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3.
Clin Infect Dis ; 33(10): 1782-5, 2001 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-11641829

RESUMO

A human immunodeficiency virus-negative woman with severe classic Kaposi's sarcoma, idiopathic leukopenia, and massive spread of human herpesvirus 8 (HHV-8) in circulating cells showed stable disease remission in response to systemic interferon-alpha treatment that was accompanied by increased CD3(+) and CD4(+) T cell numbers and complete clearance of HHV-8 from the circulation. These results suggest a direct relationship between HHV-8 clearance from blood and regression of Kaposi's sarcoma and are consistent with the in vitro inhibitory effects of interferon-alpha on HHV-8 infection.


Assuntos
Antivirais/uso terapêutico , DNA Viral/sangue , Herpesvirus Humano 8/fisiologia , Interferon-alfa/uso terapêutico , Leucopenia/complicações , Sarcoma de Kaposi/tratamento farmacológico , Feminino , Soronegatividade para HIV , Herpesvirus Humano 8/isolamento & purificação , Humanos , Interferon alfa-2 , Leucopenia/tratamento farmacológico , Proteínas Recombinantes , Sarcoma de Kaposi/virologia , Resultado do Tratamento
4.
Mol Biol Cell ; 12(10): 2934-46, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11598182

RESUMO

Previous studies indicated that the Tat protein of human immunodeficiency virus type-1 (HIV-1) is a progression factor for Kaposi's sarcoma (KS). Specifically, extracellular Tat cooperates with basic fibroblast growth factor (bFGF) in promoting KS and endothelial cell growth and locomotion and in inducing KS-like lesions in vivo. Here we show that Tat and bFGF combined increase matrix-metalloproteinase-2 (MMP-2) secretion and activation in endothelial cells in an additive/synergistic manner. These effects are due to the activation of the membrane-type-1-matrix-metalloproteinase and to the induction of the membrane-bound tissue inhibitor of metalloproteinase-2 (TIMP-2) by Tat and bFGF combined, but also to Tat-mediated inhibition of both basal or bFGF-induced TIMP-1 and -2 secretion. Consistent with this, Tat and bFGF promote vascular permeability and edema in vivo that are blocked by a synthetic MMP inhibitor. Finally, high MMP-2 expression is detected in acquired immunodeficiency virus syndrome (AIDS)-KS lesions, and increased levels of MMP-2 are found in plasma from patients with AIDS-KS compared with HIV-uninfected individuals with classic KS, indicating that these mechanisms are operative in AIDS-KS. This suggests a novel pathway by which Tat can increase KS aggressiveness or induce vasculopathy in the setting of HIV-1 infection.


Assuntos
Endotélio Vascular/enzimologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Produtos do Gene tat/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloendopeptidases/metabolismo , Síndrome da Imunodeficiência Adquirida/enzimologia , Animais , Permeabilidade Capilar/fisiologia , Células Cultivadas , Edema/metabolismo , Endotélio Vascular/citologia , Ativação Enzimática/fisiologia , Cobaias , Humanos , Pulmão/citologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinases da Matriz Associadas à Membrana , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Sarcoma de Kaposi/enzimologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana
5.
AIDS Res Hum Retroviruses ; 17(11): 1035-9, 2001 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-11485620

RESUMO

HIV-1-infected patients develop a generalized vasculopathy that is clinically most evident as Kaposi's sarcoma (KS), a multifocally appearing endothelial cell-derived tumor. Fibroblast growth factor 2 (FGF-2) is a potent autocrine and paracrine mitogen of endothelial cells and has been implicated in the cell proliferation and angiogenesis observed in KS. Here we determined by ELISA the FGF-2 serum concentrations in different clinical groups of HIV-1-infected patients. AIDS-KS patients (n = 53) and HIV-1-infected patients without KS (n = 39) revealed significantly increased FGF-2 serum concentrations (median, 4.5 and 4.6 pg/ml, respectively), as compared with the healthy control group (n = 22; median, 2.2 pg/ml; p < 0.01). FGF-2 concentrations were highest in untreated HIV-1-infected patients (median, 8.6 pg/ml) and were significantly decreased in patients undergoing antiretroviral therapy (AZT-median, 4.5 pg/ml; HAART-median, 2.5 pg/ml; p < 0.01). In addition, FGF-2 serum concentrations above 5.2 pg/ml were associated with a statistically significant higher risk of death in HIV-1-infected patients. Multivariate analysis showed that this effect is independent of CD4 levels, localization of KS (cutaneous or visceral), AIDS-defining opportunistic diseases, and therapy. Circulating FGF-2 may contribute to AIDS-associated vasculopathy and may be a sensitive and easily accessible surrogate marker to determine the survival time of HIV-1-infected patients and the efficacy of antiretroviral therapy.


