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1.
Sci Rep ; 8(1): 658, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29330517

RESUMO

In CKD patients, arteriosclerotic lesions, including calcification, can occur in vascular smooth muscle cells in a process called Moenckeberg's medial arteriosclerosis. Iron overload induces several complications, including the acceleration of arteriosclerosis. However, the relationship between Moenckeberg's arteriosclerosis in vascular smooth muscle cells and iron accumulation has remained unknown. We tested the accelerated effect of iron on calcification in cultured human aortic vascular smooth muscle cells (HASMCs). After establishment of this model, we performed a microarray analysis using mRNA from early stage culture HASMCs after iron stimulation with or without TNF-alpha stimulation. The role of interleukin-24 (IL-24) was confirmed from candidate genes that might contribute to calcification. HASMCs demonstrated calcification induced by iron and TNF-alpha. Calcification of HASMCs was synergistically enhanced by stimulation with both iron and TNF-alpha. In the early phase of calcification, microarray analysis revealed up-regulation of IL-24. Stimulation of HASMCs by IL-24 instead of iron induced calcification. The anti-IL-24 antibody reversed the effect of IL-24, supporting the important role of IL-24 in HASMCs calcification. In conclusion, iron-induced calcification in vascular smooth muscle cells occurred via IL-24, IL-24 was increased during the calcification process induced by iron, and IL-24 itself caused calcification in the absence of iron.


Assuntos
Interleucinas/genética , Ferro/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia , Calcificação Vascular/induzido quimicamente , Aorta , Linhagem Celular , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Regulação para Cima , Calcificação Vascular/genética
2.
Immunogenetics ; 68(1): 55-65, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26552659

RESUMO

Interleukin 12 receptor ß chain (IL12RB2) is a crucial regulatory factor involved in cell-mediated immune responses, and genetic variants of the gene encoding IL12RB2 are associated with susceptibility to various immune-related diseases. We previously demonstrated that haplotypes with single nucleotide polymorphisms (SNPs) in the 5' flanking region of IL12RB2, including -1035A>G (rs3762315) and -1023A>G (rs3762316), affect the expression of IL12RB2, thereby altering susceptibility to leprosy and periodontal diseases. In the present study, we identified transcription factors associated with the haplotype-specific transcriptional activity of IL12RB2 in T cells and NK cells. The -1023G polymorphism was found to create a consensus binding site for the transcription factor activating protein (AP)-1, and enzyme-linked immunosorbent assay (ELISA)-based binding assays showed that these SNPs enhanced AP-1 binding to this region. In reporter assays, suppression of JunB expression using siRNA eliminated differences in the -1035G/-1023G and -1035A/-1023A regions containing IL12RB2 promoter activity in Jurkat T cells and NK3.3 cells. These results suggested that the -1035/-1023 polymorphisms created differential binding affinities for JunB that could lead to differential IL12RB2 expression. Moreover, the -1035G and -1035A alleles formed binding sites for GATA-3 and myocyte enhancer factor-2 (MEF-2), respectively. Our data indicated that in addition to JunB, the SNP at -1035/-1023 influenced GATA-3 and MEF-2 binding affinity, potentially altering IL12RB2 transcriptional activity. These findings confirm the effects of rs3762315 and rs3762316 on IL12RB2 transcription. These genetic variants may alter cellular activation of T cells and NK cells and modify cell-mediated immune responses.


Assuntos
Região 5'-Flanqueadora , Receptores de Interleucina-12/genética , Receptores de Interleucina-12/metabolismo , Fator de Transcrição GATA3/metabolismo , Haplótipos , Humanos , Células Jurkat , Células Matadoras Naturais/metabolismo , Fatores de Transcrição MEF2/metabolismo , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fator de Transcrição AP-1/metabolismo , Transcrição Gênica
3.
Med Mol Morphol ; 48(3): 169-76, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25547245

RESUMO

Tumor necrosis factor-α (TNF-α) directly and indirectly plays a crucial role in osteoclastogenesis. However, the indirect effects of TNF-α on colony-stimulating factor-1 receptor (CSF-1R)-mediated osteoclastogenesis achieved via periodontal ligament (PDL) cells are not fully understood. We herein examined the potency of osteoclast differentiation and maturation induced by fivefold supernatants in the stimulated human PDL cells with a physiologically high concentration (10 ng/mL) of recombinant TNF-α to human peripheral blood monocytes/macrophages in the simultaneous presence of the receptor activator of nuclear factor kappa-B ligand. The number of tartrate-resistant acid phosphatase-positive cells with multiple nuclei, but not those with a single nucleus, was decreased by approximately 50% by neutralization with rabbit IgG against either interleukin-34 (IL-34) or CSF-1. Small and large amounts of IL34 and CSF1 transcripts were measured in the stimulated PDL cells using real-time polymerase chain reaction. The corresponding amounts of proteins to IL34 and CSF1 transcripts were observed in the stimulated PDL cells on immunohistochemical staining or Western blotting. Moreover, 0.13 ng/mL of IL-34 and 5.0 ng/mL of CSF-1 were measured in the supernatants of the stimulated PDL cells using an enzyme-linked immunosorbent assay. IL-34 derived from the stimulated PDL cells with TNF-α appeared to synergistically function with CSF-1 in the CSF-1R-mediated maturation of osteoclastogenesis.


