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1.
Breast Cancer Res Treat ; 182(3): 591-600, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32529408

RESUMO

PURPOSE: This study evaluates the oncogenic role of PIBF1 in triple-negative breast cancer (TNBC). TNBC is considered to have a poorer prognosis than other types of breast cancer and is associated with high risk of recurrence and distant metastasis. Currently, there are no effective therapies for the TNBC patients with distant metastasis due to the lack of targeted therapeutic options. METHODS: The effects of PIBF1 knockdown on the cell viability and motility of TNBC cell lines were investigated. Effects of PIBF1 overexpression on tumorigenicity and cell motility were confirmed using Ba/F3 cell line and xenograft study on BALB/c nude mice. RESULTS: In TNBC cell lines that highly express PIBF1, knockdown of PIBF1 induces apoptosis and suppresses cell viability and motility with activation of the ATR/CHK1 signaling pathway. Moreover, the oncogenic function of PIBF1 was confirmed using the Ba/F3 cell line. CONCLUSION: For the first time, these findings clarify the role of PIBF1 in regulating ATR/CHK1 signaling pathway and inhibiting the proliferation and migration of TNBC cell lines. These results demonstrate the oncogenic roles of PIBF1 and provide new insights into the function and the molecular mechanism of PIBF1 in malignant TNBC.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Proteínas da Gravidez/metabolismo , Fatores Supressores Imunológicos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Animais , Apoptose/fisiologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Quinase 1 do Ponto de Checagem/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas da Gravidez/biossíntese , Proteínas da Gravidez/genética , Transdução de Sinais , Fatores Supressores Imunológicos/biossíntese , Fatores Supressores Imunológicos/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas
2.
Technol Cancer Res Treat ; 17: 1533033818783911, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29962287

RESUMO

BACKGROUND: Progesterone-induced blocking factor, which is released from maternal lymphocytes during pregnancy mediates the immune effect of progesterone. According to new reports, it is suggested that proliferating cells, such as human trophoblasts, mesenchymal stem cells, and malignant tumors, can excrete progesterone-induced blocking factor at high ratio to escape from maternal immunity. It is shown in recent studies that progesterone-induced blocking factor is overexpressed in many malignant tumors such as breast, cervical, lymphoma, and leukemia. There are no data about progesterone-induced blocking factor expression in ovarian cancer cells. Hence, it is aimed to determine the progesterone-induced blocking factor expression levels in epithelial ovarian cancer. METHODS: The study which was a retrospective cross-sectional study was conducted in a University Hospital. Twenty tissue specimens of patients with epithelial ovarian cancer and 20 tissue specimens of patients with healthy ovary were included in the study. Primary rabbit polyclonal anti- progesterone-induced blocking factor antibody was used to incubate the sections at a ratio of 1:300. RESULTS: When the tissue sections were compared based on immunostaining with progesterone-induced blocking factor, we detected high stromal progesterone-induced blocking factor expression in the epithelial ovarian cancer group as check against to the normal ovarian group ( P = .007). Similarly, we found high glandular progesterone-induced blocking factor expression in the epithelial ovarian cancer group as check against to the normal ovarian group ( P < .001). CONCLUSION: Proving the existence of progesterone-induced blocking factor expression in epithelial ovarian cancer cells may lead new visions or new studies for epithelial ovarian cancer immunotherapy. As a result, epithelial ovarian cancer cells have greater levels of expression of progesterone-induced blocking factor protein than normal ovarian tissue according to immunohistochemistry. Further research is needed to understand the clinical importance of this finding, to learn outcomes of high levels of progesterone-induced blocking factor, and to investigate its underlying mechanisms.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Epitelial do Ovário/imunologia , Proteínas da Gravidez/biossíntese , Fatores Supressores Imunológicos/biossíntese , Evasão Tumoral/fisiologia , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
3.
Pathol Res Pract ; 210(1): 47-54, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24225150

RESUMO

Kisspeptin and its receptor GPR54 play a major role in trophoblast invasion, and progesterone-induced blocking factor (PIBF) is needed for maintaining pregnancy. The expression of kisspeptin/GPR54 and PIBF/progesterone receptor (PR) in trophoblasts and deciduas and the relationship between kisspeptin and PIBF were investigated in the same women with recurrent spontaneous abortion (RSA). Trophoblastic and decidual tissues were collected from 32 RSA women who miscarried a genetically normal fetus, and 35 women who had voluntary abortion. Kisspeptin, GPR54, PIBF and PR were investigated using immunohistochemistry. Kisspeptin, GPR54 and PIBF expressions in syncytiotrophoblasts and cytotrophoblasts were decreased in RSA women as compared to controls (P<0.05). Kisspeptin, PIBF and PR expressions in deciduas were significantly decreased in RSA women as compared to controls (P<0.01). GPR54 expression in deciduas nearly showed no difference between the RSA group and the control group (P=0.958). Kisspeptin and PIBF expressions in syncytiotrophoblasts, cytotrophoblasts and deciduas were correlated with each other in the RSA group (Kappa=0.602, P=0.001; Kappa=0.590, P=0.001; Kappa=0.392, P=0.011). These data support the hypothesis that decreased kisspeptin and PIBF expressions in trophoblasts and deciduas are associated with RSA.