Assuntos
Fator 2 de Crescimento de Fibroblastos/sangue , Infecções por HIV/sangue , HIV-1 , Sarcoma de Kaposi/complicações , Neoplasias Cutâneas/complicações , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Ensaio de Imunoadsorção Enzimática , Infecções por HIV/mortalidade , HIV-1/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
6.
Eur J Cancer ; 37(10): 1251-69, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11423257

RESUMO

Kaposi's sarcoma (KS) is an angioproliferative disease occurring in several different clinical-epidemiological forms that, however, share the same histological traits and are all associated with infection by the human herpesvirus 8 (HHV8). KS initiates in a context of immune dysregulation characterised by CD8+ T cell activation and the production of Th1-type cytokines that induce a generalised activation of endothelial cells leading to adhesion and tissue extravasation of lympho-monocytes, spindle cell formation and angiogenesis. These phenomena are triggered or enhanced by infection with HHV8 that, in turn, is reactivated by the same cytokines. Productively-infected circulating cells are recruited into 'activated' tissue sites where HHV8 finds an optimal environment for establishing a persistent, latent infection of KS spindle cells (KSC). HHV8 dissemination is favoured by virus escape mechanisms and immune dysregulation, and leads to immune responses that are not effective against the virus but, paradoxically, exacerbates the reactive process. Although early KS is a reactive process of polyclonal nature that can regress, in time it can progress in to a true sarcoma. The progression of KS appears to be due to the deregulated expression of oncogenes and oncosuppressor genes, to the long-lasting expression of the HHV8 latency genes and, for AIDS-KS, is promoted by the proliferative and angiogenic effects of the HIV-1 Tat protein.


Assuntos
Herpesvirus Humano 8 , Peptídeos e Proteínas de Sinalização Intracelular , Sarcoma de Kaposi/imunologia , Antígenos Virais , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD , Proteínas de Transporte/imunologia , Ciclinas/imunologia , Citocinas/imunologia , Progressão da Doença , Produtos do Gene tat/imunologia , Humanos , Proteínas Nucleares/imunologia , Fatores de Risco , Sarcoma de Kaposi/patologia , Células Th1/imunologia , Proteínas Virais
7.
J Leukoc Biol ; 69(5): 779-84, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11358987

RESUMO

Human Epstein-Barr virus (EBV)-negative Burkitt lymphomas cells usually grow as malignant subcutaneous tumors in athymic mice, but these tumors regress when the Burkitt cells are injected in conjunction with EBV-positive lymphoblastoid cells or when the Burkitt cells are transfected with the EBV latent membrane protein-1 (LMP-1) gene. Tumor regression is mediated, in part, by murine interferon gamma (IFN-gamma) and the IFN-gamma-induced murine chemokine IFN-gamma-inducible protein-10 (IP-10). The mechanisms by which EBV-LMP-1 promotes the expression of IFN-gamma has remained unclear. Here we show that murine interleukin (IL)-18 was consistently expressed in regressing Burkitt tumors but was either expressed at low levels or absent from progressively growing Burkitt tumors. By immunohistochemical methods, IL-18 protein was visualized in regressing but not in progressively growing Burkitt tumors. In contrast, IL-12 p35 and IL-12 p40 were only rarely expressed in regressing Burkitt tumors. In splenocyte cultures, EBV-infected lymphoblastoid cells and LMP-1-transfected Burkitt cells promoted the expression of IL-18 but not the expression of IL-12 p35 and IL-12 p40. A neutralizing antibody directed at murine IL-18 reduced murine IP-10 expression induced by EBV-immortalized cells in splenocyte cultures. These results provide evidence for IL-18 expression in response to a viral latency protein and suggest that IL-18 may play an important role as an endogenous inducer of IFN-gamma expression, thereby contributing to tumor regression.


