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1.
Proc Natl Acad Sci U S A ; 117(2): 1119-1128, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31888983

RESUMO

Reprogramming the tumor microenvironment to increase immune-mediated responses is currently of intense interest. Patients with immune-infiltrated "hot" tumors demonstrate higher treatment response rates and improved survival. However, only the minority of tumors are hot, and a limited proportion of patients benefit from immunotherapies. Innovative approaches that make tumors hot can have immediate impact particularly if they repurpose drugs with additional cancer-unrelated benefits. The seasonal influenza vaccine is recommended for all persons over 6 mo without prohibitive contraindications, including most cancer patients. Here, we report that unadjuvanted seasonal influenza vaccination via intratumoral, but not intramuscular, injection converts "cold" tumors to hot, generates systemic CD8+ T cell-mediated antitumor immunity, and sensitizes resistant tumors to checkpoint blockade. Importantly, intratumoral vaccination also provides protection against subsequent active influenza virus lung infection. Surprisingly, a squalene-based adjuvanted vaccine maintains intratumoral regulatory B cells and fails to improve antitumor responses, even while protecting against active influenza virus lung infection. Adjuvant removal, B cell depletion, or IL-10 blockade recovers its antitumor effectiveness. Our findings propose that antipathogen vaccines may be utilized for both infection prevention and repurposing as a cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/uso terapêutico , Injeções Intralesionais , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Linfócitos B , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Celular , Vírus da Influenza A Subtipo H1N1/imunologia , Influenza Humana , Interleucina-10 , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Repressoras/genética , Estações do Ano , Pele , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Esqualeno/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Vacinação
2.
Am J Pathol ; 191(1): 66-78, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33039352

RESUMO

BCCIP was originally identified as a BRCA2 and CDKN1A/p21 interaction protein. Although a partial loss of BCCIP function is sufficient to trigger genomic instability and tumorigenesis, complete deletion of BCCIP is lethal to cells. Using Rosa26-CreERT2 mouse models, we found that induced Bccip deletion in adult mice caused an acute intestinal epithelial denudation that cannot be relieved by co-deletion of Trp53. The critical role of Bccip in intestine epithelial renewal was verified with a Villin-CreERT2 mouse model. The epithelium degeneration was associated with a rapid loss of the proliferative capability of the crypt progenitor cells in vivo, lack of crypt base columnar stem cell markers, and a failure of in vitro crypt organoid growth. RNA-Seq analysis of freshly isolated intestinal crypt cells showed that Bccip deletion caused an overwhelming down-regulation of genes involved in mitotic cell division but an up-regulation of genes involved in apoptosis and stress response to microbiomes. Our data not only indicate that intestinal epithelium is the most sensitive tissue to whole-body deletion of Bccip but also point to Bccip as a novel and critical factor for the proliferation of the intestinal progenitors. These findings have significant implications for understanding why a hypomorphic loss of BCCIP functions is more relevant to tumorigenesis.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Mucosa Intestinal/metabolismo , Regeneração/fisiologia , Animais , Proliferação de Células/fisiologia , Camundongos , Células-Tronco/metabolismo
3.
Nucleic Acids Res ; 48(22): 12817-12832, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33245766

RESUMO

Ribosome biogenesis is a fundamental process required for cell proliferation. Although evolutionally conserved, the mammalian ribosome assembly system is more complex than in yeasts. BCCIP was originally identified as a BRCA2 and p21 interacting protein. A partial loss of BCCIP function was sufficient to trigger genomic instability and tumorigenesis. However, a complete deletion of BCCIP arrested cell growth and was lethal in mice. Here, we report that a fraction of mammalian BCCIP localizes in the nucleolus and regulates 60S ribosome biogenesis. Both abrogation of BCCIP nucleolar localization and impaired BCCIP-eIF6 interaction can compromise eIF6 recruitment to the nucleolus and 60S ribosome biogenesis. BCCIP is vital for a pre-rRNA processing step that produces 12S pre-rRNA, a precursor to the 5.8S rRNA. However, a heterozygous Bccip loss was insufficient to impair 60S biogenesis in mouse embryo fibroblasts, but a profound reduction of BCCIP was required to abrogate its function in 60S biogenesis. These results suggest that BCCIP is a critical factor for mammalian pre-rRNA processing and 60S generation and offer an explanation as to why a subtle dysfunction of BCCIP can be tumorigenic but a complete depletion of BCCIP is lethal.