Assuntos
Aborto Habitual/metabolismo , Decídua/metabolismo , Kisspeptinas/biossíntese , Proteínas da Gravidez/biossíntese , Receptores Acoplados a Proteínas G/biossíntese , Receptores de Progesterona/biossíntese , Fatores Supressores Imunológicos/biossíntese , Trofoblastos/metabolismo , Adulto , Feminino , Humanos , Imuno-Histoquímica , Gravidez , Primeiro Trimestre da Gravidez , Receptores de Kisspeptina-1
5.
J Reprod Immunol ; 92(1-2): 103-7, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22032897

RESUMO

Progesterone is indispensable in creating a suitable endometrial environment for implantation, and also for the maintenance of pregnancy. Successful pregnancy depends on an appropriate maternal immune response to the fetus. A protein called progesterone-induced blocking factor (PIBF) acts by inducing Th2-dominant cytokine production to mediate the immunological effects of progesterone. The aim of this prospective study was to compare serum concentrations of progesterone (P), estradiol (E2), anti-inflammatory (IL-10) and pro-inflammatory (IL-6, TNFα, IFNγ) cytokines, and serum PIBF concentrations in women with threatened preterm delivery who were given progesterone supplementation (study group) with those of women with threatened preterm delivery who were not given progesterone supplementation (control group). After dydrogesterone treatment of patients in the study group, serum PIBF as well as progesterone concentrations significantly increased. Women in this group had significantly higher serum levels of IL-10 than controls. The length of gestation was significantly higher in the group of women who were given progesterone supplementation. Our data suggest that dydrogesterone treatment of women at risk of preterm delivery results in increased PIBF production and IL-10 concentrations, and lower concentrations of IFNγ.


Assuntos
Didrogesterona/administração & dosagem , Interleucina-10/biossíntese , Proteínas da Gravidez/biossíntese , Nascimento Prematuro/tratamento farmacológico , Progesterona/biossíntese , Fatores Supressores Imunológicos/biossíntese , Suplementos Nutricionais , Didrogesterona/efeitos adversos , Implantação do Embrião/efeitos dos fármacos , Estradiol/biossíntese , Estradiol/sangue , Estradiol/genética , Feminino , Terapia de Reposição Hormonal , Humanos , Interleucina-10/sangue , Interleucina-10/genética , Gravidez , Proteínas da Gravidez/sangue , Proteínas da Gravidez/genética , Nascimento Prematuro/sangue , Nascimento Prematuro/imunologia , Nascimento Prematuro/fisiopatologia , Progesterona/sangue , Progesterona/genética , Estudos Prospectivos , Fatores Supressores Imunológicos/sangue , Fatores Supressores Imunológicos/genética , Equilíbrio Th1-Th2/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
6.
Reprod Biomed Online ; 21(3): 304-11, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20638907

RESUMO

It is well known that the reproductive steroid hormones, particularly progesterone, in addition to its widely recognized effects on endometrial epithelial and stromal cells and spiral arteries, affect the activities of T cells and natural killer cells in the deciduas, thus inducing active immune tolerance against the fetal antigens. The immunomodulatory effects of progesterone on T cells, B cells and natural killer cells have been discussed extensively in the literature. The aim of the present review is to sum up and discuss the results from this and other laboratories of investigations on the effects of progesterone on dendritic cells and adult stem cells, which are some of the other cell populations present at the fetal-maternal interface and possibly are related to the immunoregulation during pregnancy. These cells have been shown to have a number of specific functions but their involvement in the entire process of regulation of the immune response in pregnancy is still under discussion. The present review focuses on facts showing that the progesterone is a kind of 'regulator of regulators' in the decidua, thus creating the most favourable conditions for the development of the semi-allogeneic fetus in successful pregnancy.