Assuntos
Linfoma de Burkitt/imunologia , Herpesvirus Humano 4/imunologia , Interleucina-18/imunologia , Animais , Quimiocina CXCL10 , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Feminino , Expressão Gênica , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-18/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Baço/citologia , Baço/imunologia , Células Tumorais Cultivadas
8.
J Immunol ; 165(1): 509-17, 2000 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-10861090

RESUMO

Kaposi's sarcoma (KS) is an angioproliferative disease characterized by proliferation of spindle-shaped cells predominantly of endothelial cell origin, neoangiogenesis, inflammatory cell infiltration, and edema. At least in early stage, KS behaves as a reactive lesion sustained by the action of inflammatory cytokines and growth factors, has a polyclonal nature, and can regress. However, in time it can become monoclonal, especially in the nodular stage, evolving into a true sarcoma, likely in association with the increased expression of antiapoptotic oncogenes. We have recently demonstrated by immunohistochemical analysis that Bcl-2, a proto-oncogene known to prolong cellular viability and to antagonize apoptosis, is highly expressed in spindle cells and vessels of both AIDS-KS and classical KS lesions and that its expression increases with lesion stage. Paclitaxel, a microtubule-stabilizing drug known to inhibit Bcl-2 antiapoptotic activity and to be highly effective in the treatment of certain neoplasms, has recently been found to be active also in patients with advanced HIV-associated KS. In this report we investigated the mechanism(s) of paclitaxel activity in KS. By using a model of experimental KS induced by the inoculation of KS-derived spindle cells in nude mice and primary cultures of KS spindle cells, we found that paclitaxel promotes regression of KS lesions in vivo and that it blocks the growth, migration, and invasion of KS cells in vitro. Furthermore, paclitaxel treatment promoted apoptosis and down-regulated Bcl-2 protein expression in KS cells in vitro and in KS-like lesions in mice. Our results suggest that paclitaxel interferes with KS by down-regulating Bcl-2 antiapoptotic effect.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Paclitaxel/farmacologia , Sarcoma de Kaposi/tratamento farmacológico , Sarcoma de Kaposi/patologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Inibidores do Crescimento/administração & dosagem , Inibidores do Crescimento/farmacologia , Humanos , Camundongos , Camundongos Nus , Invasividade Neoplásica , Transplante de Neoplasias , Paclitaxel/administração & dosagem , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Sarcoma Experimental/tratamento farmacológico , Sarcoma Experimental/metabolismo , Sarcoma Experimental/patologia , Sarcoma de Kaposi/metabolismo , Células Tumorais Cultivadas/efeitos dos fármacos , Células Tumorais Cultivadas/metabolismo , Células Tumorais Cultivadas/patologia
9.
J Immunol ; 163(4): 1929-35, 1999 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-10438928

RESUMO

The Tat protein of HIV-1, a transactivator of viral gene expression, is released by acutely infected T cells and, in this form, exerts angiogenic activities. These have linked the protein to the pathogenesis of Kaposi's sarcoma (KS), a vascular tumor frequent and aggressive in HIV-1-infected individuals (AIDS-KS). In this study, we show that a combination of the same inflammatory cytokines increased in KS lesions, namely IL-1 beta, TNF-alpha, and IFN-gamma, synergizes with Tat to promote in nude mice the development of angioproliferative KS-like lesions that are not observed with each factor alone. Inflammatory cytokines induce the tissue expression of both basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), two angiogenic molecules highly produced in primary KS lesions. However, bFGF, but not VEGF, synergizes with Tat in vivo and induces endothelial cells to migrate, to adhere, and to grow in response to Tat in vitro. Tat angiogenic effects correlate with the expression of the alpha v beta 3 integrin that is induced by bFGF and binds the arginine-glycine-aspartic acid (RGD) region of Tat. In contrast, no correlation is observed with the expression of alpha v beta 5, which is promoted by VEGF and binds Tat basic region. Finally, KS lesion formation induced by bFGF and Tat in nude mice is blocked by antagonists of RGD-binding integrins. Because alpha v beta 3 is an RGD-binding integrin that is highly expressed in primary KS lesions, where it colocalizes with extracellular Tat on vessels and spindle cells, these results suggest that alpha v beta 3 competitors may represent a new strategy for the treatment of AIDS-KS.