Assuntos
Diferenciação Celular , Interleucinas/metabolismo , Fator Estimulador de Colônias de Macrófagos/metabolismo , Ligamento Periodontal/citologia , Fator de Necrose Tumoral alfa/fisiologia , Ensaio de Imunoadsorção Enzimática , Expressão Gênica , Humanos , Imuno-Histoquímica , Interleucinas/análise , Interleucinas/genética , Fator Estimulador de Colônias de Macrófagos/análise , Fator Estimulador de Colônias de Macrófagos/genética , Ligamento Periodontal/efeitos dos fármacos , Ligamento Periodontal/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Estimulação Química
4.
Anticancer Res ; 34(6): 3061-5, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24922673

RESUMO

AIM: In order to determine if metastatic malignant mesothelioma cells are more aggressive than primary malignant mesothelioma cells, an analysis of the expression of the adhesion molecules E-cadherin and ß-catenin, concomitant with an assessment of the proliferative activity at primary and metastatic sites, was conducted in post-mortem samples. MATERIALS AND METHODS: E-cadherin or ß-catenin expression was graded according to the percentage of positively-stained tumor cells. The proliferative activity was quantified by the Ki-67 labeling index. RESULTS: Histologically, the majority of metastatic tumors matched the primary tumor. In the epithelioid component of primary tumors, E-cadherin and ß-catenin expression ranged from 1+ to 4+. CONCLUSION: Malignant mesothelioma cells acquire a higher proliferative potential after metastasis, without any significant changes in their histology, although metastasis produces no definite trend on the expression of E-cadherin or ß-catenin.


Assuntos
Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Proliferação de Células , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Mesotelioma/metabolismo , Mesotelioma/secundário , beta Catenina/metabolismo , Idoso , Autopsia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Mesotelioma Maligno , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Prognóstico
5.
Endocr J ; 61(7): 705-15, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24759004

RESUMO

Vascular endothelial (VE)-cadherin and claudin-5 are major components of the adherens and tight junctions of vascular endothelial cells, respectively, and decreases in their expression are associated with increases in endothelial paracellular permeability. In the uterus, estrogen induces endometrial edema. However, the in vivo effect of estrogen on endothelial paracellular permeability is unknown. Therefore, we studied the expression of VE-cadherin and claudin-5 in vascular endothelial cells in murine uteri stimulated by estrogen or progesterone. Ovariectomized mature mice were injected with estradiol-17ß (1 µg/mouse) or progesterone (1 mg/mouse) at intervals of 24 hours for 6 days. The frozen transverse sections of the uteri of these mice and untreated mice were stained for CD31 (vascular endothelial cell marker) plus VE-cadherin or claudin-5 using a double-immunofluorescence method. Then, the percentages of VE-cadherin- or claudin-5-positive vessels among CD31-positive vessels were examined in the uterine endometria. VE-cadherin and claudin-5 were expressed in most CD31-positive vessels in the endometria of the untreated mice. Progesterone did not affect the expression of both VE-cadherin and claudin-5 and estradiol-17ß also did not affect the VE-cadherin expression, but estradiol-17ß significantly decreased the claudin-5 expression. This decreasing effect of estradiol-17ß was detected from 24 hours later when the water content per a uterus significantly increased. The present study indicates that estrogen, but not progesterone, decreases the expression of claudin-5 in vascular endothelial cells in the murine uterine endometrium from 24 hours later, suggesting that the decrease in the claudin-5 expression contributes to the endometrial edema late after the estrogen stimulation.