Assuntos
Carcinogênese/genética , Proteínas de Ciclo Celular/genética , Proliferação de Células/genética , Ribossomos/genética , Animais , Proteína BRCA2/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Fatores de Iniciação em Eucariotos/genética , Fibroblastos , Instabilidade Genômica/genética , Humanos , Camundongos , Células NIH 3T3 , Mapas de Interação de Proteínas/genética , RNA Ribossômico/genética , RNA Ribossômico 5,8S/genética , Subunidades Ribossômicas Maiores de Eucariotos/genética
4.
J Genet Couns ; 31(1): 218-229, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34309124

RESUMO

Much emphasis has been placed on participant's psychological safety within genomic research studies; however, few studies have addressed parental psychological health effects associated with their child's participation in genomic studies, particularly when parents meet the threshold for clinical concern for depression. We aimed to determine if parents' depressive symptoms were associated with their child's participation in a randomized-controlled trial of newborn exome sequencing. Parents completed the Edinburgh Postnatal Depression Scale (EPDS) at baseline, immediately post-disclosure, and 3 months post-disclosure. Mothers and fathers scoring at or above thresholds for clinical concern on the EPDS, 12 and 10, respectively, indicating possible Major Depressive Disorder with Peripartum Onset, were contacted by study staff for mental health screening. Parental concerns identified in follow-up conversations were coded for themes. Forty-five parents had EPDS scores above the clinical threshold at baseline, which decreased by an average of 2.9 points immediately post-disclosure and another 1.1 points 3 months post-disclosure (both p ≤ .014). For 28 parents, EPDS scores were below the threshold for clinical concern at baseline, increased by an average of 4.7 points into the elevated range immediately post-disclosure, and decreased by 3.8 points at 3 months post-disclosure (both p < .001). Nine parents scored above thresholds only at 3 months post-disclosure after increasing an average of 5.7 points from immediately post-disclosure (p < .001). Of the 82 parents who scored above the threshold at any time point, 43 (52.4%) were reached and 30 (69.7%) of these 43 parents attributed their elevated scores to parenting stress, balancing work and family responsibilities, and/or child health concerns. Only three parents (7.0%) raised concerns about their participation in the trial, particularly their randomization to the control arm. Elevated scores on the EPDS were typically transient and parents attributed their symptomatology to life stressors in the postpartum period rather than participation in a trial of newborn exome sequencing.


Assuntos
Depressão Pós-Parto , Transtorno Depressivo Maior , Criança , Depressão , Depressão Pós-Parto/diagnóstico , Depressão Pós-Parto/prevenção & controle , Depressão Pós-Parto/psicologia , Feminino , Genômica , Humanos , Recém-Nascido , Mães/psicologia , Pais/psicologia
5.
Stem Cells ; 32(2): 327-37, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24123709