Assuntos
Citocinas/fisiologia , Fator 2 de Crescimento de Fibroblastos/biossíntese , Produtos do Gene tat/fisiologia , HIV-1/fisiologia , Cadeias beta de Integrinas , Neovascularização Fisiológica/imunologia , Receptores de Vitronectina/biossíntese , Sarcoma de Kaposi/imunologia , Animais , Antígenos CD/biossíntese , Antígenos CD/metabolismo , Adesão Celular/imunologia , Divisão Celular/imunologia , Linhagem Celular , Movimento Celular/imunologia , Citocinas/administração & dosagem , Sinergismo Farmacológico , Fatores de Crescimento Endotelial/biossíntese , Endotélio Vascular/citologia , Endotélio Vascular/imunologia , Endotélio Vascular/fisiologia , Endotélio Vascular/virologia , Fator 2 de Crescimento de Fibroblastos/fisiologia , Produtos do Gene tat/administração & dosagem , Humanos , Injeções Subcutâneas , Integrina beta3 , Integrinas/biossíntese , Integrinas/metabolismo , Linfocinas/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Oligopeptídeos/metabolismo , Glicoproteínas da Membrana de Plaquetas/biossíntese , Glicoproteínas da Membrana de Plaquetas/metabolismo , Receptores de Vitronectina/metabolismo , Receptores de Vitronectina/fisiologia , Sarcoma de Kaposi/etiologia , Sarcoma de Kaposi/patologia , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Produtos do Gene tat do Vírus da Imunodeficiência Humana
10.
Blood ; 94(2): 663-72, 1999 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-10397733

RESUMO

The Tat protein of human immunodeficiency virus type-1 (HIV-1) has been shown to be released during acute infection of T cells by HIV-1 and to promote angiogenesis and Kaposi's sarcoma (KS) development in infected individuals. In this study, we investigated the molecular mechanisms responsible for the angiogenic effects of Tat. The results shown herein indicate that two different Tat domains cooperate to induce these effects by different pathways. The arginine-glycine-aspartic acid (RGD) sequence present at the carboxyterminal of Tat mediates vascular cell migration and invasion by binding to the alpha5beta1 and alphavbeta3 integrins. This interaction also provides endothelial cells with the adhesion signal they require to grow in response to mitogens. At the same time, the Tat basic sequence retrieves into a soluble form extracellular basic fibroblast growth factor (bFGF) bound to heparan sulfate proteoglycans by competing for heparin-binding sites. This soluble bFGF mediates Tat-induced vascular cell growth. These effects resemble those of extracellular matrix proteins, suggesting that Tat enhances angiogenesis and promotes KS progression by a molecular mimicry of these molecules.


Assuntos
Endotélio Vascular/citologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Produtos do Gene tat/fisiologia , HIV-1/fisiologia , Neovascularização Patológica/virologia , Receptores de Fibronectina/fisiologia , Receptores de Vitronectina/fisiologia , Ligação Competitiva , Adesão Celular/fisiologia , Divisão Celular , Movimento Celular , Citocinas/farmacologia , Proteínas da Matriz Extracelular/fisiologia , Produtos do Gene tat/química , Genes tat , HIV-1/genética , Proteoglicanas de Heparan Sulfato/metabolismo , Humanos , Substâncias Macromoleculares , Mimetismo Molecular , Oligopeptídeos/fisiologia , Fragmentos de Peptídeos/farmacologia , Conformação Proteica , Proteínas Recombinantes/farmacologia , Sarcoma de Kaposi/patologia , Neoplasias Cutâneas/patologia , Solubilidade , Produtos do Gene tat do Vírus da Imunodeficiência Humana
11.
Blood ; 93(12): 4044-58, 1999 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-10361101