Assuntos
Claudina-5/antagonistas & inibidores , Endotélio Vascular/efeitos dos fármacos , Estradiol/efeitos adversos , Terapia de Reposição de Estrogênios/efeitos adversos , Estrogênios/efeitos adversos , Regulação da Expressão Gênica/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Caderinas/genética , Caderinas/metabolismo , Claudina-5/genética , Claudina-5/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Edema/patologia , Endométrio/irrigação sanguínea , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Endométrio/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Estradiol/administração & dosagem , Estrogênios/administração & dosagem , Feminino , Injeções Subcutâneas , Camundongos Endogâmicos C57BL , Ovariectomia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Progesterona/administração & dosagem , Progesterona/farmacologia , Progestinas/administração & dosagem , Progestinas/farmacologia , Doenças Uterinas/induzido quimicamente , Doenças Uterinas/metabolismo , Doenças Uterinas/patologia , Útero/irrigação sanguínea , Útero/metabolismo , Útero/patologia
6.
Cell Tissue Res ; 352(3): 647-57, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23474739

RESUMO

VE-cadherin and claudin-5 are major components of adherens and tight junctions of vascular endothelial cells and a decrease in their expression and an increase in the tyrosine-phosphorylation of VE-cadherin are associated with an increase in endothelial paracellular permeability. To clarify the mechanism underlying the development of edema in nasal polyps, we studied these molecules in polyp microvessels. Normal inferior turbinate mucosal tissues and nasal polyps from patients treated with or without glucocorticoid were stained for VE-cadherin or claudin-5 and CD31 by a double-immunofluorescence method and the immunofluorescence intensities were graded 1-3 with increasing intensity. To correct for differences in fluorescence intensity attributable to a different endothelial area being exposed in a section or to the thickness of a section, the relative immunofluorescence intensity was estimated by dividing the grade of VE-cadherin or claudin-5 by that of CD31 in each microvessel. Tyrosine-phosphorylation of VE-cadherin was examined by Western blot analysis. The relative intensities of VE-cadherin and claudin-5 in the CD31-positive microvessels significantly decreased in the following order; inferior turbinate mucosa, treated polyps and untreated polyps. The ratio of tyrosine-phosphorylated VE-cadherin to VE-cadherin was significantly higher in untreated polyps than in the inferior turbinate mucosa and treated polyps, between which no significant difference in the ratio was seen. Thus, in nasal polyps, the barrier function of endothelial adherens and tight junctions is weakened, although glucocorticoid treatment improves this weakened barrier function.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Claudina-5/metabolismo , Endotélio Vascular/metabolismo , Pólipos Nasais/metabolismo , Adulto , Idoso , Feminino , Fluorescência , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pólipos Nasais/patologia , Neutrófilos/metabolismo , Fosforilação , Fosfotirosina/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteínas de Transporte Vesicular/metabolismo
7.
Exp Toxicol Pathol ; 65(3): 351-6, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22206608

RESUMO

The oral administration of thioacetamide to rats induces cholangiofibrosis characterized by hyperplasia of ductules surrounded by fibrous tissue. In the present study, we examined the expression of markers of cholangiocyte and hepatocyte phenotypes in these hyperplastic ductule cells and their proliferative activity immunohistochemically. The oral administration of thioacetamide to 21-day-old male Fisher 344 rats for 12 weeks induced multiple areas of various sizes with hyperplastic ductules. The ductules consisted of two types of ductules; ductules composed of cholangiocyte-like cuboidal cells with transparent nuclei and cytoplasm, and of intestinal epithelium-like (IE-like) cells of basophilic nuclei and cytoplasm, and the transition of these two types of cells in the same ductule was sometimes observed. The cholangiocyte-like cells expressed cytokeratin (CK)-7, CK-19 and OV-6 (cholangiocyte phenotype markers) but not Hep Par-1 antigen or HNF4α (hepatocyte phenotype markers). In contrast, the IE-like cells expressed Hep Par-1 antigen and HNF4α but not CK-7, CK-19 or OV-6. The examination of Ki-67 expression showed a much higher proliferative activity for the IE-like cells compared to the cholangiocyte-like cells. The present results show that the hyperplastic ductules induced by thioacetamide are composed of IE-like cells with a high proliferative activity expressing the hepatocyte phenotype markers and of cholangiocyte-like cells with a low proliferative activity expressing the cholangiocyte phenotype markers.


Assuntos
Ductos Biliares/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Cirrose Hepática/induzido quimicamente , Tioacetamida/toxicidade , Animais , Ductos Biliares/metabolismo , Ductos Biliares/patologia , Biomarcadores/metabolismo , Fibrose , Hepatócitos/metabolismo , Hepatócitos/patologia , Hiperplasia , Imuno-Histoquímica , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Fenótipo , Ratos , Ratos Endogâmicos F344
8.
Int J Oncol ; 41(6): 2005-12, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22992985