RESUMO

An imbalance between normal adipogenesis and osteogenesis by mesenchymal stem cells (MSCs) has been shown to be related to various human metabolic diseases, such as obesity and osteoporosis; however, the underlying mechanisms remain elusive. We found that the interaction between osteopontin (OPN), an arginine-glycine-aspartate-containing glycoprotein, and integrin αv/ß1 plays a critical role in the lineage determination of MSCs. Although OPN is a well-established marker during osteogenesis, its role in MSC differentiation is still unknown. Our study reveals that blockade of OPN function promoted robust adipogenic differentiation, while inhibiting osteogenic differentiation. Re-expression of OPN restored a normal balance between adipogenesis and osteogenesis in OPN(-/-) MSCs. Retarded bone formation by OPN(-/-) MSCs was also verified by in vivo implantation with hydroxyapatite-tricalcium phosphate, a bone-forming matrix. The role of extracellular OPN in MSC differentiation was further demonstrated by supplementation and neutralization of OPN. Blocking well-known OPN receptors integrin αv/ß1 but not CD44 also affected MSC differentiation. Further studies revealed that OPN inhibits the C/EBPs signaling pathway through integrin αv/ß1. Consistent with these in vitro results, OPN(-/-) mice had a higher fat to total body weight ratio than did wild-type mice. Therefore, our study demonstrates a novel role for OPN-integrin αv/ß1 in regulating MSC differentiation.


Assuntos
Adipogenia/genética , Osteogênese/genética , Osteopontina/metabolismo , Receptores de Vitronectina/metabolismo , Adipócitos/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula , Humanos , Células-Tronco Mesenquimais , Camundongos , Osteoblastos/metabolismo , Osteopontina/genética , Mapas de Interação de Proteínas/genética , Receptores de Vitronectina/genética
6.
Trends Immunol ; 33(3): 136-43, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22227317

RESUMO

Mesenchymal stem cells (MSCs), also called multipotent mesenchymal stromal cells, exist in almost all tissues and are a key cell source for tissue repair and regeneration. Under pathological conditions, such as tissue injury, these cells are mobilized towards the site of damage. Tissue damage is usually accompanied by proinflammatory factors, produced by both innate and adaptive immune responses, to which MSCs are known to respond. Indeed, recent studies have shown that there are bidirectional interactions between MSCs and inflammatory cells, which determine the outcome of MSC-mediated tissue repair processes. Although many details of these interactions remain to be elucidated, we provide here a synthesis of the current status of this newly emerging and rapidly advancing field.


Assuntos
Células-Tronco Mesenquimais/imunologia , Imunidade Adaptativa , Animais , Doença Crônica , Humanos , Imunidade Inata , Inflamação/imunologia
7.
J Pathol ; 231(2): 248-56, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24151637

RESUMO

The mechanisms by which inflammation or autoimmunity causes proteinuric kidney disease remain elusive. Yet proteinuria is a hallmark and a prognostic indicator of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Podocytes are an integral component of the kidney filtration barrier and podocyte injury leads to proteinuria. Here we show that podocytes, which receive signals from the vascular space including circulating antigens, constitutively express TLR1­6 and TLR8. We find that podocytes can respond to TLR ligands including staphylococcal enterotoxin B (SEB), poly I:C, or lipopolysaccharide (LPS) with pro-inflammatory cytokine release and activation of type I interferon (IFN) signalling. This in turn stimulates podocyte B7-1 expression and actin remodelling in vitro and transient proteinuria in vivo. Importantly, the treatment of mice with a type I IFN receptor-blocking antibody (Ab) prevents LPS-induced proteinuria. These results significantly extend our understanding of podocyte response to immune stimuli and reveal a novel mechanism for infection- or inflammation-induced transient proteinuria. Dysregulation or aberrant activation of this response may result in persistent proteinuria and progressive glomerular disease. In summary, the inhibition of glomerular type I IFN signalling with anti-IFN Abs may be a novel therapy for proteinuric kidney diseases.


Assuntos
Interferon Tipo I/metabolismo , Podócitos/metabolismo , Proteinúria/metabolismo , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Glomérulos Renais/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Proteinúria/fisiopatologia
8.
iScience ; 27(5): 109628, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38628961

RESUMO

Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) affects up to half of people living with HIV-1 and causes long term neurological consequences. The pathophysiology of HIV-1-induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC)-derived microglia combined with sliced neocortical organoids. Incubation of microglia with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2) elicited productive infection and inflammatory activation. RNA sequencing revealed significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate a role for persistent type I interferon signaling in HIV-1-infected microglia in a human neural model, suggesting its potential significance in the pathogenesis of HAND.