RESUMO

Patients with Kaposi's sarcoma (KS) have a human herpesvirus-8 (HHV-8) load higher than patients without KS and present a CD8(+) T-cell activation with production of Th1-type cytokines both in tissues and peripheral blood mononuclear cells (PBMC). Because in tissues of KS patients detection of inflammatory cytokines (IC) can precede detection of HHV-8 DNA and because signs of immunoactivation and/or dysregulation can precede KS development, we investigated the effect of IC on HHV-8 infection. To achieve this goal, PBMC and purified cell populations from 45 patients with KS and 45 patients at risk of KS were analyzed for HHV-8 DNA and/or gene expression and for cell survival, growth, and phenotype before or after culture with or without the IC increased in KS. The results indicate that PBMC that are polymerase chain reaction (PCR)-positive at day 0 generally loose the virus upon culture. However, the presence of IC maintains HHV-8 DNA load in cultured cells. In addition, IC increase viral load to detectable levels in PBMC from serologically positive patients that were PCR-negative before culture. gamma Interferon is sufficient for these effects, whereas tumor necrosis factor and interleukin-6 have little or no activity. The increase of HHV-8 DNA by IC is observed after short-term (7 days) or long-term (28 days) culture of the cells and occurs in one or both of the two circulating cell types that are infected in vivo: B cells and monocytes. In both cases it is associated with lytic gene expression, suggesting that virus reactivation is one of the most likely mechanisms for the effect of IC on virus load. However, IC have also effects on the cells target of HHV-8 infection, because they increase B-cell survival and induce the growth and differentiation of monocytes into KS-like spindle cells with markers of endothelial macrophages. Because cells with markers of endothelial macrophages are present in blood and lesions from KS patients and are infected by HHV-8, these data may explain the high HHV-8 load associated with KS development and suggest that infected monocytes may carry the virus to tissues, transmit the infection, or differentiate in loco in spindle cells with endothelial macrophage markers.


Assuntos
Linfócitos B/virologia , Citocinas/farmacologia , Herpesvirus Humano 8/crescimento & desenvolvimento , Monócitos/virologia , Sarcoma de Kaposi/metabolismo , Ativação Viral , Síndrome da Imunodeficiência Adquirida/complicações , Linfócitos B/citologia , Divisão Celular , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , DNA Viral/análise , Herpesvirus Humano 8/genética , Humanos , Masculino , Monócitos/citologia , Fenótipo , Reação em Cadeia da Polimerase , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/virologia
12.
J Virol ; 73(5): 4029-41, 1999 May.
Artigo em Inglês | MEDLINE | ID: mdl-10196299

RESUMO

Infection by human herpesvirus 8 (HHV-8) is associated with the development of Kaposi's sarcoma (KS). Since regression of KS can be achieved by treatment of the patients with alpha interferon (IFN-alpha), we analyzed the effects of IFN-alpha or anti-IFN-alpha antibodies (Ab) on HHV-8 latently infected primary effusion lymphoma-derived cell lines (BCBL-1 and BC-1) and on peripheral blood mononuclear cells (PBMC) from patients with all forms of KS and from at-risk subjects. IFN-alpha inhibited in a dose-dependent manner the amplification of HHV-8 DNA in BCBL-1 cells induced to lytic infection with tetradecanoyl phorbol acetate (TPA). This effect was associated with the inhibition of the expression of HHV-8 nut-1 and kaposin genes that are induced early and several hours, respectively, after TPA treatment. In addition, IFN-alpha inhibited virus production and/or release from BCBL-1 cells. Inhibition of nut-1 and kaposin genes by IFN-alpha was also observed in BC-1 cells induced with n-butyrate. Conversely, the addition of anti-IFN-alpha Ab to TPA-induced BCBL-1 cells resulted in a larger number of mature enveloped particles and in a more extensive cytopathic effect due to the neutralization of the endogenous IFN produced by these cells. IFN was also produced by cultured PBMC from HHV-8-infected individuals, and this was associated with a loss of viral DNA during culture. However, the addition of anti-IFN-alpha Ab or anti-type I IFN receptor Ab promoted the maintenance of HHV-8 DNA in these cells that was associated with the detection of the latency-associated kaposin RNA. Finally, the addition of IFN-alpha reduced the HHV-8 load in PBMC. Thus, IFN-alpha appears to have inhibitory effects on HHV-8 persistent infection of PBMC. These results suggest that, in addition to inhibiting the expression of angiogenic factors that are key to KS development, IFN-alpha may induce KS regression by reducing the HHV-8 load and/or inhibiting virus reactivation.