RESUMO

Tumor cells express NKG2D ligands on their cell surface, which are the ligands of the activating receptor, NKG2D, that is expressed on the surface of NK cells. The binding of NK cells to tumor cells through the interaction of NKG2D and its ligands induces the cytolysis of the tumor cells. In the present study, we investigated the effects of hypoxia on the expression of NKG2D ligands on the surface of human osteosarcoma cells using three cell lines. To produce hypoxic and normoxic conditions, the osteosarcoma cell lines were cultured under 1 and 20% O2 conditions, respectively. The osteosarcoma cells expressed NKG2D ligands such as MHC class I-related chain molecules A and B (MICA and MICB) and the UL16-binding proteins 1, 2 and 3 (ULBP 1, 2 and 3). MICA was the most frequently expressed NKG2D ligand in the osteosarcoma cells. Hypoxia decreased the expression of cell surface MICA only without increasing the secretion of soluble MICA, which is produced by proteolytic cleavage of cell surface MICA. Hypoxia consistently decreased the susceptibility of the osteosarcoma cells to the cytotoxicity of the NK cells. Hypoxia induced the expression of hypoxia-inducible factor-1α (HIF-1α), and knockdown of the expression of HIF-1α using small interfering RNA increased the expression of cell surface MICA and concomitantly increased the level of soluble MICA. Hypoxia decreased the production of nitric oxide (NO) metabolites (nitrite and nitrate), thus, indicating a decreasing effect on NO production. However, a NO donor, NOC18, decreased the expression of cell surface MICA without any apparent effects on the expression of HIF-1α under both hypoxic and normoxic conditions. The present results indicate that hypoxia downregulates the expression of cell surface MICA without increasing the level of soluble MICA in a HIF-1α-dependent manner and suggest that the effects of hypoxia are not linked to the hypoxia-induced reduction of NO production.


Assuntos
Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Osteossarcoma/genética , Osteossarcoma/metabolismo , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células , Citotoxicidade Imunológica/imunologia , Regulação para Baixo/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células Matadoras Naturais/imunologia , Ligantes , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Óxido Nítrico , Osteossarcoma/imunologia
9.
Oncol Rep ; 28(5): 1585-90, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22923031

RESUMO

Valproic acid, a histone deacetylase inhibitor, increases the expression of cell surface MHC class I-related chain molecules (MICs) A and B (MICA and B) in osteosarcoma cells and decreases their secretion of soluble MICA and MICB, which are produced by the proteolytic cleavage of cell surface MICs. Osteosarcoma cells have been reported to produce high levels of matrix metalloproteinase (MMP)-2 and -9. In this study, we investigated the involvement of MMP-2 and -9 in the inhibitory action of valproic acid (VPA) on the proteolytic cleavage of cell surface MICs using the U-2 OS and SaOS-2 osteosarcoma cell lines. VPA caused a marked decrease in the expression of MMP-9 mRNA in the U-2 OS and SaOS-2 cells and in the expression of MMP-2 mRNA in the U-2 OS cells, but only a slight decrease in the expression of MMP-2 mRNA in the SaOS-2 cells. The transfection of small interfering RNA (siRNA) for MMP-9 decreased the secretion of soluble MICA and MICB by both U-2 OS and SaOS-2 cells, but that of siRNA for MMP-2 did not. The present study therefore demonstrates that the downregulation of MMP-9 mRNA by VPA plays a role in the inhibitory action of VPA on the secretion of soluble MICA and MICB in osteosarcoma cells.


Assuntos
Antígenos de Histocompatibilidade Classe I/biossíntese , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Osteossarcoma/genética , Ácido Valproico/farmacologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Dipeptídeos/farmacologia , Regulação para Baixo , Humanos , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/biossíntese , Proteínas de Membrana/biossíntese , Osteossarcoma/metabolismo , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno
10.
Int J Oncol ; 41(1): 83-91, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22576685

RESUMO

We investigated the effects of valproic acid (VPA), a histone deacetylase inhibitor, in combination with hydralazine, a DNA methylation inhibitor, on the expression of cell-surface Fas and MHC-class I-related chain molecules A and B (MICA and B), the ligands of NKG2D which is an activating receptor of NK cells, and on production of their soluble forms in HOS, U-2 OS and SaOS-2 human osteosarcoma cell lines. We also examined the susceptibility of these cells to Fas- and NK cell-mediated cell death. VPA did not increase the expression of Fas on the surface of osteosarcoma cells, while hydralazine did, and the combination of VPA with hydralazine increased the expression of cell-surface Fas. In contrast, the combination of VPA with hydralazine did not increase the production of soluble Fas by osteosarcoma cells. Both VPA and hydralazine increased the expression of cell-surface MICA and B in osteosarcoma cells, and their combination induced a greater increase in their expression. VPA inhibited the production of both soluble MICA and MICB by osteosarcoma cells while hydralazine produced no effect. Both VPA and hydralazine enhanced the susceptibility of osteosarcoma cells to Fas- and NK cell-mediated cell death and the combination of VPA with hydralazine further enhanced the effects. The present results suggest that combined administration of VPA and hydrazine is valuable for enhancing the therapeutic effects of immunotherapy for osteosarcomas.