Assuntos
Decídua/citologia , Decídua/imunologia , Fatores Imunológicos/imunologia , Progesterona/imunologia , Adulto , Decídua/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Feminino , Antígenos HLA/biossíntese , Antígenos HLA-G , Antígenos de Histocompatibilidade Classe I/biossíntese , Humanos , Fatores Imunológicos/farmacologia , Imunomodulação/efeitos dos fármacos , Imunomodulação/imunologia , Técnicas In Vitro , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/imunologia , Gravidez , Proteínas da Gravidez/biossíntese , Progesterona/farmacologia , Fatores Supressores Imunológicos/biossíntese
7.
Genome Biol ; 9(7): R119, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18664279

RESUMO

BACKGROUND: CD8+ NKT-like cells are naturally occurring but rare T cells that express both T cell and natural killer cell markers. These cells may play key roles in establishing tolerance to self-antigens; however, their mechanism of action and molecular profiles are poorly characterized due to their low frequencies. We developed an efficient in vitro protocol to produce CD8+ T cells that express natural killer cell markers (CD8+ NKT-like cells) and extensively characterized their functional and molecular phenotypes using a variety of techniques. RESULTS: Large numbers of CD8+ NKT-like cells were obtained through culture of naïve CD8+ T cells using anti-CD3/anti-CD28-coated beads and high dose IL-2. These cells possess potent activity in suppressing the proliferation of naïve responder T cells. Gene expression profiling suggests that the cultured CD8+ NKT-like cells and the naïve CD8+ T cells differ by more than 2-fold for about 3,000 genes, among which 314 are upregulated by more than 5-fold and 113 are upregulated by more than 10-fold in the CD8+ NKT-like cells. A large proportion of the highly upregulated genes are soluble factors or surface markers that have previously been implicated in immune suppression or are likely to possess immunosuppressive properties. Many of these genes are regulated by two key cytokines, IL-10 and IFN-gamma. The immunosuppressive activities of cells cultured from IL-10-/- and IFN-gamma-/- mice are reduced by about 70% and about 50%, respectively, compared to wild-type mice. CONCLUSION: Immunosuppressive CD8+ NKT-like cells can be efficiently produced and their immunosuppressive activity is related to many surface and soluble molecules regulated by IL-10 and IFN-gamma.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Tolerância Imunológica , Interferon gama/fisiologia , Interleucina-10/fisiologia , Fatores Supressores Imunológicos/biossíntese , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/classificação , Células Cultivadas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Interferon gama/genética , Interleucina-10/genética , Células Matadoras Naturais/imunologia , Proteínas de Membrana/biossíntese , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Fatores Supressores Imunológicos/genética , Linfócitos T Reguladores/imunologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
J Pharmacol Exp Ther ; 318(2): 899-906, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16714403

RESUMO

A common in vitro response for many chemopreventive and antitumor agents, including some cyclooxygenase inhibitors, is the increased expression of nonsteroidal anti-inflammatory drug-activated gene (NAG)-1/macrophage inhibitory cytokine (MIC)-1/prostate-derived factor (PDF). The experimental anticancer drug 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203) was a potent inducer of NAG-1 expression, and in MCF-7 cells, it inhibited cell growth and induced apoptosis. NAG-1 small interfering RNA blocked NAG-1 expression and 5F203-induced apoptosis in MCF-7 cells, indicating that NAG-1 may mediate the apoptosis and anticancer activity. One mechanism by which 5F203 increases NAG-1 expression is by increasing the stability of NAG-1 mRNA, dependent of de novo protein synthesis. Extracellular signal-regulated kinase (ERK) 1/2 phosphorylation was increased by 5F203, and inhibition of ERK1/2 phosphorylation abolished the induction of NAG-1 protein expression and increased the stability of NAG-1 mRNA. Thus, 5F203 regulates NAG-1 expression by a unique mechanism compared with other drugs. A mouse orthotopic mammary tumor model was used to determine whether 5F203 increased NAG-1 expression in vivo and suppressed tumor growth. Treatment of the mice with Phortress, the prodrug of 5F203, increased the in vivo expression of NAG-1 as measured by real-time reverse transcription-polymerase chain reaction from RNA obtained by needle biopsy, and the expression correlated with a reduction of tumor volume. These results confirm that NAG-1 suppresses tumor growth, and its in vivo expression can be controlled by treating mice with anticancer drugs, such as Phortress. Drugs that target NAG-1 could lead to a unique strategy for the development of chemotherapeutic and chemopreventive agents.


Assuntos
Antineoplásicos/farmacologia , Citocinas/biossíntese , Expressão Gênica/efeitos dos fármacos , Fatores Supressores Imunológicos/biossíntese , Tiazóis/farmacologia , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cicloeximida/farmacologia , Citocinas/genética , Dactinomicina/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Fator 15 de Diferenciação de Crescimento , Humanos , Camundongos , Transplante de Neoplasias , Fosforilação , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA Interferente Pequeno/farmacologia , Fatores Supressores Imunológicos/genética , Transplante Heterólogo , Regulação para Cima/efeitos dos fármacos
9.
Cancer Res ; 66(7): 3852-8, 2006 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-16585213

RESUMO

Regeneration and tolerance factor (RTF) was originally identified in placenta where it is thought to be essential for fetal allograft survival. Here we report that RTF mRNA and protein are also expressed in human glioma cells in vitro and in vivo. Suppression of RTF expression by RNA interference promotes the lysis of glioma cells by natural killer (NK) and T cells in vitro. Moreover, RTF-depleted glioma cells are less tumorigenic than control cells in nude mice in vivo. Depletion of NK cells in these animals abolished this effect. RTF is thus a novel aberrantly expressed molecule which confers immune privilege to human malignant gliomas.


