was assessed at day 21. Transwell M1 + IL-4-MC3T3 significantly enhanced the secretion of CCL2/MCP-1, IGF-1 and to a lesser degree, CCL5/RANTES at day 6. At day 3, alkaline phosphatase (Alpl) was upregulated in direct M1-MC3T3. At day 6, Smurf2 and Insulin growth factor-1 (IGF-1) were downregulated and upregulated, respectively, in direct M1 + IL-4-MC3T3. Finally, M1 + IL-4-MC3T3 increased bone matrix mineralization compared with MC3T3 cells in transwell, but this was significantly less than M1-MC3T3. Taken together, macrophage subtypes enhanced the osteogenesis in transwell setting and the transition from M1 to M2 was associated with an increase in bone anabolic factors CCL2/MCP-1, CCL5/RANTES and IGF-1 in vitro. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3069-3076, 2017.


Assuntos
Quimiocina CCL2/imunologia , Quimiocina CCL5/imunologia , Imunomodulação , Fator de Crescimento Insulin-Like I/imunologia , Macrófagos/imunologia , Osteogênese , Animais , Linhagem Celular , Células Cultivadas , Técnicas de Cocultura , Inflamação/imunologia , Interleucina-4/imunologia , Macrófagos/citologia , Camundongos
15.
Sci Rep ; 7(1): 5747, 2017 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-28720797

RESUMO

Despite knowledge the gut microbiota regulates bone mass, mechanisms governing the normal gut microbiota's osteoimmunomodulatory effects on skeletal remodeling and homeostasis are unclear in the healthy adult skeleton. Young adult specific-pathogen-free and germ-free mice were used to delineate the commensal microbiota's immunoregulatory effects on osteoblastogenesis, osteoclastogenesis, marrow T-cell hematopoiesis, and extra-skeletal endocrine organ function. We report the commensal microbiota has anti-anabolic effects suppressing osteoblastogenesis and pro-catabolic effects enhancing osteoclastogenesis, which drive bone loss in health. Suppression of Sp7(Osterix) and Igf1 in bone, and serum IGF1, in specific-pathogen-free mice suggest the commensal microbiota's anti-osteoblastic actions are mediated via local disruption of IGF1-signaling. Differences in the RANKL/OPG Axis in vivo, and RANKL-induced maturation of osteoclast-precursors in vitro, indicate the commensal microbiota induces sustained changes in RANKL-mediated osteoclastogenesis. Candidate mechanisms mediating commensal microbiota's pro-osteoclastic actions include altered marrow effector CD4+T-cells and a novel Gut-Liver-Bone Axis. The previously unidentified Gut-Liver-Bone Axis intriguingly implies the normal gut microbiota's osteoimmunomodulatory actions are partly mediated via immunostimulatory effects in the liver. The molecular underpinnings defining commensal gut microbiota immunomodulatory actions on physiologic bone remodeling are highly relevant in advancing the understanding of normal osteoimmunological processes, having implications for the prevention of skeletal deterioration in health and disease.


Assuntos
Medula Óssea/imunologia , Osso e Ossos/imunologia , Microbioma Gastrointestinal/imunologia , Homeostase/imunologia , Fígado/imunologia , Animais , Células da Medula Óssea/imunologia , Osso e Ossos/metabolismo , Células Cultivadas , Hematopoese/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos Endogâmicos C57BL , Osteoblastos/imunologia , Osteoblastos/metabolismo , Osteoclastos/imunologia , Osteoclastos/metabolismo , Osteogênese/imunologia , Organismos Livres de Patógenos Específicos
16.
Int J Cancer ; 141(6): 1201-1214, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28580661

RESUMO

Increasing reports show noninflammation underlying HCC, challenging our understanding of the roles of the immune system in hepatocarcinogenesis. By exploring a mouse model of hepatic tumor induced by hepatocyte-specific expression of the Hras12V oncogene without obvious inflammation, we found that the proportion of B cells, but not T cells, progressively and significantly decreased in 3, 5-month-old transgenic mice (Tg) compared with non-transgenic mice. Notably, the proportions of total and activated B and T cells all significantly decreased in 9-month-old Tg with multiple massive hepatic tumors. Together with the decreased B cell proportion, serum IgG1/2 also significantly decreased in 5, 9-month-old Tg. Interestingly, homozygous Tg showed significantly higher B cell proportion and IgG2 levels, accompanied by significantly lower incidences of liver nodules but not adenomas and carcinomas compared with heterozygous Tg. Treatment of Tg with PCI-32765, a potent Bruton's tyrosine kinase (BTK) inhibitor for suppressing B cell proliferation and activation, significantly decreased the B cell proportion and IgG2 levels, accompanied by a significantly higher incidence of liver nodules, but had no effects on adenoma and carcinoma. Treatment of Tg with insulin-like growth factor 1 (IGF-1) significantly increased the B cell proportion and IgG2 levels, accompanied by a significantly lower incidence of liver nodules and carcinoma, but had no effects on adenoma. Conclusively, B cells and IgG2 may play important roles in suppressing hepatic tumorigenesis, but not development. In addition, hepatocyte-specific expression of the ras oncogene may play roles in suppressing B cells, while developed hepatic tumors suppress both B and T cells.