9.
Blood ; 117(5): 1652-61, 2011 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-21115974

RESUMO

Both the canonical and noncanonical nuclear factor κB (NF-κB) pathways have been linked to tumorigenesis. However, it remains unknown whether and how the 2 signaling pathways cooperate during tumorigenesis. We report that inhibition of the noncanonical NF-κB pathway significantly delays tumorigenesis mediated by the viral oncoprotein Tax. One function of noncanonical NF-κB activation was to repress expression of the WWOX tumor suppressor gene. Notably, WWOX specifically inhibited Tax-induced activation of the canonical, but not the noncanonical NF-κB pathway. Mechanistic studies indicated that WWOX blocked Tax-induced inhibitors of κB kinaseα (IKKα) recruitment to RelA and subsequent RelA phosphorylation at S536. In contrast, WWOX Y33R, a mutant unable to block the IKKα recruitment and RelA phosphorylation, lost the ability to inhibit Tax-mediated tumorigenesis. These data provide one important mechanism by which Tax coordinates the 2 NF-κB pathways for tumorigenesis. These data also suggest a novel role of WWOX in NF-κB regulation and viral tumorigenesis.


Assuntos
Transformação Celular Neoplásica , Produtos do Gene tax/fisiologia , Linfoma de Células T/patologia , NF-kappa B/metabolismo , Oxirredutases/metabolismo , Transdução de Sinais , Proteínas Supressoras de Tumor/metabolismo , Animais , Western Blotting , Proliferação de Células , Células Cultivadas , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Citometria de Fluxo , Genes Supressores de Tumor , Infecções por HTLV-I/metabolismo , Infecções por HTLV-I/patologia , Infecções por HTLV-I/virologia , Vírus Linfotrópico T Tipo 1 Humano/genética , Humanos , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Imunoprecipitação , Células Jurkat , Linfoma de Células T/metabolismo , Linfoma de Células T/virologia , Camundongos , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , NF-kappa B/genética , Subunidade p52 de NF-kappa B , Oxirredutases/antagonistas & inibidores , Oxirredutases/genética , Fosforilação , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW
10.
bioRxiv ; 2023 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-37961371

RESUMO

Human immunodeficiency virus type-1 (HIV-1) associated neurocognitive disorder (HAND) affects up to half of HIV-1 positive patients with long term neurological consequences, including dementia. There are no effective therapeutics for HAND because the pathophysiology of HIV-1 induced glial and neuronal functional deficits in humans remains enigmatic. To bridge this knowledge gap, we established a model simulating HIV-1 infection in the central nervous system using human induced pluripotent stem cell (iPSC) derived microglia combined with sliced neocortical organoids. Upon incubation with two replication-competent macrophage-tropic HIV-1 strains (JRFL and YU2), we observed that microglia not only became productively infected but also exhibited inflammatory activation. RNA sequencing revealed a significant and sustained activation of type I interferon signaling pathways. Incorporating microglia into sliced neocortical organoids extended the effects of aberrant type I interferon signaling in a human neural context. Collectively, our results illuminate the role of persistent type I interferon signaling in HIV-1 infected microglial in a human neural model, suggesting its potential significance in the pathogenesis of HAND.

11.
Blood ; 116(16): 2994-3003, 2010 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-20634377

RESUMO

Infection with the human T-cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T-cell leukemia/lymphoma (ATL). Although the pathogenesis of these disorders is poorly understood, it involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To test this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T-cell receptor stimulation of LTR-Tax CD4(+) T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the antiapoptotic gene, mcl-1, previously implicated as important in T-cell survival. Immortalized cells exhibited a CD4(+)CD25(+)CD3(-) phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4(+) T cells into NOD/Shi-scid/IL-2Rγ null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax(+), CD4(+) lymphocytes. We suggest that immune activation of infected CD4(+) T cells plays an important role in the induction of Tax expression, T-cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Produtos do Gene tax/imunologia , Animais , Apoptose , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células , Citocinas/imunologia , Expressão Gênica , Produtos do Gene tax/genética , Camundongos , Camundongos Transgênicos , Linfócitos T Auxiliares-Indutores/imunologia
12.
Haematologica ; 97(8): 1255-63, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22371181