Assuntos
Glioblastoma/imunologia , Fatores Supressores Imunológicos/imunologia , Animais , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Tolerância Imunológica , Camundongos , Camundongos Nus , Interferência de RNA , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Fatores Supressores Imunológicos/biossíntese , Fatores Supressores Imunológicos/genética , Transfecção , Transplante Heterólogo
10.
Int Immunol ; 17(10): 1303-13, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16113235

RESUMO

In an attempt to identify new immunoreceptor tyrosine-based activation motif (ITAM)-containing human molecules that may regulate hitherto unknown immune cell functions, we BLAST searched the National Center for Biotechnology Information database for ITAM-containing sequences. A human expressed sequence tag showing partial homology to the murine TJ6 (mTJ6) gene and encoding a putative ITAM sequence has been identified and used to clone the human TJ6 (hTJ6) gene from an HL-60-derived cDNA library. hTJ6 was found to encode a protein of 856 residues with a calculated mass of 98 155 Da. Immunolocalization and sequence analysis revealed that hTJ6 is a membrane protein with predicted six transmembrane-spanning regions, typical of ion channels, and a single putative ITAM (residues 452-466) in a juxtamembrane or hydrophobic intramembrane region. hTJ6 is highly homologous to Bos taurus 116-kDa subunit of the vacuolar proton-translocating ATPase. Over-expression of hTJ6 in HEK 293 cells increased H+ uptake into intracellular organelles, an effect that was sensitive to inhibition by bafilomycin, a selective inhibitor of vacuolar H+ pump. Northern blot analysis demonstrated three different hybridizing mRNA transcripts corresponding to 3.2, 5.0 and 7.3 kb, indicating the presence of several splice variants. Significant differences in hTJ6 mRNA levels in human tissues of different origins point to possible tissue-specific function. Although hTJ6 was found to be a poor substrate for tyrosine-phosphorylating enzymes, suggesting that its ITAM sequence is non-functional in protein tyrosine kinase-mediated signaling pathways, its role in organellar H+ pumping suggests that hTJ6 function may participate in protein trafficking/processing.


Assuntos
Proteínas da Gravidez/química , Proteínas da Gravidez/genética , Subunidades Proteicas/química , Subunidades Proteicas/genética , Fatores Supressores Imunológicos/química , Fatores Supressores Imunológicos/genética , Tirosina/química , ATPases Vacuolares Próton-Translocadoras/fisiologia , Motivos de Aminoácidos/imunologia , Sequência de Aminoácidos , Animais , Northern Blotting , Bovinos , Linhagem Celular , Clonagem Molecular , Sequência Conservada , Humanos , Células Jurkat , Dados de Sequência Molecular , Proteínas da Gravidez/biossíntese , Proteínas da Gravidez/fisiologia , Processamento de Proteína Pós-Traducional/imunologia , Subunidades Proteicas/fisiologia , Transporte Proteico/imunologia , Receptores Imunológicos/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Fatores Supressores Imunológicos/biossíntese , Fatores Supressores Imunológicos/fisiologia , Tirosina/genética , Tirosina/metabolismo , ATPases Vacuolares Próton-Translocadoras/biossíntese , ATPases Vacuolares Próton-Translocadoras/genética
11.
J Immunol ; 174(5): 2770-7, 2005 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15728486

RESUMO

The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix-PER-ARNT-SIM superfamily. Xenobiotics, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, bind the receptor and trigger diverse biological reactions. Thymocyte development and T cell-dependent immune reactions are sensitive targets of AhR-dependent 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity. However, the exact role of the AhR in T cells in animals exposed to exogenous ligands has not been clarified because indirect effects of activated AhR in other cell types cannot be excluded. In this study, we generated transgenic (Tg) mice expressing a constitutively active mutant of AhR under the regulation of a T cell-specific CD2 promoter to examine AhR function in T cells. The mRNAs of the constitutively active mutant of AhR and an AhR-induced gene, CYP1A1, were expressed in the thymus and spleen of the Tg mice. The transgene expression was clearly detected in the thymocytes, CD4, and CD8 T cells, but not in the B cells or thymus stromal cells. These Tg mice had a decreased number of thymocytes and an increased percentage of CD8 single-positive thymocytes, but their splenocytes were much less affected. By contrast, the increase in number of T cells and B cells taking place in the spleen after immunization was significantly suppressed in the Tg mice. These results clearly show that AhR activation in the T-lineage cells is directly involved in thymocyte loss and skewed differentiation. They also indicate that AhR activation in T cells and not in B cells suppresses the immunization-induced increase in both T cells and B cells.