Assuntos
Herpesvirus Humano 8/imunologia , Interferon-alfa/imunologia , Genes Virais , Herpesvirus Humano 8/crescimento & desenvolvimento , Humanos , Interferon alfa-2 , Interferon-alfa/farmacologia , Leucócitos Mononucleares/virologia , Linfoma , Masculino , Morfogênese , Proteínas Recombinantes , Acetato de Tetradecanoilforbol/farmacologia , Células Tumorais Cultivadas , Carga Viral , Vírion , Ativação Viral
13.
Blood ; 93(5): 1612-21, 1999 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-10029590

RESUMO

Interleukin-12 (IL-12) inhibits angiogenesis in vivo by inducing interferon-gamma (IFN-gamma) and other downstream mediators. Here, we report that neutralization of natural killer (NK) cell function with antibodies to either asialo GM1 or NK 1.1 reversed IL-12 inhibition of basic fibroblast growth factor (bFGF)-induced angiogenesis in athymic mice. By immunohistochemistry, those sites where bFGF-induced neovascularization was inhibited by IL-12 displayed accumulation of NK cells and the presence of IP-10-positive cells. Based on expression of the cytolytic mediators perforin and granzyme B, the NK cells were locally activated. Experimental Burkitt lymphomas treated locally with IL-12 displayed tumor tissue necrosis, vascular damage, and NK-cell infiltration surrounding small vessels. After activation in vitro with IL-12, NK cells from nude mice became strongly cytotoxic for primary cultures of syngeneic aortic endothelial cells. Cytotoxicity was neutralized by antibodies to IFN-gamma. These results document that NK cells are required mediators of angiogenesis inhibition by IL-12, and provide evidence that NK-cell cytotoxicity of endothelial cells is a potential mechanism by which IL-12 can suppress neovascularization.


Assuntos
Interleucina-12/imunologia , Células Matadoras Naturais/imunologia , Neovascularização Fisiológica/imunologia , Animais , Citotoxicidade Imunológica , Feminino , Fator 2 de Crescimento de Fibroblastos/farmacologia , Interleucina-12/farmacologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neovascularização Fisiológica/efeitos dos fármacos
14.
J Immunol ; 162(2): 1165-70, 1999 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-9916748

RESUMO

Previous studies indicated that the Tat protein of HIV functions as a progression factor in Kaposi's sarcoma (KS), an angioproliferative disease common and aggressive in HIV-1-infected individuals (AIDS-KS). In particular, Tat that is released by infected cells stimulates the growth and invasion of spindle cells of endothelial origin derived from KS lesions (KS cells). Other work suggested that inflammatory cytokines may act as initiating factors in KS since they induce normal endothelial cells to acquire the same phenotype and functional features of KS cells, including the responsiveness to Tat. In this study, we show that among the inflammatory cytokines increased in AIDS-KS lesions, IFN-gamma alone is sufficient to induce endothelial cells to proliferate and to invade the extracellular matrix in response to Tat. This is because IFN-gamma up-regulates the expression and activity of the receptors for Tat identified as the integrins alpha5beta1 and alpha(v)beta3. These results suggest that, by triggering Tat effects, IFN-gamma plays a major role in AIDS-KS pathogenesis.


