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Dexamethasone prevents granulocyte-macrophage colonystimulating factor-induced nuclear factor-kB activation, inducible nitric oxide synthase expression and nitric oxide production in a skin dendritic cell line

Vital, Ana Luísa; Gonçalo, Margarida; Cruz, M. Teresa; Figueiredo, Américo; Duarte, Carlos B.; Lopes, M. Celeste
Fonte: Taylor & Francis Publicador: Taylor & Francis
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
66.05%
AIMS: Nitric oxide (NO) has been increasingly implicated in inflammatory skin diseases, namely in allergic contact dermatitis. In this work, we investigated the effect of dexamethasone on NO production induced by the epidermal cytokine granulocyte / macrophage colony-stimulating factor (GM-CSF) in a mouse fetal skin dendritic cell line.Methods: NO production was assessed by the method of Griess. Expression of the inducible isoform of nitric oxide synthase (iNOS) protein was evaluated by western blot analysis and immunofluorescence microscopy. Western blot analysis was also performed to evaluate cytosolic IkappaB-alpha (IkB-a) protein levels. The electrophoretic mobility shift assay was used to evaluate the activation or inhibition of nuclear factor kappa B (NF-kB).Results: GM-CSF induced iNOS expression and NO production, and activated the transcription factor NF-kB. Dexamethasone inhibited, in a dose-dependent manner, NO production induced by GM-CSF. Addition of dexamethasone to the culture, 30 min before GM-CSF stimulation, significantly inhibited the cellular expression of iNOS. Dexamethasone also inhibited GM-CSF-induced NFkB activation by preventing a significant decrease on the IkB-a protein levels, thus blocking NF-kB migration to the nucleus.Conclusions: The corticosteroid dexamethasone inhibits GM-CSF-induced NF-kB activation...

Dexamethasone prevents interleukin-1beta-induced nuclear factor-kappaB activation by upregulating IkappaB-alpha synthesis, in lymphoblastic cells

Castro-Caldas, M.; Mendes, A. F.; Carvalho, A. P.; Duarte, C. B.; Lopes, M. C.
Fonte: Taylor & Francis Ltd Publicador: Taylor & Francis Ltd
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
75.84%
AIMS: Glucocorticoids (GCs) exert some of their anti-inflammatory actions by preventing the activation of the transcription factor nuclear factor (NF)-kappaB. The GC-dependent inhibition of NF-kappaB may occur at different levels, but the mechanisms involved are still incompletely understood. In this work, we investigated whether the synthetic GC, dexamethasone (Dex), modulates the activity of NF-kappaB in the lymphoblastic CCRF-CEM cell line. We also evaluated the ability of Dex to prevent the activation of NF-kappaB in response to the potent proinflammatory cytokine, interleukin (IL)-1beta. RESULTS: Exposure of the cells to Dex (1 microM) induced the rapid degradation of IkappaB-alpha, leading to the transient translocation of the NF-kappaB family members p65 and p50 from the cytoplasm to the nucleus, as evaluated by western blot. Electrophoretic mobility shift assays revealed that, in the nucleus, these NF-kappaB proteins formed protein-DNA complexes, indicating a transient activation of NF-kappaB. Additionally, Dex also induced de novo synthesis of IkappaB-alpha, following its degradation. Finally, when the cells were exposed to Dex (1 microM) prior to stimulation with IL-1beta (20 ng/ml), Dex was efficient in preventing IL-1beta-induced NF-kappaB activation. The GC antagonist...

Identification of the nuclear factor kappa-beta (NF-kB) in cortical of mice Wistar using Technovit 7200 VCR (R)

SALLES, Marcos B.; KOENIG JR., Bruno; ALLEGRINI JR., Sergio; YOSHIMOTO, Marcelo; MARTINS, Marilia T.; COELHO, Paulo G.
Fonte: MEDICINA ORAL S L Publicador: MEDICINA ORAL S L
Tipo: Artigo de Revista Científica
ENG
Relevância na Pesquisa
55.97%
Objective: this study aimed to develop a nondecalcified bone sample processing technique enabling immunohistochemical labeling of proteins by kappa-beta nuclear factor (NF-kB) utilizing the Technovit 7200 VCR (R) in adult male Wistar rats. Study Method: A 1.8 mm diameter defect was performed 0.5mm from the femur proximal joint by means of a round bur. Experimental groups were divided according to fixing solution prior to histologic processing: Group 1- ethanol 70%; Group 2-10% buffered formalin; and Group 3- Glycerol diluted in 70% ethanol at a 70/30 ratio + 10% buffered formalin. The post-surgical periods ranged from 01 to 24 hours. Control groups included a nonsurgical procedure group (NSPG) and surgical procedures where bone exposure was performed (SPBE) without drilling. Prostate carcinoma was the positive control (PC) and samples subjected to incomplete immunohistochemistry protocol were the negative control (NC). Following euthanization, all samples were kept at 4 degrees C for 7 days, and were dehydrated in a series of alcohols at -20 degrees C. The polymer embedding procedure was performed at ethanol/polymer ratios of 70%-30%, 50%-50%, 30%-70%, 100%, and 100% for 72 hours at -20 degrees C. Polymerization followed the manufacturer`s recommendation. The samples were grounded and polished to 10-15 mu m thickness...