Assuntos
Dibenzodioxinas Policloradas/administração & dosagem , Dibenzodioxinas Policloradas/imunologia , Receptores de Hidrocarboneto Arílico/fisiologia , Baço/citologia , Fatores Supressores Imunológicos/fisiologia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Timo/patologia , Animais , Linhagem da Célula/imunologia , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Epitopos de Linfócito T/imunologia , Humanos , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Tamanho do Órgão/genética , Tamanho do Órgão/imunologia , RNA Mensageiro/biossíntese , Receptores de Hidrocarboneto Arílico/biossíntese , Receptores de Hidrocarboneto Arílico/genética , Baço/imunologia , Fatores Supressores Imunológicos/biossíntese , Subpopulações de Linfócitos T/metabolismo , Regulação para Cima/genética , Regulação para Cima/imunologia
12.
J Neuroimmunol ; 138(1-2): 83-91, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12742657

RESUMO

We studied plasma factors mediating suppression of NK activity (NKA) following surgery. Plasma from operated rats suppressed NKA of splenocytes, leukocytes, and purified natural killer (NK) cells, and charcoal stripping nullified suppression. The glucocorticoid antagonist mifepristone prevented suppression, whereas blockers of reactive oxygen metabolites, opioids, catecholamines, prostaglandin-E2, and histamine did not. NKA dropped as corticosterone levels peaked postoperatively, and administration of relevant doses of corticosterone suppressed NKA. Inhibition of glucocorticoid synthesis prevented plasma from suppressing NKA but merely attenuated NKA suppression in operated rats. Thus, postoperative concentrations of corticosterone can directly suppress NKA but additional factors probably act in vivo.


Assuntos
Citotoxicidade Imunológica/fisiologia , Glucocorticoides/fisiologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Laparotomia , Fatores Supressores Imunológicos/fisiologia , Alprostadil/imunologia , Animais , Cimetidina/sangue , Cimetidina/farmacologia , Corticosterona/administração & dosagem , Corticosterona/antagonistas & inibidores , Corticosterona/sangue , Corticosterona/fisiologia , Citotoxicidade Imunológica/efeitos dos fármacos , Dinoprostona/imunologia , Glucocorticoides/antagonistas & inibidores , Glucocorticoides/biossíntese , Glucocorticoides/sangue , Soros Imunes/sangue , Soros Imunes/farmacologia , Injeções Subcutâneas , Cinética , Masculino , Mifepristona/sangue , Mifepristona/farmacologia , Período Pós-Operatório , Ratos , Ratos Endogâmicos F344 , Fatores Supressores Imunológicos/antagonistas & inibidores , Fatores Supressores Imunológicos/biossíntese , Fatores Supressores Imunológicos/sangue , Células Tumorais Cultivadas
13.
J Immunol ; 170(8): 4036-44, 2003 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-12682232

RESUMO

Fibrinogen-like protein 2 (fgl2)/fibroleukin is a member of the fibrinogen-related protein superfamily. In addition to its established role in triggering thrombosis, it is known to be secreted by T cells. The soluble fgl2 ((s)fgl2) protein generated in a baculovirus expression system bound to both T cells and bone marrow-derived dendritic cells (DC) in a specific manner. (s)fgl2 exhibited immunomodulatory properties capable of inhibiting T cell proliferation stimulated by alloantigens, anti-CD3/anti-CD28 mAbs, and Con A in a dose-dependent manner; however, it had no inhibitory effects on CTL activity. The time- and dose-dependent inhibitory effect of (s)fgl2 on alloreactive T cell proliferation could be neutralized by a mAb against mouse fgl2. Polarization toward a Th2 cytokine profile with decreased production of IL-2 and IFN-gamma and increased production of IL-4 and IL-10 was observed in (s)fgl2-treated allogeneic cultures. Exposure of immature DC to (s)fgl2 abrogated the expression of CD80(high) and MHC class II(high) molecules and markedly inhibited NF-kappaB nuclear translocation, thus inhibiting their maturation. (s)Fgl2-treated DC had an impaired ability to stimulate allogeneic T cell proliferation. Maximal inhibition of proliferation was observed when allogeneic T cells were cultured with (s)fgl2-treated DC and (s)fgl2 protein was added in the culture. These data provide the first evidence to demonstrate that (s)fgl2 exerts immunosuppressive effects on T cell proliferation and DC maturation.