Assuntos
Antineoplásicos/farmacologia , Citotoxicidade Imunológica/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Hidralazina/farmacologia , Células Matadoras Naturais/fisiologia , Ácido Valproico/farmacologia , Receptor fas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Metilação de DNA/efeitos dos fármacos , Metilases de Modificação do DNA/antagonistas & inibidores , Sinergismo Farmacológico , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Células Matadoras Naturais/imunologia , Osteossarcoma , Regiões Promotoras Genéticas , Evasão Tumoral/efeitos dos fármacos , Receptor fas/imunologia
11.
Cytokine ; 59(1): 41-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22537848

RESUMO

OBJECTIVES: Interleukin (IL)-22 acts on non-immune cells to induce anti-microbial responses, protection from tissue damage, and enhance cell regeneration. However, little is known about the involvement of IL-22 in periodontal biology. This study investigated the biological effects of IL-22 on periodontal ligament (PDL) cells as part of studies to assess the involvement of IL-22 in periodontal disease. MATERIALS AND METHODS: Gene expression levels of IL-22 and its receptors in PDL cells and gingival tissue samples were evaluated by real-time PCR. Proliferative responses and mineralized-matrix forming activities of PDL cells were examined in the presence and absence of IL-22. RESULTS: In contrast to the expression of IL-22 receptors detected in PDL tissues and their cell lines, gingival tissues showed modest or no gene expressions of IL-22. The production of several cytokines including IL-11, IL-8 and CCL2 was upregulated by IL-22 treatment of PDL cells in a dose-dependent manner. IL-22 treatment had no effect on the proliferative response in PDL cells. Meanwhile, IL-22 precipitated mineralized nodule formation and induced gene expressions of RUNX2, MSX2 and osteocalcin in PDL cells, suggesting that IL-22 enhances the mineralized matrix-forming activities of PDL cells. CONCLUSION: IL-22 has the potential to promote mineralizing activity in PDL cells and to develop appropriate regenerative therapy.


Assuntos
Calcificação Fisiológica , Interleucinas/metabolismo , Ligamento Periodontal/patologia , Biomarcadores/metabolismo , Calcificação Fisiológica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Clonais , Regulação da Expressão Gênica/efeitos dos fármacos , Gengiva/efeitos dos fármacos , Gengiva/metabolismo , Humanos , Interleucinas/farmacologia , Ligantes , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Ligamento Periodontal/efeitos dos fármacos , Periodontite/genética , Periodontite/patologia , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Interleucina 22
12.
Med Mol Morphol ; 45(1): 7-13, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22431178

RESUMO

Expression of phenotype markers of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) in HCC and CC components of 20 combined hepatocellular and cholangiocarcinomas (CHCs) of the liver was investigated immunohistochemically. Both HCC and CC components of all CHCs expressed at least one of the CC phenotype markers [cytokeratin (CK)-7, CK-19, and carbohydrate (CA) 19-9]. HCC components in 90% of CHCs and CC components in 95% of CHCs expressed at least one of these CC phenotype markers in more than 40% of cancer cells. HCC components in all CHCs expressed at least one of the HCC phenotype markers [hepatocyte antigen (HA), α-fetoprotein (AFP), and canalicular carcinoembryonic antigen]. HCC components in 90% of CHCs and CC components in 75% of CHCs expressed HA, AFP, or both. HCC components in 75% of CHCs and CC components in 60% of CHCs expressed HA, AFP, or both in more than 10% of cancer cells. The present results show that both HCC and CC components of most of the CHCs expressed both HCC and CC phenotypes, supporting the hypothesis that CHC originates from a hepatic progenitor cell capable of differentiating into hepatocytes and cholangiocytes.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Colangiocarcinoma/patologia , Neoplasias Hepáticas/patologia , Idoso , Neoplasias dos Ductos Biliares/metabolismo , Ductos Biliares Intra-Hepáticos/metabolismo , Biomarcadores Tumorais/genética , Antígeno Carcinoembrionário/genética , Antígeno Carcinoembrionário/metabolismo , Carcinoma Hepatocelular/metabolismo , Colangiocarcinoma/metabolismo , Feminino , Humanos , Queratina-19/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Fenótipo , alfa-Fetoproteínas/genética , alfa-Fetoproteínas/metabolismo
13.
Innate Immun ; 18(1): 164-70, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21239459