O papel do fator nuclear kappa B (NF-kB) e do eixo IL-12/23-IFN-g na ativação do sistema NADPH oxidase.; The role of nuclear factor kappa B (NF-kB) and the IL-12/23-IFN-g axis in the activation of the NADPH oxidase system.

Aragão Filho, Walmir Cutrim
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 26/03/2009 PT
Relevância na Pesquisa
56.1%
O sistema NADPH oxidase é um complexo enzimático gerador de superóxido. O NF-kB é um fator de transcrição envolvido no controle da expressão de diversos genes ligados à resposta inflamatória. Defeitos no eixo IL-12/23-IFN-g resultam em infecções recorrentes e à susceptibilidade mendeliana a micobacterioses, podendo diminuir a expressão do componente gp91-phox da NADPH oxidase. Estudamos qual é a relação direta do NF-kB e de defeitos no eixo IL-12/23-IFN-g na regulação dos genes CYBA, NCF1, NCF2 e NCF4 do sistema NADPH oxidase humano em células U937, células B EBV transformadas provenientes de pacientes com EDA-ID, DGC, ou de pacientes com defeitos no eixo IL-12/23-IFN-g. A expressão dos genes NCF1 e NCF2 foi diminuída em células com defeitos no eixo (IFNGR1 e INFGR2) e em células U937 IkB S32A/S36A. A expressão do gene NCF1 também foi diminuída em células EDA-ID S32I e em células EDA-ID NEMO/IKKg W420X. O NF-kB e os IFNGR1 e INFGR2 são necessários para a expressão dos genes NCF1 e NCF2 e para a ativação do sistema NADPH oxidase humano neste sistema modelo.; The NADPH oxidase system is an enzymatic complex that generates superoxide. The NF-kB is a transcriptional factor involved in the expression of several genes related to the inflammatory response. The IL-12/23-IFN-g axis defects lead to recurrent infections and to the mendelian susceptibility of mycobacterial disease (MSMD)...

Avaliação dos produtos finais de glicosilação e o fator nuclear K-B em glandulas lacrimais e superficie ocular de modelos animais de diabetes e envelhecimento; Advanced glycation end-products and Nuclear Factor K-B in lacrimal glands and ocular surface of diabetes and aging animal models

Monica de Cassia Alves
Fonte: Biblioteca Digital da Unicamp Publicador: Biblioteca Digital da Unicamp
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 21/07/2006 PT
Relevância na Pesquisa
75.89%
Este estudo avaliou as possíveis vias comuns na fisiopatogênese da síndrome do olho seco no Diabetes Mellitus (DM) e no envelhecimento, envolvendo o acúmulo dos produtos de glicosilação ("Advanced Glycation End-products" - AGEs), seu receptor RAGE e a ativação do Fator Nuclear-?B (NF-?B) na glândula lacrimal (GL) e alterações do filme lacrimal nessas condições. Modelos animais de DM induzido com estreptozotocina e animais senis (24 meses de vida) foram comparados a animais controle tratados com tampão citrato e adultos jovens (2 meses de vida). Foram avaliadas vias de sinalização, envolvendo AGEs, RAGE e a ativação do NF-?B na GL e alterações no filme lacrimal em ratos Wistar de todos os grupos. A análise do filme lacrimal foi realizada através de medidas de volume de secreção basal e dosagem de citocinas como a Interleucina-1 ß (IL-1 ß) e Fator de Necrose Tumoral - a (TNF- a). A capacidade secretória da GL foi avaliada através de medidas da atividade de peroxidase. Técnicas de "western blot" foram utilizadas para avaliar a expressão e ativação do NF-?B na GL. A expressão de AGE, RAGE e NF-?B na GL e córnea nos grupos estudados, foi avaliada através de microscopia confocal com imunofluorescência. O volume lacrimal foi significativamente menor nos animais diabéticos e senis (P=0...