Assuntos
Células da Medula Óssea/citologia , Células Dendríticas/citologia , Fibrinogênio/fisiologia , Inibidores do Crescimento/fisiologia , Fatores Supressores Imunológicos/fisiologia , Linfócitos T/citologia , Tromboplastina/fisiologia , Animais , Apoptose/imunologia , Antígeno B7-1/biossíntese , Baculoviridae/genética , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/biossíntese , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Fibrinogênio/biossíntese , Fibrinogênio/genética , Fibrinogênio/metabolismo , Vetores Genéticos , Inibidores do Crescimento/biossíntese , Inibidores do Crescimento/genética , Inibidores do Crescimento/metabolismo , Antígenos de Histocompatibilidade Classe II/biossíntese , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos A , Camundongos Endogâmicos BALB C , Ligação Proteica/imunologia , Solubilidade , Fatores Supressores Imunológicos/biossíntese , Fatores Supressores Imunológicos/genética , Fatores Supressores Imunológicos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Th2/imunologia , Células Th2/metabolismo , Tromboplastina/biossíntese , Tromboplastina/genética , Tromboplastina/metabolismo
14.
J Immunol ; 169(10): 5590-4, 2002 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-12421936

RESUMO

Bacterial DNA and synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs stimulate a strong innate immune response. This stimulation can be abrogated by either removing the CpG DNA or adding inhibitory/suppressive motifs. Suppression is dominant over stimulation and is specific for CpG-induced immune responses (having no effect on LPS- or Con A-induced activation). Individual cells noncompetitively internalize both stimulatory and suppressive ODN. Studies using ODN composed of both stimulatory and suppressive motifs indicate that sequence recognition proceeds in a 5'-->3' direction, and that a 5' motif can block recognition of immediately 3' sequences. These findings contribute to our understanding of the immunomodulatory activity of DNA-based products and the rules that govern immune recognition of stimulatory and suppressive motifs.


Assuntos
Adjuvantes Imunológicos/farmacologia , Ilhas de CpG/imunologia , DNA/farmacologia , Imunossupressores/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Oligodesoxirribonucleotídeos/farmacologia , Adjuvantes Imunológicos/metabolismo , Animais , Feminino , Citometria de Fluxo , Imunossupressores/metabolismo , Interferon gama/biossíntese , Interleucina-12/biossíntese , Interleucina-6/biossíntese , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Oligodesoxirribonucleotídeos/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo , Fatores Supressores Imunológicos/biossíntese
15.
J Immunol ; 169(7): 3581-8, 2002 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12244148

RESUMO

Human endothelial cells (ECs) provide costimulatory signals sufficient to activate resting memory T cells to produce IL-2 and IFN-gamma, at least in part through CD58-CD2 interactions. Recently, the B7-like molecule, B7-H1 (PD-L1), was described and shown to regulate T cell activation; however, there are conflicting reports on whether it stimulates or inhibits T cell cytokine synthesis. B7-H1 is not expressed constitutively by ECs; however, it is rapidly induced by IFN-gamma, and synergistically by IFN-gamma and TNF. In inflamed skin, B7-H1 is expressed by a subset of microvessels, and by keratinocytes, but is barely detectable in normal skin. Blocking the interaction of EC-expressed B7-H1 with its T cell ligand, programmed death-1 (PD-1), using a PD-1-Fc fusion protein, or by blocking B7-H1 expression with morpholino antisense oligonucleotides, augments expression of IL-2 and IFN-gamma, implicating B7-H1 as a negative regulator of cytokine synthesis. However, signaling through PD-1 does not affect induction of the activation markers CD25 or CD69 on T cells, suggesting that its effects are specific to cytokine synthesis. The suppressive effects of B7-H1 on cytokine expression are proportional to the strength of the primary stimulus, allowing for B7-H1 to determine the level of T cell activation in response to ECs. Our results demonstrate that B7-H1 negatively regulates cytokine synthesis in T cells activated by ECs.


Assuntos
Antígeno B7-1/biossíntese , Antígeno B7-1/fisiologia , Proteínas Sanguíneas , Citocinas/biossíntese , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Peptídeos , Fatores Supressores Imunológicos/biossíntese , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Antígenos CD , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-H1 , Células Cultivadas , Citocinas/antagonistas & inibidores , Endotélio Vascular/citologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Ativação Linfocitária , Glicoproteínas de Membrana , Microcirculação/citologia , Microcirculação/imunologia , Microcirculação/metabolismo , RNA Mensageiro/biossíntese , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Pele/imunologia , Pele/metabolismo , Pele/patologia , Células Estromais/citologia , Células Estromais/imunologia , Células Estromais/metabolismo , Fatores Supressores Imunológicos/antagonistas & inibidores , Fatores Supressores Imunológicos/genética , Fatores Supressores Imunológicos/fisiologia , Fatores de Tempo , Veias Umbilicais , Regulação para Cima/genética , Regulação para Cima/imunologia
16.
J Immunol ; 169(7): 3661-6, 2002 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-12244158