RESUMO

BACKGROUND: There is increasing evidence that stromal cell interactions are required for the survival and drug resistance of several types of B-cell malignancies. There is relatively little information regarding the role of the bone marrow/lymphoid microenvironment in the pathogenesis of mantle cell lymphoma. In this study we investigated the interaction of primary mantle cell lymphoma cells with stromal cells in an ex vivo co-culture system. DESIGN AND METHODS: The murine stromal cell line MS-5 and human bone marrow mesenchymal stromal cells were each co-cultured with primary mantle cell lymphoma cells for up to 7 months. Mantle cell lymphoma cultures alone or combined with human stromal cells were analyzed for cell number, cell migration, nuclear factor-κB activation and drug resistance. RESULTS: Co-culture of mantle cell lymphoma cells and human stromal cells results in the survival and proliferation of primary mantle cell lymphoma cells for at least 7 months compared to mantle cell lymphoma cells cultured alone. Mantle cell lymphoma-human stromal cell interactions resulted in activation of the B-cell activating factor/nuclear factor-κB signaling axis resulting in reduced apoptosis, increased mantle cell lymphoma migration and increased drug resistance. CONCLUSIONS: Direct mantle cell lymphoma-human stromal cell interactions support long-term expansion and increase the drug-resistance of primary mantle cell lymphoma cells. This is due in part to activation of the canonical and non-canonical nuclear factor κB pathways. We also demonstrated the ability of B-cell activating factor to augment CXCL12- and CXCL13-induced cell migration. Collectively, these findings demonstrate that human stromal cell-mantle cell lymphoma interactions play a pivotal role in the pathogenesis of mantle cell lymphoma and that analysis of mantle cell lymphoma-human stromal cell interactions may help in the identification of novel targets for therapeutic use.


Assuntos
Fator Ativador de Células B/metabolismo , Linfoma de Célula do Manto/metabolismo , Células-Tronco Mesenquimais/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Comunicação Celular , Sobrevivência Celular , Quimiocina CXCL12/metabolismo , Quimiocina CXCL13/metabolismo , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Camundongos , Células Estromais/fisiologia
13.
Sci Immunol ; 7(71): eabf3717, 2022 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-35522722

RESUMO

The expression of BTB-ZF transcription factors such as ThPOK in CD4+ T cells, Bcl6 in T follicular helper cells, and PLZF in natural killer T cells defines the fundamental nature and characteristics of these cells. Screening for lineage-defining BTB-ZF genes led to the discovery of a subset of T cells that expressed Zbtb20. About half of Zbtb20+ T cells expressed FoxP3, the lineage-defining transcription factor for regulatory T cells (Tregs). Zbtb20+ Tregs were phenotypically and genetically distinct from the larger conventional Treg population. Zbtb20+ Tregs constitutively expressed mRNA for interleukin-10 and produced high levels of the cytokine upon primary activation. Zbtb20+ Tregs were enriched in the intestine and specifically expanded when inflammation was induced by the use of dextran sodium sulfate. Conditional deletion of Zbtb20 in T cells resulted in a loss of intestinal epithelial barrier integrity. Consequently, knockout (KO) mice were acutely sensitive to colitis and often died because of the disease. Adoptive transfer of Zbtb20+ Tregs protected the Zbtb20 conditional KO mice from severe colitis and death, whereas non-Zbtb20 Tregs did not. Zbtb20 was detected in CD24hi double-positive and CD62Llo CD4 single-positive thymocytes, suggesting that expression of the transcription factor and the phenotype of these cells were induced during thymic development. However, Zbtb20 expression was not induced in "conventional" Tregs by activation in vitro or in vivo. Thus, Zbtb20 expression identified and controlled the function of a distinct subset of Tregs that are involved in intestinal homeostasis.