Polysaccharides from the fungus Scleroderma nitidum with anti-inflammatory potential modulate cytokine levels and the expression of Nuclear Factor kB

Nascimento,Marília S.; Magalhães,Joedyson E. M.; Pinheiro,Thuane S.; Silva,Thayse Azevedo da; Coutinho,Leonam Gomes; Baseia,Iuri G.; Lima,Lucymara F. Agnez; Leite,Edda Lisboa
Fonte: Sociedade Brasileira de Farmacognosia Publicador: Sociedade Brasileira de Farmacognosia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/02/2012 EN
Relevância na Pesquisa
55.75%
Several pharmacological properties are attributed to polysaccharides and glucans derived from fungi such as tumor, anti-inflammatory, and immunomodulatory activity. In this work, the anti-inflammatory potential of polysaccharides from the fungus Scleroderma nitidum and their possible action mechanism were studied. The effect of these polymers on the inflammatory process was tested using the carrageenan and histamine-induced paw edema model and the sodium thioglycolate and zymosan-induced model. The polysaccharides from S. nitidum were effective in reducing edema (73% at 50 mg/kg) and cell infiltrate (37% at 10 mg/kg) in both inflammation models tested. Nitric oxide, a mediator in the inflammatory process, showed a reduction of around 26% at 10 mg/kg of body weight. Analysis of pro-and anti-inflammatory cytokines showed that in the groups treated with polysaccharides from S. nitidum there was an increase in cytokines such as IL-1ra, IL-10, and MIP-1β concomitant with the decrease in INF-γ (75%) and IL-2 (22%). We observed the influence of polysaccharides on the modulation of the expression of nuclear factor κB. This compound reduced the expression of NF-κB by up to 64%. The results obtained suggest that NF-κB modulation an mechanisms that explain the anti-inflammatory effect of polysaccharides from the fungus S. nitidum.

Insights into the regulation of TNF-a production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition

Deree,Jessica; Martins,Joilson O.; Melbostad,Heidi; Loomis,William H.; Coimbra,Raul
Fonte: Faculdade de Medicina / USP Publicador: Faculdade de Medicina / USP
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/01/2008 EN
Relevância na Pesquisa
66.13%
OBJECTIVE: The objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-a) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells. INTRODUCTION: The production of TNF-a following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-a production in the presence of LPS remains unclear. METHODS: Human mononuclear cells were stimulated with LPS (1 µg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-kBa, nuclear factor-kB p65 (NF-kB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-kB and CREB was verified by electrophoretic mobility shift assay. TNF-a levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA). RESULTS: PTX was demonstrated to significantly reduce cytoplasmic I-kBa phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-kB. In contrast...

Diminished forkhead box P3/CD25 double-positive T regulatory cells are associated with the increased nuclear factor-kB ligand (RANKL+) T cells in bone resorption lesion of periodontal disease

Ernst, C W O; Lee, J E; Nakanishi, T; Karimbux, N Y; Rezende, T M B; Stashenko, P; Seki, M; Taubman, M A; Kawai, T
Fonte: Blackwell Science Inc Publicador: Blackwell Science Inc
Tipo: Artigo de Revista Científica
Publicado em /05/2007 EN
Relevância na Pesquisa
65.89%
Periodontal disease involves multi-bacterial infections accompanied by inflammatory bone resorption lesions. The abundant T and B lymphocyte infiltrates are the major sources of the osteoclast differentiation factor, receptor activator for nuclear factor-kB ligand (RANKL) which, in turn, contributes to the development of bone resorption in periodontal disease. In the present study, we found that the concentrations of RANKL and regulatory T cell (Treg)-associated cytokine, interleukin (IL)-10, in the periodontal tissue homogenates were correlated negatively, whereas RANKL and proinflammatory cytokine, IL-1β, showed positive correlation. Also, according to the fluorescent-immunohistochemistry, the frequency of forkhead box P3 (FoxP3)/CD25 double-positive cells was diminished strikingly in the bone resorption lesion of periodontal disease compared to healthy gingival tissue, while CD25 or FoxP3 single positive cells were still observed in lesions where abundant RANKL+ lymphocytes were present. Very importantly, few or no expressions of FoxP3 by the RANKL+ lymphocytes were observed in the diseased periodontal tissues. Finally, IL-10 suppressed both soluble RANKL (sRANKL) and membrane RANKL (mRANKL) expression by peripheral blood mononuclear cells (PBMC) activated in vitro in a bacterial antigen-specific manner. Taken together...