RESUMO

Inhibitory Ly49 receptors expressed on NK cells provide a mechanism for tolerance to normal self tissues. The immunoregulatory tyrosine-based inhibitory motifs present in some Ly49s are able to transmit an inhibitory signal upon ligation by MHC class I ligands. In our system, as well as others, mice transgenic for inhibitory Ly49 receptors express these receptors on both NK and T cells. FVB (H2(q)) mice transgenic for the B6 strain Ly49I (Ly49I(B6)) express the inhibitory Ly49 receptor on the surface of both T and NK cells. Although Ly49I functions to prevent NK-mediated rejection of H2(b) donor bone marrow cells in this transgenic mouse strain, the T cells do not appear to be affected by the expression of the Ly49I transgene. FVB.Ly49I T cells have normal proliferative capabilities both in vitro and in vivo in response to the Ly49I ligand, H2(b). In vivo functional T cell assays were also done, showing that transgenic T cells were not functionally affected. T cells in these mice also appear to undergo normal T cell development and activation. Only upon stimulation with suboptimal doses of anti-CD3 in the presence of anti-Ly49I is T cell proliferation inhibited. These data are in contrast with findings in Ly49A, and Ly49G2 receptor transgenic models. Perhaps Ly49I-H2(b) interactions are weaker or of lower avidity than Ly49A-H-2D(d) interactions, especially in T cells.


Assuntos
Antígenos Ly/biossíntese , Antígenos Ly/genética , Regulação da Expressão Gênica/imunologia , Receptores Imunológicos/biossíntese , Receptores Imunológicos/genética , Fatores Supressores Imunológicos/biossíntese , Fatores Supressores Imunológicos/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transgenes/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Memória Imunológica/genética , Imunofenotipagem , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Subpopulações de Linfócitos T/citologia
17.
Clin Exp Immunol ; 129(3): 493-501, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12197891

RESUMO

Studies in humans suggest that allo-immunization induces CC-chemokines, CD8-suppressor factors (SF) and anti-HIV immunity. Here we report that allo-immunization with unmatched leucocytes from partners of women with recurrent spontaneous abortion elicits specific antibodies to the CCR5 receptor. Such antibodies inhibit replication of M-tropic HIV-1 (R5) and MIP-1beta-mediated chemotaxis. These CCR5 antibodies were also found in the sera of multiparous women that were naturally immunized by semi-allogeneic fetal antigens. The specificity of these antibodies was demonstrated by adsorption with CCR5 transfected HEK-293 cells, a baculovirus CCR5 preparation and a peptide of the 2nd extra-cellular loop of CCR5. Allo-immunization also stimulated increased concentrations of the CXC chemokine, SDF-1alpha and CD8-SF that inhibit T-tropic HIV-1 (X4) replication. We suggest that allo- immunization may elicit (a) CC chemokines, CCR5 antibodies and CD8-SF that inhibit M-tropic HIV-1 infection and (b) the CXC chemokine SDF-1alpha and CD8-SF that inhibit T-tropic HIV-1 infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiocinas CXC/biossíntese , Infecções por HIV/imunologia , HIV-1 , Isoanticorpos/sangue , Receptores CCR5/imunologia , Aborto Habitual/terapia , Sequência de Aminoácidos , Linhagem Celular , Células Cultivadas , Quimiocina CXCL12 , Estudos de Coortes , Feminino , Infecções por HIV/transmissão , Humanos , Imunização , Imunoglobulina G/sangue , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Isoanticorpos/imunologia , Isoantígenos/imunologia , Transfusão de Leucócitos , Ativação Linfocitária , Teste de Cultura Mista de Linfócitos , Dados de Sequência Molecular , Paridade , Gravidez , Receptores CCR5/química , Fatores Supressores Imunológicos/biossíntese , Fatores Supressores Imunológicos/farmacologia
18.
J Immunol Methods ; 264(1-2): 1-10, 2002 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-12191503

RESUMO

The capacity of CD8+ and CD4+ T cells and CD14+ monocytes to generate the CC chemokines, RANTES, MIP-1alpha and MIP-1beta, and SIV suppressor factors were studied using cells separated from PBMC of macaques immunized with the 70-kDa heat shock protein (HSP70). Unimmunized macaques showed low levels of the three CC chemokines and SIV-SF, and they showed little variation between PBMC and the two subsets of T cells stimulated with PHA. Immunization with HSP70 elicited an increase in the in vitro concentration of each of the three CC chemokines and SF. This was found with PBMC, CD4+ and CD8+ T cells and to a lesser extent with monocytes, when conventionally separated enriched cell subsets were examined from the same PBMC. However, the concentrations of the three CC chemokines derived from highly purified cell-sorted populations (>95%) were greatly increased, as compared with the enriched cell subsets. The concentration of each of the three chemokines was highest for CD8+ T cells, decreased with CD4+ T cells and was lowest with the CD14+ monocytes, but the latter were not stimulated. Neutralization assays with antibodies to the three CC chemokines showed that the antiviral activity generated by the four populations of cells could be largely accounted for by the three CC chemokines. The results of this comparative study suggests that CD8+ as well as CD4+ T cells and CD14+ monocytes generate the three CC chemokines and SIV-SF when stimulated with a mitogen, and that the baseline innate level can be upregulated by adaptive immune responses to a specific antigen.