Assuntos
Linfócitos B/imunologia , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/imunologia , Tirosina Quinase da Agamaglobulinemia , Animais , Linfócitos B/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/imunologia , Imunoglobulina G/sangue , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/farmacologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Oncogênicas/genética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Proteínas ras/biossíntese , Proteínas ras/genética
17.
J Immunol Methods ; 446: 30-36, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28389174

RESUMO

Monitoring anti-drug antibody (ADA) responses in patients receiving protein therapeutics treatment is an important safety assessment for regulatory agencies, drug manufacturers, clinicians and patients. Recombinant human IGF-1/IGFBP-3 (rhIGF-1/rhIGFBP-3) is a 1:1 formulation of naturally occurring protein complex. The individual IGF-1 and IGFBP-3 proteins have multiple binding partners in serum matrix with high binding affinity to each other, which presents challenges in ADA assay development. We have developed a biotin-drug extraction with acid dissociation (BEAD) procedure followed by an electrochemiluminescence (ECL) direct assay to overcome matrix and drug interference. The method utilizes two step acid dissociation and excess biotin-drug to extract total ADA, which are further captured by soluble biotin-drug and detected in an ECL semi-homogeneous direct assay format. The pre-treatment method effectively eliminates interference by serum matrix and free drug, and enhances assay sensitivity. The assays passed acceptance criteria for all validation parameters, and have been used for clinical sample Ab testing. This method principle exemplifies a new approach for anti-isotype ADA assays, and could be an effective strategy for neutralizing antibody (NAb), pharmacokinetic (PK) and biomarker analysis in need of overcoming interference factors.


Assuntos
Anticorpos/sangue , Biotina , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Ácidos , Anticorpos Neutralizantes/sangue , Humanos , Imunoglobulina G/sangue , Proteínas Recombinantes/imunologia , Sensibilidade e Especificidade
18.
Cell Rep ; 19(2): 225-234, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28402847

RESUMO

In concert with their phagocytic activity, macrophages are thought to regulate the host immunometabolic responses primarily via their ability to produce specific cytokines and metabolites. Here, we show that IL-4-differentiated, M2-like macrophages secrete IGF1, a hormone previously thought to be exclusively produced from liver. Ablation of IGF1 receptors from myeloid cells reduced phagocytosis, increased macrophages in adipose tissue, elevated adiposity, lowered energy expenditure, and led to insulin resistance in mice fed a high-fat diet. The investigation of adipose macrophage phenotype in obese myeloid IGF1R knockout (MIKO) mice revealed a reduction in transcripts associated with M2-like macrophage activation. Furthermore, the MIKO mice infected with helminth Nippostrongylus brasiliensis displayed delayed resolution from infection with normal insulin sensitivity. Surprisingly, cold challenge did not trigger an overt M2-like state and failed to induce tyrosine hydroxylase expression in adipose tissue macrophages of control or MIKO mice. These results show that IGF1 signaling shapes the macrophage-activation phenotype.


Assuntos
Resistência à Insulina/genética , Fator de Crescimento Insulin-Like I/genética , Macrófagos/imunologia , Infecções por Strongylida/imunologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Adiposidade , Animais , Diferenciação Celular/imunologia , Dieta Hiperlipídica , Resistência à Insulina/imunologia , Fator de Crescimento Insulin-Like I/imunologia , Interleucina-4/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Nippostrongylus/patogenicidade , Fagocitose/genética , Transdução de Sinais/imunologia , Infecções por Strongylida/metabolismo , Infecções por Strongylida/parasitologia
19.
Horm Metab Res ; 49(3): 185-191, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28222462

RESUMO

Graves' orbitopathy (GO) is characterized by orbital T cell infiltration. We evaluated the regulatory T (Treg) cell fractions induced with IGF-1 in Graves' disease (GD) with and without GO. Peripheral blood mononuclear cells (PBMCs) were obtained from 13 patients with GD without eye manifestations; 10 patients with active GO; and 12 patients with nodular goiter (NG). All the patients from GD, GO, and NG were subclinical hyperthyroid. We analyzed the expression of Treg cell markers (CD4, CD25, CD127-, Foxp3) on T cells and their ability to respond to IGF-1 stimulation. In patients with GD without GO, we found lowered percentages of CD4+ Foxp3+ cells, as compared to nodular goiter 1.77 vs. 5.42% (p=0.0276). Similarly, significantly reduced frequencies of CD4+CD25+CD127-Foxp3+ and CD4+CD25+CD127- cells were observed in GD patients as compared to nodular goiter patients with hyperthyreosis, (0.7 vs. 1.48%) (p=0.0071) and (14.5 vs. 37.2%) (p=0.0051), respectively. In GO with active GO, only the percentage of CD4+CD25+CD127- cells was found to be decreased versus nodular goiter (9.35 vs. 37.2) (p=0.0275). Stimulation of PBMC derived from GO patients with IGF-1 resulted in significant increase of frequency of both CD4+ Foxp3+ and CD4+CD25+CD127- Foxp3 cells. Decreased frequencies of peripheral blood CD4+CD25+CD127-Foxp3+ in patients with GD and GO could be an useful marker of autoimmune process and perhaps a possible target for future therapies. This is the first study demonstrating Treg-enhancing effects of IGF-1. Thus IGF-1 can be accounted for modulating Treg cell-related action in GO.