Assuntos
Síndrome da Imunodeficiência Adquirida/patologia , Movimento Celular/imunologia , Endotélio Vascular/patologia , Matriz Extracelular/patologia , Produtos do Gene tat/fisiologia , Interferon gama/fisiologia , Sarcoma de Kaposi/etiologia , Síndrome da Imunodeficiência Adquirida/virologia , Divisão Celular/imunologia , Células Cultivadas , Endotélio Vascular/virologia , Matriz Extracelular/virologia , Produtos do Gene tat/metabolismo , Substâncias de Crescimento/fisiologia , HIV-1/fisiologia , Humanos , Receptores de Fibronectina/biossíntese , Receptores de Fibronectina/fisiologia , Receptores Virais/biossíntese , Receptores Virais/fisiologia , Receptores de Vitronectina/biossíntese , Receptores de Vitronectina/fisiologia , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia , Veias Umbilicais , Regulação para Cima/imunologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana
16.
J Leukoc Biol ; 64(3): 384-92, 1998 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-9738666

RESUMO

The mechanisms by which interleukin-12 (IL-12) exerts antitumor effects have been difficult to dissect. In this study, we examined the potential contribution of the chemokines interferon-gamma-inducible protein-10 (IP-10) and Mig to the antitumor effects of IL-12. Using an athymic mouse model, local inoculations with IL-12 consistently produced tumor size reductions associated with characteristic tumor necrosis and vascular damage. These effects were indistinguishable from those produced by IP-10 or Mig injected locally in the same tumor model. Local and systemic treatment with IL-12 was associated with expression of the interferon-gamma (IFN-gamma), IP-10, and Mig genes and proteins in the tumor. Levels of IP-10 and Mig expression in the tumor, the liver, and the kidney were inversely correlated with tumor size. Administration in vivo of neutralizing antibodies to IP-10 and Mig reduced substantially the antitumor effects of IL-12 inoculated locally into the tumors. These results support the notion that IP-10 and Mig contribute to the antitumor effects of IL-12 through their inhibitory effects on tumor vasculature.


Assuntos
Antineoplásicos/farmacologia , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/metabolismo , Quimiocinas CXC/biossíntese , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-12/farmacologia , Animais , Anticorpos/farmacologia , Divisão Celular/efeitos dos fármacos , Quimiocina CXCL10 , Quimiocina CXCL9 , Quimiocinas CXC/imunologia , Feminino , Imuno-Histoquímica , Interferon gama/biossíntese , Rim/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/metabolismo , Células Tumorais Cultivadas
17.
Blood ; 91(7): 2491-500, 1998 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-9516150

RESUMO

By stimulating the expression of murine IP-10 and Mig, CXC chemokines that inhibit neovascularization and cause damage to established tumor vasculature, human B cells immortalized with Epstein-Barr virus (EBV) can promote an effective antitumor response in athymic mice. In the present study, we examined the potential role of EBV in the induction of this antitumor response. Using a panel of EBV+ and EBV- Burkitt lymphoma (BL) cell lines, a significant correlation was detected between the expression of the EBV latency gene LMP1 and the occurrence of spontaneous tumor regression in athymic mice. Inoculation of LMP1+ and LMP1- BL cells in the same subcutaneous site resulted in tumors that completely regressed in a manner indistinguishable from that induced by EBV-immortalized B cells. EBV-converted BL30 and BL41 sublines infected with B95-8 virus expressed LMP1, generated tumors that frequently regressed spontaneously, and promoted an effective antitumor response against progressively growing tumors. In contrast, the EBV- BL30 and BL41 cell lines and the EBV-converted BL30 and BL41 infected with P3HR-1 virus did not express LMP1 protein, and generated progressively growing tumors in nude mice. When transfected with the LMP1 gene, BL41 cells produced tumors that regressed spontaneously in most cases, and could induce the regression of tumors derived from BL41 cells transfected with vector alone. Tumors induced by LMP1-expressing cells expressed murine IP-10 and Mig and displayed histological evidence of extensive tumor tissue necrosis and vascular damage. We conclude that the EBV protein LMP1 is likely responsible for the antitumor response elicited by EBV-immortalized cells in athymic mice.