Assuntos
Antivirais/biossíntese , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Quimiocinas CC/biossíntese , Receptores de Lipopolissacarídeos/biossíntese , Monócitos/metabolismo , Vírus da Imunodeficiência Símia/imunologia , Fatores Supressores Imunológicos/biossíntese , Animais , Antivirais/antagonistas & inibidores , Antivirais/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Separação Celular/métodos , Quimiocina CCL3 , Quimiocina CCL4 , Quimiocina CCL5/biossíntese , Quimiocina CCL5/imunologia , Quimiocina CCL5/metabolismo , Quimiocinas CC/imunologia , Quimiocinas CC/metabolismo , Proteínas de Choque Térmico HSP70/administração & dosagem , Proteínas de Choque Térmico HSP70/imunologia , Proteínas de Choque Térmico HSP70/farmacologia , Imunização , Imunoglobulina G/farmacologia , Injeções Intramusculares , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Macaca mulatta , Proteínas Inflamatórias de Macrófagos/biossíntese , Proteínas Inflamatórias de Macrófagos/imunologia , Proteínas Inflamatórias de Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/virologia , Testes de Neutralização , Fito-Hemaglutininas/farmacologia , Fatores Supressores Imunológicos/metabolismo
19.
Clin Exp Immunol ; 127(1): 145-50, 2002 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11882045

RESUMO

A panel of 22 CD8+ T cell lines, with a broad range of CD8+ anti-HIV-1 suppressor activity (CASA) were generated from a single patient with HIV-1 infection. CD8+ T cell lines with either strong or weak CASA were examined and compared for cell surface and intracellular markers, constitutive chemokine and lymphokine mRNA levels and inducible lymphokine expression. Strong CASA significantly correlated with CD8+ T cell lines that highly coexpressed the molecule CD28+ (r=0.52, P=0.01) and Ki67+ (r=0.88, P=0.02), with strong CASA CD8+ T cell lines demonstrating significantly higher (P < 0.05) expression of CD8+CD28+ and CD8+Ki67+ compared to those with weak activity. No such correlations or findings were observed for the markers CD38, HLA-DR, CD57 or perforin. The Th1 cytokines were expressed at greater levels than the Th2 cytokines, with strong CASA significantly associated with an increased inducible level of IL-2 production (P=0.05). Constitutive RANTES, IP-10 and I-309 mRNA expression were significantly (P < 0.05) elevated in CD8+ T cell lines exhibiting strong CASA compared to those with weak CASA. There was no significant difference in the mRNA expression of the lymphokines IL-2, 4, 5, 8, 9, 10, 14, 15, or chemokines MIP-1alpha, MIP-1beta, MCP-1, and Ltn. Strong CASA was therefore associated with rapidly replicating CD8+ T cells of the phenotype CD8+CD28+Ki67+ that expressed greater levels of IL-2 and the ligands RANTES and I-309.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica , Infecções por HIV/imunologia , HIV-1/imunologia , Linfocinas/imunologia , Linfócitos T CD8-Positivos/patologia , Linhagem Celular , Citometria de Fluxo , Infecções por HIV/patologia , Humanos , Imunofenotipagem , Linfocinas/biossíntese , Fatores Supressores Imunológicos/biossíntese , Fatores Supressores Imunológicos/imunologia
20.
Clin Diagn Lab Immunol ; 8(6): 1292-4, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11687481

RESUMO

Regeneration and tolerance factor (RTF) is a protein with immunosuppressive activity and is normally present in the thymus and placenta. RTF was measured in the livers of patients with regenerating nodules due to alcoholic cirrhosis and hepatitis C. RTF was expressed in the regenerating nodules of 26 patients with alcoholic cirrhosis. All patients with chronic hepatitis C without cirrhosis failed to express RTF. Flow cytometry revealed upregulation of RTF on the lymphocytes from alcoholic cirrhosis and downregulation in hepatitis C disease.


Assuntos
Antígenos CD , Hepatócitos/metabolismo , Cirrose Hepática Alcoólica/imunologia , Cirrose Hepática Alcoólica/metabolismo , Proteínas da Gravidez/biossíntese , Fatores Supressores Imunológicos/biossíntese , Linfócitos T/metabolismo , ADP-Ribosil Ciclase , ADP-Ribosil Ciclase 1 , Antígenos de Diferenciação/análise , Citometria de Fluxo , Antígenos HLA-DR/análise , Hepatite C Crônica/imunologia , Hepatite C Crônica/metabolismo , Hepatócitos/química , Humanos , Imuno-Histoquímica , Glicoproteínas de Membrana , NAD+ Nucleosidase/análise , Proteínas da Gravidez/análise , Fatores Supressores Imunológicos/análise , Linfócitos T/química
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