RESUMO

Chronic low-grade infection has been suggested to be associated with metabolic disorder such as diabetes. However, the molecular mechanism underlying this important association is largely unknown. The only clue established so far is that many subjects exhibit elevated levels of C-reactive protein as measured by highly sensitive assay. Here, we hypothesized that adipocyte-macrophage interaction plays a key role in amplifying such low grade infection to the level of influencing metabolic disorders. The presence of macrophages in abdominal adipose tissues was investigated by immunohistochemistry. To see whether molecules associated with acute phase protein, LPS signaling, and persistent recruitment of monocytes, are produced at higher amounts in adipocytes co-cultured with macrophages stimulated with low concentration of LPS (1 ng/ml), we measured serum amyloid A (SAA), LPS binding protein (LBP), soluble CD14 (sCD14), and RANTES levels in culture supernatant of co-cultures. Lastly, we investigated in vivo effect of low-grade LPS infusion on the production of these molecules using obese model mice. The macrophages were certainly identified in abdominal adipose tissues. Investigated molecules, especially LBP, SAA, and RANTES were produced at higher amounts in co-cultures stimulated with LPS compared with the cells without LPS. The ob/ob, and high-fat diet-induced obesity mice produced higher amounts of LBP, SAA, and RANTES one day after LPS infusion (1 ng/ml/g body weight) compared with ob/- and normal-fat fed control mice. Thus, adipocytes and infiltrated macrophages, and their interaction with low endotoxin stimulation appear to play an important role in amplifying and maintaining LPS-induced low-grade inflammation.


Assuntos
Adipócitos/metabolismo , Transtornos do Metabolismo dos Lipídeos/genética , Transtornos do Metabolismo dos Lipídeos/imunologia , Macrófagos/metabolismo , Gordura Abdominal/patologia , Proteínas de Fase Aguda/genética , Proteínas de Fase Aguda/metabolismo , Adipócitos/imunologia , Adipócitos/patologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Comunicação Celular , Células Cultivadas , Quimiocina CCL5/genética , Quimiocina CCL5/metabolismo , Técnicas de Cocultura , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação/imunologia , Leptina/genética , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/administração & dosagem , Macrófagos/imunologia , Macrófagos/patologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Obesos , Proteína Amiloide A Sérica/genética , Proteína Amiloide A Sérica/metabolismo
14.
Oncol Lett ; 2(6): 1041-1046, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22848265

RESUMO

In this study, the expression of hepatocyte markers, including α-fetoprotein (AFP), HepPar-1 antigen and arginase-1, was examined immunohistochemically in 14 mass-forming peripheral intrahepatic cholangiocarcinomas (ICCs) that arose from the peripheral portion of the biliary tree, and in 14 periductal-infiltrating hilar ICCs that arose from intrahepatic large bile ducts. Only 2 (14.3%) of the 14 hilar ICCs and 2 (14.3%) of the 14 peripheral ICCs expressed AFP or HepPar-1 antigen. Conversely, arginase-1 was expressed in 8 (57.1%) and 11 (78.6%) of the hilar and peripheral ICCs, respectively, and 4 (28.6%) hilar ICCs and 7 (50%) peripheral ICCs expressed arginase-1 in more than 10% of the cancer cells. The expression of arginase-1 did not differ between peripheral ICCs showing major histology of poorly differentiated adenocarcinoma and those showing other major histologies, including well-or moderately differentiated tubular adenocarcinoma or papillary adenocarcinoma. Results of the present study showed that common hepatocyte markers, including AFP and HepPar-1 antigen, are rarely but definitely expressed in hilar and peripheral ICCs, and that a third hepatocyte marker, arginase-1, is expressed at a high rate in both hilar and peripheral ICCs, irrespective of their histology. These results indicate that care should be taken when using arginase-1 as a hepatocyte marker for distinguishing between a poorly differentiated hepatocellular carcinoma and a mass-forming peripheral ICC showing the histology of poorly differentiated adenocarcinoma.

15.
Jpn J Infect Dis ; 63(6): 427-32, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21099094

RESUMO

Periodontitis is a chronic inflammatory disease caused by the infection of periodontopathic bacteria in dental plaque. However, an individual's susceptibility to this disease appears to be associated with multiple genetic factors, as seen in the case of leprosy. In order to gain a better understanding of the pathophysiology of periodontal disease in subjects with leprosy, we investigated the clinical features of periodontitis and the immunological responses against periodontopathic bacteria in 382 subjects with a history of leprosy and 451 age-matched control subjects. The prevalence of periodontitis and the degree of periodontal pocket depth were found to be significantly higher in leprosy patients than in age-matched controls. Furthermore, a comparison of the clinical parameters of lepromatous leprosy (L-lep) and tuberculoid leprosy (T-lep) patients showed that the probing pocket depth of L-lep patients with periodontal disease was significantly higher than that for T-lep patients. In contrast, serum IgG titers against Porphyromonas gingivalis in L-lep patients were significantly lower than in T-lep patients. These results imply that L-lep patients show more severe periodontal disease than T-lep patients or age-matched control subjects, and that low humoral immunity against P. gingivalis might be one of the genetic factors determining periodontal disease susceptibility in leprosy patients.