Assuntos
Linfoma de Burkitt/patologia , Linfoma de Burkitt/virologia , Regulação Neoplásica da Expressão Gênica , Regulação Viral da Expressão Gênica , Herpesvirus Humano 4/isolamento & purificação , Regressão Neoplásica Espontânea/genética , Proteínas da Matriz Viral/biossíntese , Animais , Herpesvirus Humano 4/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Oncogênicas Virais/genética , Células Tumorais Cultivadas , Proteínas da Matriz Viral/genética , Latência Viral/genética
18.
Cancer Res ; 57(12): 2508-15, 1997 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-9192833

RESUMO

Burkitt's lymphoma (BL) cell lines carry a translocated c-myc gene and, in 60-80% of cases, exhibit mutations in the p53 tumor suppressor gene. We examined the potential role of the p53 gene in BL tumorigenicity using an in vitro assay that measures p53-dependent cell cycle arrest in the G1 phase of the cell cycle and an in vivo athymic murine model that detects differences in the tumorigenicity of BL cell lines. A highly significant inverse correlation was found between the ability of BL cells to arrest in G1 after irradiation and their tumorigenicity in athymic mice, consistent with the notion that loss of p53 function is associated with increased tumorigenicity. Inactivation of wild-type (wt) p53 function by expression of the human papillomavirus E6 protein in the AG876V BL cell line, which carries both wt and mutant p53 proteins, rendered the cell line significantly more tumorigenic in athymic mice. Transfection of the wt p53 gene into the p53 mutant and highly tumorigenic BL-41 cell line caused it to acquire wt p53 function and rendered it less tumorigenic in mice. In addition to confirming a role for the loss of p53 function in tumor progression, the data demonstrate that wt p53 protein can reduce BL tumorigenicity in vivo.


Assuntos
Linfoma de Burkitt/genética , Ciclo Celular/fisiologia , Genes p53/genética , Animais , Biópsia , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação , Transplante de Neoplasias , Nocodazol/farmacologia , Polimorfismo Conformacional de Fita Simples , Transfecção , Células Tumorais Cultivadas/efeitos da radiação
19.
Blood ; 89(8): 2635-43, 1997 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-9108380

RESUMO

Mig, the monokine induced by interferon-gamma, is a CXC chemokine active as a chemoattractant for activated T cells. Mig is related functionally to interferon-inducible protein 10 (IP-10), with which it shares a receptor, CXCR3. Previously, IP-10 was found to have antitumor activity in vivo. In the present study, murine Mig RNA was found to be expressed at higher levels in regressing Burkitt's lymphoma tumors established in nude mice compared with progressively growing tumors. Daily inoculations of purified recombinant human Mig into Burkitt's tumors growing subcutaneously in nude mice consistently caused tumor necrosis associated with extensive vascular damage. These effects were indistinguishable from those produced by intratumor inoculations of Burkitt's tumors with IP-10. These results support the notion that Mig, like IP-10, has antitumor activity in vivo.


Assuntos
Antineoplásicos/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Quimiocinas CXC , Quimiocinas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular , Animais , Antineoplásicos/farmacologia , Vasos Sanguíneos/patologia , Linfoma de Burkitt/patologia , Células CHO , Quimiocina CXCL10 , Quimiocina CXCL9 , Quimiocinas/biossíntese , Quimiocinas/genética , Quimiocinas/farmacologia , Cricetinae , Cricetulus , Citocinas/biossíntese , Citocinas/genética , Citocinas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Necrose , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Reação em Cadeia da Polimerase , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Células Tumorais Cultivadas
20.
Biochem Biophys Res Commun ; 233(1): 231-7, 1997 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-9144429

RESUMO

IL-15, a cytokine with biological functions on cells of lymphoid lineage similar to those of IL-2, mediates its activities through the beta and gamma chains of the IL-2/15R and its own alpha chain. Unlike IL-2, IL-15 also binds to endothelial cells with high affinity. We report here that IL-15 is a stimulator of angiogenesis in vivo. When injected subcutaneously into nude mice, IL-15 consistently induced neovascularization of Matrigel plugs. Endothelial cells were found to express the IL-15R alpha chain and the IL-2/15R beta and common gamma chains. IL-15 induced the rapid tyrosine phosphorylation of proteins in endothelial cells, but did not stimulate endothelial cell proliferation in vitro. These findings document a previously unrecognized biological property of IL-15 and emphasize the role of IL-15 as an important mediator outside the immune system.


Assuntos
Interleucina-15/fisiologia , Neovascularização Fisiológica/fisiologia , Animais , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Receptores de Interleucina-15 , Receptores de Interleucina-2/metabolismo
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