Assuntos
Colite , Linfócitos T Reguladores , Fatores de Transcrição , Animais , Colite/induzido quimicamente , Homeostase , Intestinos , Camundongos , Camundongos Knockout , Linfócitos T Reguladores/metabolismo , Fatores de Transcrição/genética
14.
Carcinogenesis ; 32(9): 1381-7, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21665891

RESUMO

We investigated the effects of caloric restriction (CR) on growth of tumors and metastases in the 4T1 mammary tumor model and found that CR, compared with normal diet, reduced the growth of mammary tumors and metastases and the total number of metastases that originated both spontaneously from the primary tumor and also experimentally from i.v. injection of the tumor cells. CR also decreased proliferation and angiogenesis and increased apoptosis in tumors. CR reduced levels of insulin, leptin, insulin-like growth factor 1, insulin-like growth factor binding protein 3 and increased adiponectin in tumors. We also demonstrated that tumors from CR mice possessed lower levels of transforming growth factor-ß, lower intratumor deposition of collagen IV and reduced invasiveness due to a decrease in tumor secretion of active matrix metalloproteinase 9. Our results suggest that CR-induced metabolic and signaling changes affect the stroma and the tumor cells resulting in a microenvironment that prevents proliferation of breast tumors and their metastases.


Assuntos
Restrição Calórica , Neoplasias Mamárias Experimentais/prevenção & controle , Animais , Apoptose , Peso Corporal , Linhagem Celular Tumoral , Proliferação de Células , Colágeno/metabolismo , Ingestão de Alimentos , Feminino , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/irrigação sanguínea , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Neovascularização Patológica/prevenção & controle , Fator de Crescimento Transformador beta/sangue
15.
PLoS Negl Trop Dis ; 15(7): e0009559, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34314415

RESUMO

Viral and parasitic coinfections are known to lead to both enhanced disease progression and altered disease states. HTLV-1 and Strongyloides stercoralis are co-endemic throughout much of their worldwide ranges resulting in a significant incidence of coinfection. Independently, HTLV-1 induces a Th1 response and S. stercoralis infection induces a Th2 response. However, coinfection with the two pathogens has been associated with the development of S. stercoralis hyperinfection and an alteration of the Th1/Th2 balance. In this study, a model of HTLV-1 and S. stercoralis coinfection in CD34+ umbilical cord blood hematopoietic stem cell engrafted humanized mice was established. An increased level of mortality was observed in the HTLV-1 and coinfected animals when compared to the S. stercoralis infected group. The mortality was not correlated with proviral loads or total viral RNA. Analysis of cytokine profiles showed a distinct shift towards Th1 responses in HTLV-1 infected animals, a shift towards Th2 cytokines in S. stercoralis infected animals and elevated TNF-α responses in coinfected animals. HTLV-1 infected and coinfection groups showed a significant, yet non-clonal expansion of the CD4+CD25+ T-cell population. Numbers of worms in the coinfection group did not differ from those of the S. stercoralis infected group and no autoinfective larvae were found. However, infective larvae recovered from the coinfection group showed an enhancement in growth, as was seen in mice with S. stercoralis hyperinfection caused by treatment with steroids. Humanized mice coinfected with S. stercoralis and HTLV-1 demonstrate features associated with human infection with these pathogens and provide a unique opportunity to study the interaction between these two infections in vivo in the context of human immune cells.