Assuntos
Hanseníase Virchowiana/complicações , Hanseníase Tuberculoide/complicações , Periodontite/imunologia , Periodontite/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/sangue , Infecções por Bacteroidaceae/epidemiologia , Infecções por Bacteroidaceae/imunologia , Infecções por Bacteroidaceae/microbiologia , Infecções por Bacteroidaceae/fisiopatologia , Estudos de Casos e Controles , Feminino , Humanos , Japão/epidemiologia , Hanseníase Virchowiana/epidemiologia , Hanseníase Virchowiana/microbiologia , Hanseníase Tuberculoide/epidemiologia , Hanseníase Tuberculoide/microbiologia , Masculino , Pessoa de Meia-Idade , Bolsa Periodontal , Periodontite/epidemiologia , Periodontite/microbiologia , Porphyromonas gingivalis/imunologia , Prevalência , Índice de Gravidade de Doença
16.
Oncol Rep ; 24(6): 1621-7, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21042760

RESUMO

MHC class I-related chain molecules A and B (MICA and B) expressed on the cell-surface of tumor cells are ligands for an activating receptor, NKG2D, expressed on natural killer (NK) cells and stimulate the NK cell-mediated cytotoxicity. On the other hand, the soluble form of MICA and B produced by proteolytic cleavage of cell-surface MIC interferes with NK cell-mediated cytotoxicity. We investigated effect of sodium valproate (VPA), a histone deacetylase inhibitor, on the production of cell-surface and soluble MICA and B and NK cell-mediated cytotoxicity in four human osteosarcoma cells. VPA at 0.5 and 1.0 mM induced acetylation of histones bound to MICA and B gene promoters, increased cell-surface but not soluble MICA and B, and augmented the susceptibility of osteosarcoma cells to NK cell-mediated cytotoxicity. The present results indicate that VPA sensitizes human osteosarcoma cells to cytotoxicity of NK cells.


Assuntos
Neoplasias Ósseas/terapia , Antígenos de Histocompatibilidade Classe I/genética , Imunidade Celular/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Osteossarcoma/terapia , Ácido Valproico/farmacologia , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Neoplasias Ósseas/genética , Neoplasias Ósseas/imunologia , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Terapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Imunoterapia/métodos , Ligantes , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Osteossarcoma/genética , Osteossarcoma/imunologia , Osteossarcoma/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Solubilidade , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
17.
Lab Invest ; 90(12): 1747-56, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20680009

RESUMO

Fibroblasts act as important immune regulatory cells via their ability to cross-talk with T cells accumulating in lesions. Our previous study showed that fibroblasts produce several cytokines and chemokines by crosslinking HLA class II (HLA-II) molecules with monoclonal antibodies or by making T-cell receptor-peptide-HLA complexes. It is thus conceivable that the interaction of T cells and fibroblasts via HLA-II affects fibroblast responses to stimuli. This study used human gingival fibroblasts (HGF) to investigate possible effects of these fibroblast-derived soluble factors on the differentiation of naïve T cells and on the subsequent fibroblast responses. After mixed lymphocyte reaction culture between naïve T cells and allogeneic dendritic cells in the presence of culture supernatant from HGF stimulated via HLA-DQ molecules (DQ-sup), but not via DR, T cells exhibited a Th2-shifted phenotype, thereby producing quantitatively more IL-13 and IL-5 compared with interferon-γ. Astonishingly, analyses to identify possible factors affecting the Th2 polarization secreted from HLA-II-stimulated HGF, prostaglandin E2, was detected only in DQ-sup. The Th2 polarization of naïve T cells was blocked in the presence of supernatants from indomethacin-treated HGF with HLA-DQ stimulation. In addition, we found that the culture supernatants of Th cells activated following mixed lymphocyte reaction culture in the presence of DQ-sup had the potential to induce gene expression of type I and III collagens in HGF. These results suggested that fibroblasts stimulated via HLA-DQ molecules promote Th2 polarization in Th-cell responses and showed the counter activation of collagen synthesis, implicating orchestrated responses among these cells in the fibrosis of chronic inflammatory lesions.


Assuntos
Citocinas/biossíntese , Fibroblastos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Prostaglandinas E/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/imunologia , Fibroblastos/efeitos dos fármacos , Gengiva/imunologia , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DQ/metabolismo , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Técnicas In Vitro , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-13/imunologia , Interleucina-13/metabolismo , Interleucina-5/imunologia , Interleucina-5/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Masculino , Prostaglandinas E/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo
18.
Med Mol Morphol ; 42(4): 222-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20033368

RESUMO

We examined the expressions of adhesion molecules (E-cadherin, beta-catenin, CD44s, and CD44v6) and Ki-67 labeling index (Ki-67 LI) in low- and moderate-grade dysplasia and invasive carcinoma components in ten noninvasive intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and eight invasive carcinomas associated with IPMNs of the pancreas using immunohistochemical methods. There was no significant difference in regard to the proportion of components expressing either E-cadherin or beta-catenin in more than 70% of the tumor cells between the low- and moderate-grade dysplasia components. In contrast, the proportion of those in invasive carcinoma components was significantly lower than in low- or moderate-grade dysplasia components. Also, there was no significant difference in the proportion of components expressing CD44s or CD44v6 in more than 5% of tumor cells among low-grade dysplasia, moderate-grade dysplasia, and invasive carcinoma components. In contrast, the Ki-67 LI values increased in the order of low-grade dysplasia, moderate-grade dysplasia, and invasive carcinoma components, with significant differences among them. The present results indicate that carcinoma components are associated with a decrease in tumor cells expressing E-cadherin and beta-catenin and have the highest proliferative activity.


Assuntos
Adenocarcinoma Mucinoso , Caderinas/metabolismo , Carcinoma Papilar , Moléculas de Adesão Celular/metabolismo , Neoplasias Pancreáticas , beta Catenina/metabolismo , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Papilar/metabolismo , Carcinoma Papilar/patologia , Proliferação de Células , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Imuno-Histoquímica/métodos , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia
19.
Tumour Biol ; 30(4): 176-84, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19738413

RESUMO

The effect of immunotherapy with interleukin-18 (IL-18) in combination with preoperative chemotherapy on the postoperative progression of pulmonary metastasis was examined using a spontaneous pulmonary metastasis model of mouse osteosarcoma. Mice were inoculated subcutaneously with highly metastatic murine osteosarcoma cells (LM8) and then underwent chemotherapy with ifosfamide (30 or 60 mg/kg body weight, days 14-16), immunotherapy with IL-18 (2 microg/mouse, days 18-24) or combined immunotherapy and chemotherapy. Tumors developed in mice were excised 21 days after cell inoculation when microscopic but not macroscopic pulmonary metastasis was observed in mice. Three weeks after the excision of the tumors, macroscopic pulmonary metastasis was observed on the surface of the lung. Administration of ifosfamide or IL-18 alone decreased the number of macroscopic pulmonary metastases, and combined administration of ifosfamide and IL-18 resulted in much greater inhibition of pulmonary metastasis. These results suggest that immunotherapy in combination with preoperative chemotherapy is highly effective in suppressing postoperative progression of pulmonary metastasis.


Assuntos
Neoplasias Ósseas/imunologia , Ifosfamida/uso terapêutico , Imunoterapia/métodos , Interleucina-18/uso terapêutico , Osteossarcoma/imunologia , Osteossarcoma/cirurgia , Animais , Neoplasias Ósseas/cirurgia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Camundongos , Camundongos Endogâmicos C3H , Proteínas Recombinantes/uso terapêutico
20.
Jpn J Infect Dis ; 62(5): 381-3, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19762989

RESUMO

Pyogenic liver abscess (PLA) formation is thought to originate from the transmission of infection via three major routes including the biliary tract, portal vein and hepatic artery. However, about 50% of PLA cases are considered to be cryptogenic. Here we report an unusual autopsy case of PLA associated with periodontopathic bacterial infection. A 59-year-old female suddenly developed cardiopulmonary arrest and died. Despite macroscopic and microscopic examinations, the infectious routes and source of infection were unidentified, and the case appeared to be cryptogenic. Since this patient had suffered severe periodontitis for a long period of time, we investigated the involvement of periodontal infection in PLA formation by performing immunohistochemical analyses. We identified several periodontopathic bacterial species in the PLA of this patient, including Fusobacterium nucleatum, Treponema denticola, Prevotella intermedia and Porphyromonas gingivalis. Thus, we demonstrate here that periodontal infection is a potential source of infection in the formation of PLA.


Assuntos
Fusobacterium nucleatum/isolamento & purificação , Abscesso Hepático Piogênico/microbiologia , Doenças Periodontais/complicações , Porphyromonas gingivalis/isolamento & purificação , Prevotella intermedia/isolamento & purificação , Treponema denticola/isolamento & purificação , Autopsia , Evolução Fatal , Feminino , Humanos , Rim/patologia , Fígado/patologia , Pessoa de Meia-Idade , Miocárdio/patologia
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