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1.
Materials (Basel) ; 14(21)2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34771808

RESUMO

A thermoplastic intumescent coating system (IC) based on poly(vinyl acetate) was modified by two forms of multiwalled carbon nanotubes (CNTs), i.e., by a nanofiller powder and its solid dispersions in pentaerythritol (PER-CNTs). It was revealed that only the PER-CNTs modifier allows us to obtain solvent-borne ICs with a relatively high CNTs concentration (1-3 wt. parts of CNTs/100 wt. parts of paint solids) and acceptable application viscosity. Thermal insulation time (TIT) and intumescent factor (IF) of the ICs on a steel substrate (a fire test according to a cellulosic fire curve), as well as morphology, chemical structure (by the FT-IR technique) and mechanical strength of the charred systems, were investigated. It was found that the CNTs powder decreases TIT and IF values while PER-occluded CNTs improve these parameters (e.g., +4.6 min and +102% vs. an unmodified sample, respectively). Compressive strength of the charred ICs was improved by the PER-CNTs modifier as well.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33925072

RESUMO

Difficulties with interpersonal communication experienced by individuals with autism spectrum disorders (ASD) significantly contribute to their underrepresentation in the workforce as well as problems experienced while in employment. Consistently, it is vital to understand how communication within the employment cycle of this group can be improved. This study aims to identify and analyze the possibilities of modifying the communication processes around recruitment, selection, onboarding, and job retention to address the specific characteristics and needs of the representatives of this group. This qualitative study is based on 15 in-depth interviews conducted with 21 field experts, i.e.,: therapists, job trainers, and entrepreneurs employing people with ASD. The findings of this research informed the creation of an inclusive communication model supporting the employment cycle of individuals with ASD. The most important recommendations within the model that was created include the modification of job advertisements, use of less structured job interviews, providing opportunities for mentorship, and supportive and non-direct, electronically mediated communication. To apply the above-mentioned solutions and take full advantage of the talents of people with ASD, it is also necessary to provide tailored sensitivity and awareness training programs for their direct addressees as well as their neurotypical colleagues, including managerial staff.


Assuntos
Transtorno do Espectro Autista , Comunicação , Emprego , Humanos , Pesquisa Qualitativa
3.
Sensors (Basel) ; 18(10)2018 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-30347649

RESUMO

The application of a Bluetooth skin resistance sensor in assisting people with Autism Spectrum Disorders (ASD), in their day-to-day work, is presented in this paper. The design and construction of the device are discussed. The authors have considered the best placement of the sensor, on the body, to gain the most accurate readings of user stress levels, under various conditions. Trial tests were performed on a group of sixteen people to verify the correct functioning of the device. Resistance levels were compared to those from the reference system. The placement of the sensor has also been determined, based on wearer convenience. With the Bluetooth Low Energy block, users can be notified immediately about their abnormal stress levels via a smartphone application. This can help people with ASD, and those who work with them, to facilitate stress control and make necessary adjustments to their work environment.


Assuntos
Transtorno do Espectro Autista/psicologia , Redes de Comunicação de Computadores/instrumentação , Pele/fisiopatologia , Tecnologia sem Fio/instrumentação , Local de Trabalho/psicologia , Humanos , Smartphone/instrumentação
4.
Cancer Res ; 76(2): 339-46, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26773096

RESUMO

Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet. Our findings show how caloric suppression of the guanylin-GUCY2C signaling axis links obesity to negation of a universal tumor suppressor pathway in colorectal cancer, suggesting an opportunity to prevent colorectal cancer in obese patients through hormone replacement with the FDA-approved oral GUCY2C ligand linaclotide.


Assuntos
Neoplasias Colorretais/metabolismo , Hormônios Gastrointestinais/metabolismo , Peptídeos Natriuréticos/metabolismo , Obesidade/metabolismo , Receptores Acoplados a Guanilato Ciclase/metabolismo , Receptores de Peptídeos/metabolismo , Animais , Células CACO-2 , Neoplasias Colorretais/patologia , Modelos Animais de Doenças , Genótipo , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/patologia , Comunicação Parácrina , Receptores de Enterotoxina , Fatores de Risco , Transdução de Sinais
5.
Inflamm Bowel Dis ; 21(12): 2879-85, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26288002

RESUMO

BACKGROUND: Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients. METHODS: Patients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6, and 14. Efficacy was assessed using the Harvey-Bradshaw index for CD, the simple clinical colitis activity index for UC and physician assessment, along with C-reactive protein and decrease of corticosteroid therapy. Clinical response was defined as decrease in Harvey-Bradshaw index ≥3 and simple clinical colitis activity index ≥3 and remission as Harvey-Bradshaw index ≤4, simple clinical colitis activity index ≤2 and physician assessment of response and remission. RESULTS: Our study included 172 patients (107 CD, 59 UC, 6 inflammatory bowel disease-unclassified, men 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had ostomy and 9 ileoanal pouch, and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14, respectively. Adverse events occurred in 10.5%. CONCLUSIONS: VDZ is safe and well tolerated in refractory inflammatory bowel disease patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Fármacos Gastrointestinais/administração & dosagem , Quimioterapia de Indução/métodos , Corticosteroides/uso terapêutico , Adulto , Proteína C-Reativa/análise , Estudos de Coortes , Colite Ulcerativa/sangue , Doença de Crohn/sangue , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Falha de Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/uso terapêutico
6.
Gut ; 64(12): 1889-97, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25367873

RESUMO

OBJECTIVE: IBD is a group of complex, systemic disorders associated with intestinal inflammation and extraintestinal manifestations. Recent studies revealed Mendelian forms of IBD, which contributed significantly to our understanding of disease pathogenesis and the heritability of IBD. DESIGN: We performed exome sequencing in a family with Crohn's disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed in silico and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function. RESULTS: A novel missense variant was identified in CTLA4 encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased in vitro and associated with an increased ratio of memory to naive T cells in vivo, consistent with impaired regulation of T cell activation. CONCLUSIONS: Our results support the concept that variants in CTLA4 provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.


Assuntos
Doenças Autoimunes/genética , Autoimunidade/genética , Antígeno CTLA-4/genética , Doença de Crohn/genética , Doença de Crohn/imunologia , Linfócitos T Citotóxicos/metabolismo , Adolescente , Idade de Início , Doenças Autoimunes/imunologia , Antígeno B7-1/metabolismo , Contagem de Linfócito CD4 , Antígeno CTLA-4/metabolismo , Proliferação de Células/genética , Criança , Análise Mutacional de DNA , Diabetes Mellitus Tipo 1/complicações , Dimerização , Exoma , Feminino , Células HEK293 , Heterozigoto , Humanos , Memória Imunológica/genética , Mutação de Sentido Incorreto , Linhagem , Penetrância , Multimerização Proteica/genética , Análise de Sequência de DNA , Adulto Jovem
7.
Nature ; 503(7475): 272-6, 2013 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-24089213

RESUMO

The recognition of autophagy related 16-like 1 (ATG16L1) as a genetic risk factor has exposed the critical role of autophagy in Crohn's disease. Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction. As Atg16l1(HM) mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 (Xbp1) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis. Unresolved ER stress is a common feature of inflammatory bowel disease epithelium, and several genetic risk factors of Crohn's disease affect Paneth cells. Here we show that impairment in either UPR (Xbp1(ΔIEC)) or autophagy function (Atg16l1(ΔIEC) or Atg7(ΔIEC)) in intestinal epithelial cells results in each other's compensatory engagement, and severe spontaneous Crohn's-disease-like transmural ileitis if both mechanisms are compromised. Xbp1(ΔIEC) mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1. Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn's disease as a specific disorder of Paneth cells.


Assuntos
Enteropatias/fisiopatologia , Mucosa Intestinal/patologia , Celulas de Paneth/patologia , Animais , Autofagia/genética , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Estresse do Retículo Endoplasmático/genética , Inflamação , Enteropatias/genética , Mucosa Intestinal/citologia , Camundongos , Fatores de Transcrição de Fator Regulador X , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Proteína 1 de Ligação a X-Box , eIF-2 Quinase/metabolismo
8.
J Exp Med ; 210(10): 2041-56, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-24043762

RESUMO

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box-binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)-mediated increase in Lgr5(+) and Olfm4(+) ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)-related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors.


Assuntos
Transformação Celular Neoplásica/genética , Proteínas de Ligação a DNA/genética , Estresse do Retículo Endoplasmático , Mucosa Intestinal/metabolismo , Intestinos/patologia , Células-Tronco/metabolismo , Células-Tronco/patologia , Fatores de Transcrição/genética , Animais , Comunicação Autócrina/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/metabolismo , Endorribonucleases/metabolismo , Ativação Enzimática , Deleção de Genes , Genes APC , Interleucina-11/metabolismo , Interleucina-6/metabolismo , Mucosa Intestinal/patologia , Janus Quinase 1/metabolismo , MAP Quinase Quinase 4/antagonistas & inibidores , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Fatores de Transcrição de Fator Regulador X , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição/metabolismo , Carga Tumoral/genética , Proteína 1 de Ligação a X-Box
9.
Exp Cell Res ; 317(19): 2772-9, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21821022

RESUMO

The unfolded protein response (UPR) is a signaling pathway from the endoplasmic reticulum (ER) to the nucleus that protects cells from the stress caused by misfolded or unfolded proteins [1, 2]. As such, ER stress is an ongoing challenge for all cells given the central biologic importance of secretion as part of normal physiologic functions. This is especially the case for cells that are highly dependent upon secretory function as part of their major duties. Within mucosal tissues, the intestinal epithelium is especially dependent upon an intact UPR for its normal activities [3]. This review will discuss the UPR and the special role that it provides in the functioning of the intestinal epithelium and, when dysfunctional, its implications for understanding mucosal homeostasis and intestinal inflammation, as occurs in inflammatory bowel disease (IBD).


Assuntos
Homeostase/fisiologia , Inflamação/etiologia , Doenças Inflamatórias Intestinais/etiologia , Mucosa Intestinal/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Animais , Humanos , Inflamação/metabolismo , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/patologia , Mucosa Intestinal/fisiologia , Intestinos/patologia , Modelos Biológicos
10.
J Immunol ; 186(4): 1989-96, 2011 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-21217011

RESUMO

Although NF-κB1 p50/p105 has critical roles in immunity, the mechanism by which NF-κB1 regulates inflammatory responses is unclear. In this study, we analyzed the gene expression profile of LPS-stimulated Nfkb1(-/-) macrophages that lack both p50 and p105. Deficiency of p50/p105 selectively increased the expression of IFN-responsive genes, which correlated with increased IFN-ß expression and STAT1 phosphorylation. IFN Ab-blocking experiments indicated that increased STAT1 phosphorylation and expression of IFN-responsive genes observed in the absence of p50/p105 depended upon autocrine IFN-ß production. Markedly higher serum levels of IFN-ß were observed in Nfkb1(-/-) mice than in wild-type mice following LPS injection, demonstrating that Nfkb1 inhibits IFN-ß production under physiological conditions. TPL-2, a mitogen-activated protein kinase kinase kinase stabilized by association with the C-terminal ankyrin repeat domain of p105, negatively regulates LPS-induced IFN-ß production by macrophages via activation of ERK MAPK. Retroviral expression of TPL-2 in Nfkb1(-/-) macrophages, which are deficient in endogenous TPL-2, reduced LPS-induced IFN-ß secretion. Expression of the C-terminal ankyrin repeat domain of p105 in Nfkb1(-/-) macrophages, which rescued LPS activation of ERK, also inhibited IFN-ß expression. These data indicate that p50/p105 negatively regulates LPS-induced IFN signaling in macrophages by stabilizing TPL-2, thereby facilitating activation of ERK.


Assuntos
Interferon beta/antagonistas & inibidores , MAP Quinase Quinase Quinases/fisiologia , Macrófagos/imunologia , Macrófagos/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Subunidade p50 de NF-kappa B/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Toll-Like/fisiologia , Animais , Células da Medula Óssea/enzimologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células Cultivadas , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Perfilação da Expressão Gênica , Interferon beta/biossíntese , Macrófagos/enzimologia , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 3 Ativada por Mitógeno/fisiologia , Subunidade p50 de NF-kappa B/deficiência , Subunidade p50 de NF-kappa B/genética , Receptores Toll-Like/antagonistas & inibidores
12.
J Immunol ; 177(10): 7332-9, 2006 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-17082652

RESUMO

Defects within the innate immune system sensitize NF-kappaB-deficient (p50(-/-); p65(+/-)) mice to Helicobacter hepaticus (Hh)-induced colitis. Because IL-10 plays a central role in the inhibition of Hh-induced colitis, we hypothesized that the ability of IL-10 to inhibit the innate inflammatory response to Hh may be compromised in NF-kappaB-deficient mice. To test this hypothesis, we evaluated the ability of an IL-10-Ig fusion protein with IL-10-like properties to inhibit Hh-induced colitis in RAG-2(-/-) (RAG) and p50(-/-); p65(+/-); RAG-2(-/-) (3X/RAG) mice. As expected, IL-10-Ig efficiently inhibited the development of colitis in RAG mice. In contrast, the ability of IL-10-Ig to inhibit colitis was compromised in 3X/RAG mice. The defect in response to IL-10-Ig appeared to be primarily the result of the absence of the p50/p105 subunit, because the ability of IL-10-Ig to inhibit colitis was also compromised in p50(-/-); RAG-2(-/-) (p50/RAG) mice. Radiation chimeras demonstrated that the presence of p50/p105 within hemopoietic cells of the innate immune system was necessary for efficient inhibition of colitis by IL-10-Ig. Consistent with a defect in the suppressive effects of IL-10 in the absence of p50/p105, we found that the ability of IL-10 to control LPS-induced expression of IL-12 p40 was significantly compromised in macrophages lacking p50/p105. These results suggest that the absence of the p50/p105 subunit of NF-kappaB within hemopoietic cells of the innate immune system interferes with the ability of IL-10 to suppress inflammatory gene expression and Hh-induced colitis.


Assuntos
Colite/imunologia , Colite/prevenção & controle , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/prevenção & controle , Helicobacter hepaticus/imunologia , Interleucina-10/fisiologia , Subunidade p50 de NF-kappa B/fisiologia , Animais , Colite/genética , Colite/microbiologia , Colo/imunologia , Colo/microbiologia , Infecções por Helicobacter/genética , Helicobacter hepaticus/crescimento & desenvolvimento , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/fisiologia , Mediadores da Inflamação/uso terapêutico , Interleucina-10/deficiência , Interleucina-10/genética , Interleucina-10/imunologia , Subunidade p40 da Interleucina-12/biossíntese , Subunidade p40 da Interleucina-12/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Subunidade p50 de NF-kappa B/deficiência , Subunidade p50 de NF-kappa B/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/uso terapêutico
13.
J Immunol ; 176(2): 1244-51, 2006 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-16394015

RESUMO

Helicobacter hepaticus is an enterohepatic Helicobacter species that induces lower bowel inflammation in susceptible mouse strains, including those lacking the p50/p105 subunit of NF-kappaB. H. hepaticus-induced colitis is associated with elevated levels of IL-12 p40 expression, and p50/p105-deficient macrophages express higher levels of IL-12 p40 than wild-type macrophages after challenge with H. hepaticus. However, the molecular mechanisms by which the p50/p105 subunit of NF-kappaB suppresses IL-12 p40 expression have not yet been elucidated. In this study we have demonstrated that H. hepaticus challenge of macrophages induces ERK activation, and this event plays a critical role in inhibiting the ability of H. hepaticus to induce IL-12 p40. Activation of ERK requires both p50/p105 and the MAPK kinase kinase, Tpl-2. Inhibition of the induction of IL-12 p40 by ERK was independent of c-Rel, a known positive regulator of IL-12 p40. Instead, it was linked to the induction of c-Fos, a known inhibitor of IL-12 p40 expression. These results suggest that H. hepaticus induces ERK activation by a pathway dependent upon Tpl-2 and p105, and that activation of ERK inhibits the expression of IL-12 p40 by inducing c-Fos. Thus, a defect in ERK activation could play a pivotal role in the superinduction of IL-12 p40 observed after challenge of macrophages lacking the p50/p105 subunit of NF-kappaB with H. hepaticus.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Helicobacter hepaticus/patogenicidade , Interleucina-12/biossíntese , Macrófagos/imunologia , Macrófagos/metabolismo , Subunidade p50 de NF-kappa B/deficiência , Subunidades Proteicas/biossíntese , Animais , Butadienos/farmacologia , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Helicobacter hepaticus/imunologia , Técnicas In Vitro , Interleucina-10/biossíntese , Interleucina-10/deficiência , Interleucina-10/genética , Subunidade p40 da Interleucina-12 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Subunidade p50 de NF-kappa B/genética , Nitrilas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-fos/biossíntese
14.
J Immunol ; 173(9): 5786-93, 2004 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-15494531

RESUMO

To evaluate the possibility that NF-kappaB subunits p50 and p65 have a role in limiting the systemic inflammatory response induced by endotoxin, we compared the susceptibility of wild-type (WT), p65+/-, p50-/-, and p50-/-p65+/- (3X) mice to LPS-induced shock. Interestingly, whereas p65+/- mice were no more sensitive than WT mice to LPS-induced shock, 3X mice were exquisitely sensitive to the toxic effects of LPS. Mice lacking p50 alone displayed an intermediate phenotype. Sensitivity to LPS was a property of the innate immune system and was characterized by elevated circulating levels of TNF in both p50-/- and 3X mice. The ability of LPS to induce shock depended upon TNF, and 3X mice were significantly more sensitive to the toxic effects of TNF than were p50-deficient mice. The expression of several LPS-inducible proinflammatory genes, including IFN-gamma, was significantly higher within the spleens of p50-/- mice than in the spleens of WT mice, and interestingly, the expression of IFN-gamma was augmented still further within the spleens of 3X mice. These results demonstrate that NF-kappaB subunits p50 and p65 have critical inhibitory functions during the systemic response to LPS and raise the possibility that these functions could be essential in preventing mortality associated with systemic inflammatory response syndromes.


Assuntos
Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/toxicidade , NF-kappa B/fisiologia , Subunidades Proteicas/fisiologia , Choque Séptico/prevenção & controle , Animais , Apoptose/genética , Apoptose/imunologia , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Colo/irrigação sanguínea , Colo/imunologia , Edema/genética , Edema/imunologia , Edema/fisiopatologia , Predisposição Genética para Doença , Hematopoese/genética , Hematopoese/imunologia , Hepatócitos/imunologia , Hepatócitos/patologia , Imunidade Inata/genética , Pulmão/irrigação sanguínea , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/deficiência , NF-kappa B/genética , Subunidade p50 de NF-kappa B , Subunidades Proteicas/deficiência , Subunidades Proteicas/genética , Quimera por Radiação/genética , Quimera por Radiação/imunologia , Choque Séptico/genética , Choque Séptico/imunologia , Choque Séptico/patologia , Fator de Transcrição RelA , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/fisiologia , Regulação para Cima/genética , Regulação para Cima/imunologia
15.
Cancer Res ; 63(18): 6042-50, 2003 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-14522933

RESUMO

Roles for host immune response in carcinogenesis are not well defined. Recent studies have shown that microbially driven inflammation can lead to colon cancer and that prior transfer of regulatory lymphocytes expressing CD4 and CD25 prevents the innate inflammatory events that lead to colon cancer in mice. To further examine the ability of regulatory lymphocytes to inhibit carcinogenesis, 129/SvEv Rag-2-deficient mice were inoculated by gastric gavage with Helicobacter hepaticus, an enteric bacterial pathogen of mice. Mice were then treated at 1, 3, or 12 months after infection with adoptive transfer of CD4(+)CD45RB(lo)CD25(+)-regulatory cells. Mice dosed with regulatory cells at 4 or 12 weeks after H. hepaticus infection had reduced severity of inflammatory bowel disease and significantly lower risk of colon cancer during the 8 month observation period, compared with infected mice that had not received cells. This suggested that regulatory cells were able to interrupt the ongoing innate immune events in the stepwise progression to cancer. Transfer of regulatory cells into chronically infected mice with established cancer reduced severity of colitis, epithelial dysplasia, and cancer, but did not eliminate all tumors. Regulatory cells lacking anti-inflammatory cytokine interleukin (IL)-10 were unable to inhibit inflammatory bowel disease, dysplasia, or cancer, showing that IL-10 was required for the protective effects of lymphocytes in this setting. Taken together, the data suggest that IL-10-mediated suppression of host innate inflammatory response was pivotal in interrupting carcinogenesis. Regulatory lymphocytes and cytokines may have implications for novel therapies for colon cancer in humans.


Assuntos
Adenocarcinoma/imunologia , Antígenos CD4/imunologia , Linfócitos T CD4-Positivos/imunologia , Neoplasias do Colo/imunologia , Imunoterapia Adotiva/métodos , Interleucina-10/imunologia , Receptores de Interleucina-2/imunologia , Adenocarcinoma/microbiologia , Adenocarcinoma/terapia , Animais , Neoplasias do Colo/microbiologia , Neoplasias do Colo/terapia , Feminino , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter hepaticus , Interleucina-10/deficiência , Masculino , Camundongos , Camundongos Knockout
16.
Eur J Immunol ; 33(10): 2706-16, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14515254

RESUMO

Newer members of the B7-CD28 superfamily include the receptor PD-1 and its two ligands, PD-L1 and PD-L2. Here, we characterize the expression of PD-1, PD-L1, and PD-L2 in tissues of naive miceand in target organs from two models of autoimmunity, the pancreas from non-obese diabetic (NOD) mice and brain from mice with experimental autoimmune encephalomyelitis (EAE). In naive mice, proteiexpression of PD-1, PD-L1, and PD-L2 was detected in the thymus, while PD-1 and PD-L1 were detected in the spleen. PD-L1, but not PD-L2, was also detected at low levels on cardiac endothelium, pancreatic islets, and syncyciotrophoblasts in the placenta. In pre-diabetic NOD mice, PD-1 and PD-L1 were expressed on infiltrating cells in the pancreatic islets. Furthermore, PD-L1 was markedly up-regulated on islet cells. In brains from mice with EAE, PD-1, PD-L1, and PD-L2 were expressed on infiltrating inflammatory cells, and PD-L1 was up-regulated on endothelium within EAE brain. The distinct expression patterns of PD-L1 and PD-L2 led us to compare their transcriptional regulation in STAT4(-/-), STAT6(-/-), or NF-kappaB p50(-/-)p65(+/-) dendritic cells (DC).PD-L2, but not PD-L1, expression was dramatically reduced in p50(-/-)p65(+/-) DC. Thus, PD-L1 and PD-L2 exhibit distinct expression patterns and are differentially regulated on the transcriptional level.


Assuntos
Antígenos de Superfície/análise , Doenças Autoimunes/metabolismo , Antígeno B7-1 , Proteínas Sanguíneas/análise , Peptídeos/análise , Animais , Proteínas Reguladoras de Apoptose , Antígeno B7-H1 , Células CHO , Cricetinae , Encefalomielite Autoimune Experimental/metabolismo , Centro Germinativo/química , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , NF-kappa B/fisiologia , Proteína 2 Ligante de Morte Celular Programada 1 , Receptor de Morte Celular Programada 1 , Fator de Transcrição STAT6 , Baço/química , Timo/química , Transativadores/fisiologia , Transfecção , Regulação para Cima
17.
J Immunol ; 171(3): 1484-92, 2003 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-12874241

RESUMO

We have previously presented evidence demonstrating that mice deficient in NF-kappaB subunits are susceptible to colitis induced by the pathogenic enterohepatic Helicobacter species, H. hepaticus. However, it has not been determined whether NF-kappaB is required within inhibitory lymphocyte populations, within cells of the innate immune system, or both, to suppress inflammation. To examine these issues, we have performed a series of adoptive transfer experiments using recombination-activating gene (Rag)-2(-/-) or p50(-/-)p65(+/-)Rag-2(-/-) mice as hosts for wild-type (WT) and p50(-/-)p65(+/-) lymphocyte populations. We have shown that although the ability of H. hepaticus to induce colitis in Rag-2(-/-) mice is inhibited by the presence of either WT or p50(-/-)p65(+/-) splenocytes, these splenocyte populations are unable to suppress H. hepaticus-induced colitis in p50(-/-)p65(+/-)Rag-2(-/-) mice. Colitis in these animals is characterized by increased expression of inflammatory cytokines including IL-12 p40, and depletion of IL-12 p40 from p50(-/-)p65(+/-) mice ameliorates H. hepaticus-induced disease. Consistent with a primary defect in the regulation of IL-12 expression, H. hepaticus induced markedly higher levels of IL-12 p40 in p50(-/-)p65(+/-) macrophages than in WT macrophages. These results suggest that inhibition of H. hepaticus-induced IL-12 p40 expression by NF-kappaB subunits is critical to preventing colonic inflammation in response to inflammatory microflora.


Assuntos
Colite/microbiologia , Colite/prevenção & controle , Helicobacter/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/biossíntese , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , NF-kappa B/fisiologia , Subunidades Proteicas/antagonistas & inibidores , Subunidades Proteicas/biossíntese , Transferência Adotiva , Animais , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/microbiologia , Colite/genética , Colite/imunologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Soros Imunes/administração & dosagem , Imunidade Inata/genética , Injeções Intraperitoneais , Interleucina-12/imunologia , Subunidade p40 da Interleucina-12 , Mucosa Intestinal/patologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Subpopulações de Linfócitos/transplante , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Subunidades Proteicas/imunologia , Baço/imunologia , Baço/metabolismo , Baço/patologia , Baço/transplante , Regulação para Cima/genética , Regulação para Cima/imunologia
18.
Am J Pathol ; 162(2): 691-702, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12547727

RESUMO

Inflammatory bowel diseases, including ulcerative colitis and Crohn's disease, increase the risk of colorectal cancer in humans. It has been recently shown in humans and animal models that intestinal microbiota and host immunity are integral in the progression of large bowel diseases. Lymphocytes are widely believed to prevent bacterially induced inflammation in the bowel, and lymphocytes are also critical in protecting against primary tumors of intestinal epithelia in mice. Taken together, this raises the possibility that lymphocytes may inhibit colon carcinogenesis by reducing bacterially driven inflammation. To examine the role of bacteria, lymphocytes, and inflammatory bowel disease in the development of colon cancer, 129/SvEv Rag-2-deficient and congenic wild-type mice were orally inoculated with a widespread enteric mouse bacterial pathogen, Helicobacter hepaticus, or sham-dosed with media only. H. hepaticus-infected Rag2-/-, but not sham-dosed Rag2-/- mice, rapidly developed colitis and large bowel carcinoma. This demonstrated a link between microbially driven inflammation and cancer in the lower bowel and suggested that innate immune dysregulation may have an important role in inflammatory bowel disease and progression to cancer. H. hepaticus-infected wild-type mice did not develop inflammation or carcinoma showing that lymphocytes were required to prevent bacterially induced cancer at this site. Adoptive transfer with CD4+ CD45RBlo CD25+ regulatory T cells into Rag-deficient hosts significantly inhibited H. hepaticus-induced inflammation and development of cancer. These results suggested that the ability of CD4+ T cells to protect against intestinal cancer was correlated with their ability to reduce bacterially induced inflammatory bowel disease. Further, regulatory T cells may act directly on the innate immune system to reduce or prevent disease. These roles for T cells in protection against colon carcinoma may have implications for new modes of prevention and treatment of cancer in humans.


Assuntos
Antígenos CD4/imunologia , Neoplasias do Colo/prevenção & controle , Proteínas de Ligação a DNA/fisiologia , Infecções por Helicobacter/complicações , Receptores de Interleucina-2/imunologia , Linfócitos T/imunologia , Transferência Adotiva , Animais , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Transfusão de Linfócitos , Camundongos , Camundongos Knockout , Transposases/deficiência , Transposases/genética , Transposases/fisiologia
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