Assuntos
Antígenos CD34/sangue , Citocinas/metabolismo , Infecções por HTLV-I/imunologia , Células-Tronco Hematopoéticas/metabolismo , Strongyloides stercoralis/crescimento & desenvolvimento , Estrongiloidíase/imunologia , Animais , Linhagem Celular , Coinfecção , Citocinas/genética , Sangue Fetal , Infecções por HTLV-I/complicações , Vírus Linfotrópico T Tipo 1 Humano , Larva/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estrongiloidíase/complicações
16.
Stem Cells ; 27(8): 1954-62, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19544427

RESUMO

Bone marrow-derived mesenchymal stem cells (MSCs) hold great promise for treating immune disorders because of their immunoregulatory capacity, but the mechanism remains controversial. As we show here, the mechanism of MSC-mediated immunosuppression varies among different species. Immunosuppression by human- or monkey-derived MSCs is mediated by indoleamine 2,3-dioxygenase (IDO), whereas mouse MSCs utilize nitric oxide, under the same culture conditions. When the expression of IDO and inducible nitric oxide synthase (iNOS) were examined in human and mouse MSCs after stimulation with their respective inflammatory cytokines, we found that human MSCs expressed extremely high levels of IDO, and very low levels of iNOS, whereas mouse MSCs expressed abundant iNOS and very little IDO. Immunosuppression by human MSCs was not intrinsic, but was induced by inflammatory cytokines and was chemokine-dependent, as it is in mouse. These findings provide critical information about the immunosuppression of MSCs and for better application of MSCs in treating immune disorders.


Assuntos
Células-Tronco Mesenquimais/imunologia , Óxido Nítrico/imunologia , Animais , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Tolerância Imunológica , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Macaca mulatta , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Camundongos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Especificidade da Espécie
17.
Pathogens ; 9(11)2020 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-33137906

RESUMO

Infection with human T-cell leukemia/lymphoma virus type 1 (HTLV-1) has been associated with various clinical syndromes including co-infection with Strongyloides stercoralis, which is an intestinal parasitic nematode and the leading cause of strongyloidiasis in humans. Interestingly, HTLV-1 endemic areas coincide with regions citing high prevalence of S. stercoralis infection, making these communities optimal for elucidating the pathogenesis of co-infection and its clinical significance. HTLV-1 co-infection with S. stercoralis has been observed for decades in a number of published patient cases and case series; however, the implications of this co-infection remain elusive. Thus far, data suggest that S. stercoralis increases proviral load in patients co-infected with HTLV-1 compared to HTLV-1 infection alone. Furthermore, co-infection with HTLV-1 has been associated with shifting the immune response from Th2 to Th1, affecting the ability of the immune system to address the helminth infection. Thus, despite this well-known association, further research is required to fully elucidate the impact of each pathogen on disease manifestations in co-infected patients. This review provides an analytical view of studies that have evaluated the variation within HTLV-1 patients in susceptibility to S. stercoralis infection, as well as the effects of strongyloidiasis on HTLV-1 pathogenesis. Further, it provides a compilation of available clinical reports on the epidemiology and pathology of HTLV-1 with parasitic co-infection as well as data from mechanistic studies suggesting possible immunopathogenic mechanisms. Furthermore, specific areas of potential future research have been highlighted to facilitate advancing understanding of the complex interactions between these two pathogens.

18.
Cytokine Growth Factor Rev ; 17(4): 281-93, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16793322

RESUMO

While the classical pathway of NF-kappaB activation plays critical roles in a wide range of biological processes, the more recently described "non-canonical" NF-kappaB pathway has important but more restricted roles in both normal and pathological processes. The non-canonical NF-kappaB pathway, based on processing of the nf-kappab2 gene product p100 to generate p52, appears to be involved in B-cell maturation and lymphoid development. Deregulated activation of this pathway has been observed in a variety of malignant and autoimmune diseases, thus inhibitors that specifically target p100 processing might be predicted to have potential roles as immunomodulators and in the therapy of malignant diseases. We review current understandings of NF-kappaB activation, particularly the mechanisms of p100 processing under both physiological and pathological conditions.