Assuntos
Oftalmopatia de Graves/imunologia , Fator de Crescimento Insulin-Like I/farmacologia , Linfócitos T Reguladores/imunologia , Idoso , Antígenos CD4/sangue , Antígenos CD4/imunologia , Feminino , Fatores de Transcrição Forkhead/sangue , Fatores de Transcrição Forkhead/imunologia , Oftalmopatia de Graves/sangue , Oftalmopatia de Graves/patologia , Humanos , Fator de Crescimento Insulin-Like I/imunologia , Fator de Crescimento Insulin-Like I/metabolismo , Subunidade alfa de Receptor de Interleucina-2/sangue , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-7/sangue , Subunidade alfa de Receptor de Interleucina-7/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
20.
PLoS One ; 12(2): e0172684, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28235061

RESUMO

The massive meat production of broiler chickens make them continuously exposed to potential stressors that stimulate releasing of stress-related hormones like corticosterone (CORT) which is responsible for specific pathways in biological mechanisms and physiological activities. Therefore, this research was conducted to evaluate a wide range of responses related to broiler performance, immune function, plasma biochemistry, related gene expressions and cell death morphology during and after a 7-day course of CORT injection. A total number of 200 one-day-old commercial Cobb broiler chicks were used in this study. From 21 to 28 d of age, broilers were randomly assigned to one of 2 groups with 5 replicates of 20 birds each; the first group received a daily intramuscular injection of 5 mg/kg BW corticosterone dissolved in 0.5 ml ethanol:saline solution (CORT group), while the second group received a daily intramuscular injection of 0.5 ml ethanol:saline only (CONT group). Growth performance, including body weight (BW), daily weight gain (DG), feed intake (FI) and feed conversion ratio (FC), were calculated at 0, 3 and 7 d after the start of the CORT injections. At the same times, blood samples were collected in each group for hematological (TWBC's and H/L ratio), T- and B-lymphocytes proliferation and plasma biochemical assays (total protein, TP; free triiodothyronine hormone, fT3; aspartate amino transaminase, AST; and alanine amino transaminase, ALT). The liver, thymus, bursa of Fabricius and spleen were dissected and weighed, and the mRNA expression of insulin-like growth factor 1 gene (IGF-1) in liver and cell-death-program gene (caspase-9) in bursa were analyzed for each group and time; while the apoptotic/necrotic cells were morphologically detected in the spleen. From 28 to 35 d of age, broilers were kept for recovery period without CORT injection and the same sampling and parameters were repeated at the end (at 14 d after initiation of the CORT injection). In general, all parameters of broiler performance were negatively affected by the CORT injection. In addition, CORT treatment decreased the plasma concentration of fT3 and the mRNA expression of hepatic IGF-1. A significant increase in liver weight accompanied by an increase in plasma TP, AST and ALT was observed with CORT treatment, indicating an incidence of liver malfunction by CORT. Moreover, the relative weights of thymus, bursa and spleen decreased by the CORT treatment with low counts of TWBC's and low stimulation of T & B cells while the H/L ratio increased; indicating immunosuppressive effect for CORT treatment. Furthermore, high expression of caspase-9 gene occurred in the bursa of CORT-treated chickens, however, it was associated with a high necrotic vs. low apoptotic cell death pathway in the spleen. Seven days after termination of the CORT treatment in broilers, most of these aspects remained negatively affected by CORT and did not recover to its normal status. The current study provides a comprehensive view of different physiological modulations in broiler chickens by CORT treatment and may set the potential means to mount a successful defense against stress in broilers and other animals as well.


Assuntos
Proteínas Aviárias/imunologia , Galinhas/imunologia , Corticosterona/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Carne , Alanina Transaminase/genética , Alanina Transaminase/imunologia , Criação de Animais Domésticos , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/imunologia , Proteínas Aviárias/genética , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Bolsa de Fabricius/efeitos dos fármacos , Bolsa de Fabricius/imunologia , Caspase 9/genética , Caspase 9/imunologia , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas/crescimento & desenvolvimento , Ingestão de Alimentos/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Injeções Intramusculares , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Baço/efeitos dos fármacos , Baço/imunologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Timo/efeitos dos fármacos , Timo/imunologia , Tri-Iodotironina/genética , Tri-Iodotironina/imunologia , Ganho de Peso/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA