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1.
Lancet ; 376(9747): 1164-74, 2010 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-20888994

RESUMO

BACKGROUND: On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia. METHODS: Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918. FINDINGS: 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group. INTERPRETATION: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Incidência , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucopenia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Rituximab , Índice de Gravidade de Doença , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
2.
Oncogene ; 26(35): 5046-59, 2007 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-17310986

RESUMO

The phosphoinositide-3-kinase (PI3K)/Akt signaling pathway plays an important role in cell survival and the development of cancer. Macrophage migration inhibitory factor (MIF) is a critical inflammatory cytokine that was recently associated with tumorigenesis and that potently inhibits apoptosis. This may involve inhibition of p53-dependent genes, but the initiating molecular mechanism of how MIF controls survival/apoptosis is unknown. Here, we show that MIF prevents apoptosis and promotes tumor cell survival by directly activating the Akt pathway. MIF enhanced Akt activity in primary and immortalized fibroblasts (MEF and NIH/3T3), HeLa cervix carcinoma cells and various breast cancer cell lines. Activation was abolished by kinase inhibitors Ly294002 and PP2 and in Src/Yes/Fyn(SYF)(-/-) and CD74(-/-)(MEFs), while being enhanced in CD74-overexpressing MEFs, demonstrating that the MIF-induced Akt pathway encompasses signaling through the MIF receptor CD74 and the upstream kinases Src and PI3K. Akt was activated by exogenous rMIF and autocrine MIF action, as revealed by experiments in MIF(-/-)MEFs and antibody blockade. siRNA knockdown of CSN5/JAB1, a tumor marker and MIF-binding protein, showed that JAB1 controls autocrine MIF-mediated Akt signaling by inhibition of MIF secretion. Akt activation by MIF led to phosphorylation of the proapoptotic proteins BAD and Foxo3a. Apoptosis inhibition by MIF was functionally associated with Akt activation as it was abolished by overexpression of the Akt pathway inhibitor PTEN and occurred independently of p53. This was shown by studying DNA damage-induced apoptosis in fibroblasts, the Fas death pathway in HeLa cells that do not express functional p53, and etoposide-induced apoptosis in breast carcinoma cells expressing mutant p53. Importantly, dependence of breast cancer cell survival on MIF correlated with Akt activation and the PTEN status of these cells. Thus, MIF can directly promote cell survival through activation of the PI3K/Akt pathway and this effect is critical for tumor cell survival.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Neoplasias/metabolismo , Peptídeo Hidrolases/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antígenos de Diferenciação de Linfócitos B/metabolismo , Comunicação Autócrina , Neoplasias da Mama/metabolismo , Complexo do Signalossomo COP9 , Linhagem Celular Tumoral , Sobrevivência Celular , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Neoplasias/patologia , Peptídeo Hidrolases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Quinases da Família src/metabolismo
3.
Cell Death Differ ; 12(10): 1319-28, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15947793

RESUMO

Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the Emu-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null Emu-Myc B-cells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type Emu-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Myc-mediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.


Assuntos
Linfoma de Células B/metabolismo , Fatores Inibidores da Migração de Macrófagos/deficiência , Proteínas Proto-Oncogênicas c-myc/fisiologia , Animais , Apoptose/genética , Apoptose/fisiologia , Linfócitos B/citologia , Linfócitos B/metabolismo , Linfócitos B/fisiologia , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição E2F , Feminino , Deleção de Genes , Expressão Gênica , Genes myc/genética , Marcação In Situ das Extremidades Cortadas , Linfoma de Células B/genética , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-myc/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p14ARF/genética , Proteína Supressora de Tumor p14ARF/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
4.
Leukemia ; 18(6): 1093-101, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15071604

RESUMO

Patients with CLL responding to initial chemotherapy with fludarabine alone (F) or in combination with cyclophosphamide (FC) were randomized for treatment with alemtuzumab (30 mg i.v. TIW, 12 weeks) or observation. Of 21 evaluable patients, 11 were randomized to alemtuzumab before the study was stopped due to severe infections in seven of 11 patients. These infections (one life-threatening pulmonary aspergillosis IV; four CMV reactivations III requiring i.v. ganciclovir; one pulmonary tuberculosis III; one herpes zoster III) were successfully treated and not associated with cumulative dose of alemtuzumab. In the observation arm, one herpes zoster infection II and one sinusitis I were documented. At 6 months after randomization, two patients in the alemtuzumab arm converted to CR, while three patients in the observation arm progressed. After alemtuzumab treatment, five of six patients achieved a molecular remission in peripheral blood while all patients in the observation arm remained MRD-positive (P=0.048). At 21.4 months median follow-up, patients receiving alemtuzumab showed a significant longer progression-free survival (no progression vs mean 24.7 months; P=0.036). In conclusion, a consolidation therapy with alemtuzumab is able to achieve molecular remissions and longer survival in CLL, but a safe treatment regimen needs to be determined.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticorpos Antineoplásicos/administração & dosagem , Antineoplásicos/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/efeitos adversos , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Feminino , Alemanha , Humanos , Infecções/etiologia , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/mortalidade , Neutropenia/induzido quimicamente , Indução de Remissão
5.
Shock ; 8(1): 73-5, 1997 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9249916

RESUMO

We describe a patient with self-induced disease who presented with repeated urinary tract infection and sepsis due to intravesical and intravenous injection of feces. Sepsis occurred repeatedly such that the patient exhibited 10 bouts of fever > 40 degrees C in a single month. This bacterial challenge led to massive activation of the monocyte system with high levels of TNF-alpha, IL-6, and monocyte colony-stimulating factor (M-CSF). This cytokine response was followed by strong expansion of the novel CD14+CD16+ monocyte subset. These results suggest that cytokines induce the development of CD14+CD16+ cells in human septicemia and that CD14+CD16+ cells may serve as indicator for previous bouts of excessive inflammation.


Assuntos
Citocinas/biossíntese , Receptores de Lipopolissacarídeos/sangue , Monócitos/imunologia , Receptores de IgG/sangue , Sepse/imunologia , Adulto , Regulação da Temperatura Corporal/fisiologia , Feminino , Humanos , Interleucina-6/sangue , Monócitos/metabolismo , Fenótipo , Sepse/sangue , Sepse/etiologia , Fatores de Tempo
6.
J Thorac Cardiovasc Surg ; 115(5): 1172-8, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9605088

RESUMO

OBJECTIVES: Major operative trauma like aorta-coronary bypass operation may lead to postoperative immunodisturbance, putting the patient at an increased risk for infection and sepsis. The monocyte/macrophage system and the endotoxin receptor CD14 are important in the early recognition and elimination of invading bacteria. The aim of this study was to analyze changes in membrane-associated CD14 and soluble CD14 during and after cardiac involving cardiopulmonary bypass. METHODS: We studied numbers of leukocytes, monocytes, and monocyte subpopulations, expression of monocyte membrane-associated CD14 and plasma levels of soluble CD14 in 10 patients (63 +/- 8 years of age), who underwent elective cardiopulmonary bypass. RESULTS: Cardiopulmonary bypass induced marked postoperative monocytosis, which was maximal 20 hours after the operation (485 +/- 242 cells/microl before, 1080 +/- 264 cells/microl 20 hours after surgery). Expression of membrane-associated CD14 on classical CD14++ monocytes decreased significantly by 40%, reaching a nadir 20 hours after surgery (p < 0.05). At the time of maximal membrane-associated CD14 suppression, the levels of soluble CD14 measured by enzyme-linked immunosorbent assay were clearly increased (3.2 +/- 1.0 microg/ml before versus 5.6 +/- 1.0 microg/ml 20 hours after, p < 0.001). No significant change of the percentage of small (alpha) and large (beta) forms of soluble CD14 was found. CONCLUSIONS: Cardiopulmonary bypass leads to reduced membrane-associated CD14 expression on peripheral blood monocytes and increased levels of soluble CD14 through shedding or secretion of membrane-associated CD14 from the cell surface. These findings indicate that bypass is associated with significant monocyte activation.


Assuntos
Ponte Cardiopulmonar , Ponte de Artéria Coronária/métodos , Doença das Coronárias/cirurgia , Regulação para Baixo/fisiologia , Receptores de Lipopolissacarídeos/metabolismo , Monócitos/metabolismo , Western Blotting , Doença das Coronárias/sangue , Doença das Coronárias/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Monócitos/citologia , Monócitos/imunologia , Receptores de IgG/metabolismo
7.
Inflammation ; 22(4): 367-79, 1998 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-9675608

RESUMO

We have asked whether critically ill cardiac valve surgery patients identified by a high APACHE II score exhibit an increase in the number of proinflammatory CD14+CD16+ monocytes. A group of 12 patients was studied over a period of 5 days post cardiac valve surgery for changes in blood monocyte populations. Patients were selected on day 1 post surgery to either be in good clinical condition (APACHE II Score of < or = 14; N = 9) or to be critically ill (APACHE II score of > or = 24; N = 3). The < or = 14 patients had an uneventful course and could leave the ICU after 2-3 days. Among the > or = 24 patients two showed a decrease of the score to < or = 14 within the 5 days of observation and they could leave the ICU thereafter. One > or = 24 patient (patient #2) had a persistently high score and finally died on day 28. Analysis of blood monocytes on day 1 post surgery revealed that the < or = 14 patients had normal values of CD14+CD16+ monocytes (44 +/- 9/microliter). By contrast the > or = 24 patients had increased values of these cells with 243 +/- 106 cells per microliter on day 1. The numbers of CD14+CD16+ monocytes returned to the control range over the 5 days of observation in 2 of the > or = 24 patients concomitant with the improvement of the APACHE II score. CD14+CD16+ monocytes remained, however, at a high level in patient #2, the patient with persistently high APACHE II score.


Assuntos
Implante de Prótese de Valva Cardíaca/efeitos adversos , Inflamação/sangue , Inflamação/etiologia , Monócitos/imunologia , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , APACHE , Idoso , Estudos de Casos e Controles , Estado Terminal , Feminino , Antígenos HLA-DR/sangue , Humanos , Interleucina-6/sangue , Contagem de Leucócitos , Receptores de Lipopolissacarídeos/sangue , Fator Estimulador de Colônias de Macrófagos/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/patologia , Estudos Prospectivos , Receptores de IgG/sangue , Sepse/sangue , Sepse/etiologia , Fator de Necrose Tumoral alfa/metabolismo
8.
Int J Hematol ; 93(6): 791-794, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21553020

RESUMO

Bortezomib is a proteasome inhibitor demonstrating substantial activity in multiple myeloma. One of its key toxicities is peripheral neuropathy, which is reversible in most patients. The possibility that bortezomib might in rare cases induce severe neuropathies by auto-inflammatory mechanisms remains controversial. We report here the case of a 65-year-old female myeloma patient who was initially treated with bortezomib, doxorubicin, and dexamethasone (PAD). At the end of the second cycle of PAD, the patient presented with a rapid and severe onset of paresis of the left arm, accompanied by progressive sensory neuropathy and increasing neuropathic pain. After an extensive neurological work-up, including electrophysiological and laboratory evaluations as well as magnet resonance tomography imaging, we diagnosed an inflammatory autoimmune neuropathy, presumably induced by bortezomib, with accentuation of the left arm nerve plexus. We subsequently initiated regular treatment with polyvalent immunoglobulins, which gradually improved the neurological symptoms. In conclusion, the identification of an inflammatory autoimmune neuropathy, presumably associated with bortezomib, is a rare but important complication. An extensive neurological examination should be performed in patients who develop severe or unusual sensory or motor deficits under therapy with bortezomib, so as to differentiate autoimmune from toxic neuropathies, as therapeutic strategies differ for each.


Assuntos
Antineoplásicos , Doenças Autoimunes , Ácidos Borônicos , Mieloma Múltiplo/complicações , Mieloma Múltiplo/terapia , Doenças do Sistema Nervoso Periférico , Pirazinas , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/etiologia , Ácidos Borônicos/efeitos adversos , Ácidos Borônicos/uso terapêutico , Bortezomib , Feminino , Humanos , Imageamento por Ressonância Magnética , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Transplante de Células-Tronco de Sangue Periférico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/diagnóstico , Doenças do Sistema Nervoso Periférico/etiologia , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Transplante Autólogo , Resultado do Tratamento
11.
MMW Fortschr Med ; 145(27-28): 46-9, 2003 Jul 10.
Artigo em Alemão | MEDLINE | ID: mdl-14587189
12.
Leukemia ; 23(11): 2007-17, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19641522

RESUMO

Rituximab-containing regimens are becoming a therapeutic standard in chronic lymphocytic leukemia (CLL), so that a validation of flow cytometric minimal residual disease (MRD) quantification (MRD flow) in the presence of this antibody is necessary. We therefore compared results obtained by real-time quantitative (RQ)-PCR to MRD flow in 530 samples from 69 patients randomized to receive chemotherapy or chemotherapy plus rituximab. Quantitative MRD levels assessed by both techniques were closely correlated irrespective of therapy (r=0.95). The sensitivity and specificity of MRD flow was not influenced by the presence of rituximab. With 58.9% positive and 26.4% negative samples by both techniques, 85.3% of assessments (452/530) were qualitatively concordant between MRD flow and RQ-PCR. Discordant samples were typically negative by MRD flow and simultaneously positive close to the detection limit of the PCR assays, indicating a higher sensitivity of PCR for very low MRD levels. However, 93.8% of all samples were concordantly classified by both methods using a threshold of 10(-4) to determine MRD positivity. MRD flow and PCR are equally effective for MRD quantification in rituximab-treated CLL patients within a sensitivity range of up to 10(-4), whereas PCR is more sensitive for detecting MRD below that level.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos/normas , Citometria de Fluxo/normas , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Monitoramento de Medicamentos/métodos , Feminino , Citometria de Fluxo/métodos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamento farmacológico , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rituximab , Sensibilidade e Especificidade
14.
Immunol Cell Biol ; 79(4): 368-75, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11488984

RESUMO

The cytokine macrophage migration inhibitory factor (MIF) is produced by neuroendocrine and immune tissues and possesses several features that allow it to be characterized as a neuroendocrine mediator. Its pro-inflammatory action and its pathogenic role in inflammatory diseases, such as septic shock, arthritis and other diseases, have clearly been demonstrated and may be based in part on neuroendocrine mechanisms. Macrophage migration inhibitory factor possesses glucocorticoid-antagonist properties within the immune system and participates in the regulation of several endocrine circuits. This review summarizes the current state of MIF research and focuses on MIF expression and function in nervous and endocrine tissues.


Assuntos
Fatores Inibidores da Migração de Macrófagos/fisiologia , Sistemas Neurossecretores/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Feminino , Glucocorticoides/antagonistas & inibidores , Humanos , Mediadores da Inflamação/metabolismo , Fatores Inibidores da Migração de Macrófagos/química , Fatores Inibidores da Migração de Macrófagos/genética , Fatores Inibidores da Migração de Macrófagos/imunologia , Masculino , Sistemas Neurossecretores/química , Sistemas Neurossecretores/imunologia , Filogenia , Reprodução/fisiologia
15.
Clin Exp Immunol ; 112(3): 501-6, 1998 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9649222

RESUMO

Glucocorticoids (GC) are potent anti-inflammatory and immunosuppressive agents that act on many cells of the body, including monocytes. Here we show that a 5-day course of high dose GC therapy differentially affected the CD14++ and the CD14+ CD16+ monocyte subpopulations in 10 patients treated for multiple sclerosis. While the classical (CD14++) monocytes exhibited a substantial increase from 495 +/- 132 to 755 +/- 337 cells/microl, the CD14+ CD16+ monocytes responded with a pronounced decrease from 36 +/- 15 to 2 +/- 3 cells/microl (P < 0.001). In 4/10 patients the CD14+ CD16+ monocytes fell below detection limits (<0.2 cells/microl). This observation was confirmed when the CD14+ CD16+ monocytes were identified by virtue of their low CD33 expression as these cells decreased as well. After discontinuation of GC therapy the CD14+ CD16+ monocytes reappeared and reached normal levels after 1 week. The profound depletion of CD14+ CD16+ monocytes by GC as described here is a novel effect of GC action in vivo and may contribute to GC-mediated immunosuppression. Determination of the number of this monocyte subset may also serve to monitor the effectiveness of GC therapy in patients requiring immunosuppressive treatment.


Assuntos
Glucocorticoides/administração & dosagem , Terapia de Imunossupressão , Imunossupressores/administração & dosagem , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Receptores de IgG/imunologia , Adulto , Feminino , Citometria de Fluxo , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia
16.
Proc Natl Acad Sci U S A ; 100(16): 9354-9, 2003 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-12878730

RESUMO

Macrophage migration inhibitory factor (MIF) is a mediator of host immunity and functions as a high, upstream activator of cells within the innate and the adaptive immunological systems. Recent studies have suggested a potentially broader role for MIF in growth regulation because of its ability to antagonize p53-mediated gene activation and apoptosis. To better understand MIF's activity in growth control, we generated and characterized a strain of MIF-knockout (MIF-KO) mice in the inbred, C57BL/6 background. Embryonic fibroblasts from MIF-KO mice exhibit p53-dependent growth alterations, increased p53 transcriptional activity, and resistance to ras-mediated transformation. Concurrent deletion of the p53 gene in vivo reversed the observed phenotype of cells deficient in MIF. In vivo studies showed that fibrosarcomas induced by the carcinogen benzo[alpha]pyrene are smaller in size and have a lower mitotic index in MIF-KO mice relative to their WT counterparts. The data provide direct genetic evidence for a functional link between MIF and the p53 tumor suppressor and indicate an important and previously unappreciated role for MIF in carcinogenesis.


Assuntos
Técnicas de Transferência de Genes , Fatores Inibidores da Migração de Macrófagos/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Alelos , Animais , Benzo(a)pireno , Carcinógenos , Dano ao DNA , Éxons , Fibroblastos/metabolismo , Fibrossarcoma/genética , Fibrossarcoma/patologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Genéticos , Mutação , Fenótipo , Retroviridae/genética , Fatores de Tempo , Transcrição Gênica , Ativação Transcricional , Proteína Supressora de Tumor p53/metabolismo
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