Assuntos
NF-kappa B/metabolismo , Doenças Autoimunes/metabolismo , Humanos , NF-kappa B/química , Subunidade p52 de NF-kappa B/metabolismo , Neoplasias/metabolismo , Transdução de Sinais
19.
Int J Oncol ; 32(1): 257-64, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18097566

RESUMO

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) alone or in combination with an NF-kappaB inhibitor, (E)3-[(4-methylphenyl)-sulfonyl]-2-propenenitrile (BAY 11-7082; BAY), on the growth and apoptosis of human prostate cancer PC-3 cells cultured in vitro or grown in immunodeficient mice were studied. Treatment of cultured PC-3 cells with TPA (0.2-10 ng/ml) for 96 h resulted in growth inhibition and apoptosis in a concentration-dependent manner. BAY inhibited NF-kappaB activity in PC-3 cells as determined by a luciferase reporter assay and enhanced TPA-induced growth inhibition and apoptosis in cultured PC-3 cells. In animal studies, NCr immunodeficient mice were injected subcutaneously with PC-3 cells in Matrigel. Mice with well-established tumors received daily i.p. injections with TPA (100 ng/g body weight/day), BAY (4 microg/g/day), or a combination of TPA (100 ng/g/day) and BAY (4 microg/g/day) for 36 days. Tumor growth occurred in all of the vehicle-treated control mice. The percent of animals with some tumor regression after 36 days of treatment was 0% for the control group, 40% for the TPA group, 50% for the BAY group and 100% for the TPA + BAY group. Mechanistic studies indicated that treatment of the mice with TPA or TPA + BAY decreased proliferation and increased apoptosis in the tumors. Results from our studies indicate that inhibition of NF-kappaB activity is associated with enhanced TPA-induced growth inhibition and apoptosis in PC-3 cells. Inhibition of NF-kappaB activity by suitable pharmacological inhibitors may be an effective strategy for improving the therapeutic efficacy of TPA in prostate cancer.


Assuntos
Apoptose/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Nitrilas/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Sulfonas/farmacologia , Acetato de Tetradecanoilforbol/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Nus , Neoplasias da Próstata/patologia
20.
Clin Cancer Res ; 13(18 Pt 1): 5480-7, 2007 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-17875778

RESUMO

PURPOSE: To investigate the effects and mechanisms of atorvastatin and celecoxib administered individually or in combination on human prostate cancer PC-3 cells cultured in vitro or grown as xenograft tumors in immunodeficient mice. EXPERIMENTAL DESIGN: Human prostate cancer PC-3 cells in culture were treated with atorvastatin and celecoxib alone or in combination. Severe combined immunodeficient (SCID) mice were injected s.c. with PC-3 cells. The mice received daily i.p injections starting 2 days before tumor cell inoculation and continuing during the course of treatment with atorvastatin (10 microg/g body weight/d), celecoxib (10 microg/g/d), a combination of atorvastatin (10 microg/g/d) and celecoxib (10 microg/g/d), or a combination of atorvastatin (5 microg/g/d) and celecoxib (5 microg/g/d). RESULTS: Atorvastatin in combination with celecoxib had stronger effects on growth inhibition and apoptosis of PC-3 cells than either agent used individually. Atorvastatin and celecoxib in combination also had a stronger inhibitory effect on activation of nuclear factor-kappaB and extracellular signal-regulated kinase 1/2 in PC-3 cells than either agent alone. Treatment of SCID mice with combinations of atorvastatin and celecoxib more effectively inhibited the formation and growth of PC-3 tumors in the mice than either agent administered alone. CONCLUSIONS: A combination of atorvastatin and celecoxib had a more potent inhibitory effect on the growth of PC-3 cells cultured in vitro or grown in SCID mice than either agent alone. A combination of atorvastatin and celecoxib may be an effective strategy for the prevention of prostate cancer.


Assuntos
Inibidores de Ciclo-Oxigenase/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Apoptose , Atorvastatina , Celecoxib , Proliferação de Células/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/administração & dosagem , Quimioterapia Combinada , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos SCID , Pirazóis/administração & dosagem , Pirróis/administração & dosagem , Sulfonamidas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
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