Plasma and drainage fluid levels of soluble receptor activator of nuclear factor-kB (sRANK), soluble receptor activator of nuclear factor-kB ligand (sRANKL) and osteoprotegerin (OPG) during proximal humerus fracture healing

Colombini, Alessandra; Lombardi, Giovanni; Galliera, Emanuela; Dogliotti, Giada; Randelli, Pietro; Meerssemann, Alexander; Mineo, Giuseppe; Cabitza, Paolo; Corsi, Massimiliano Marco
Fonte: Springer-Verlag Publicador: Springer-Verlag
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
65.98%
Fracture healing is an ordered process that restores the structural integrity of the bone. Soluble receptor activator of nuclear factor-kB (sRANK), its ligand (sRANKL) and osteoprotegerin (OPG) are involved in bone remodelling, thus they may play a role in fracture repair. OPG, soluble RANK and RANKL levels were measured in plasma and in drainage fluid, collected from pre-surgery phase to healing in ten patients of both genders (age range 26–65 years) with proximal humerus fracture needing osteosynthesis. All patients showed fracture healing. No significant modifications in the concentrations of sRANKL and OPG were observed, while sRANK showed a significant increase in drainage fluid 24 hours post-surgery compared with intra-surgery time. OPG levels were higher in plasma and drainage fluid than sRANK and sRANKL at each time point. Since there are no published data about sRANK involvement in fracture healing, our study represents the first preliminary indication about a local increase of this marker concentration immediately after surgery.

Nuclear factor-kB p65 (RelA) transcription factor is constitutively activated in human colorectal carcinoma tissue

Yu, Liang-Liang; Yu, Hong-Gang; Yu, Jie-Ping; Luo, He-Sheng; Xu, Xi-Ming; Li, Jun-Hua
Fonte: Baishideng Publishing Group Inc Publicador: Baishideng Publishing Group Inc
Tipo: Artigo de Revista Científica
EN
Relevância na Pesquisa
55.8%
AIM: Activation of transcription factor nuclear factor-κB (NF-κB) has been shown to play a role in cell proliferation, apoptosis, cytokine production, and oncogenesis. The purpose of this study was to determine whether NF-κB was constitutively activated in human colorectal tumor tissues and, if so, to determine the role of NF-κB in colorectal tumorigenesis, and furthermore, to determine the association of RelA expression with tumor cell apoptosis and the expression of Bcl-2 and Bcl-xL.

Comparison of effects of clodronate and zoledronic acid on the repair of maxilla surgical wounds - histomorphometric, receptor activator of nuclear factor-kB ligand, osteoprotegerin, von Willebrand factor, and caspase-3 evaluation

Vasconcelos, Ana Carolina Uchoa; Berti-Couto, Soraya Azambuja; Azambuja, Alan Arrieira; Salum, Fernanda Gonçalves; Figueiredo, Maria Antonia Zancanaro; Silva, Vinícius Duval da; Cherubini, Karen
Fonte: John Wiley & Sons A/S; Porto Alegre Publicador: John Wiley & Sons A/S; Porto Alegre
Tipo: Artigo de Revista Científica
EN_US
Relevância na Pesquisa
65.92%
BACKGROUND: The aim of this study was to compare clodronate and zoledronic acid regarding their influence on the repair of surgical wounds in maxillae (soft tissue wound and tooth extraction) and their relation to osteonecrosis. MATERIAL AND METHODS: Thirty-four Wistar rats were allocated into three groups according to the treatment received: (i) 12 animals treated with zoledronic acid, (ii) 12 animals treated with clodronate and (iii) 10 animals that were given saline solution. All animals were subjected to tooth extractions and surgically induced soft tissue injury. Histological analysis of the wound sites was performed by means of hematoxylin–eosin (H&E) staining and immunohistochemical staining for receptor activator of nuclear factor-kB ligand (RANKL), osteoprotegerin (OPG), von Willebrand factor, and caspase-3. RESULTS: The zoledronic acid group showed higher incidence of non-vital bone than did the clodronate group at the tooth extraction site. At the soft tissue wound site, there were no significant differences in non-vital bone between the test groups. RANKL, OPG, von Willebrand factor, and caspase-3 did not show significant differences between the groups for both sites of surgical procedures. CONCLUSION: Both of the bisphosphonates zoledronic acid and clodronate are capable of inducing maxillary osteonecrosis. Immunohistochemical analysis suggests that the involvement of soft tissues as the initiator of osteonecrosis development is less probable than has been pointed out.

Roles of Notch and NF-kB signaling in allogeneic responses

Murase, Tosei
Fonte: Universidade Nacional da Austrália Publicador: Universidade Nacional da Austrália
Tipo: Thesis (PhD); Doctor of Philosophy (PhD)
EN_AU
Relevância na Pesquisa
55.86%
The induction of robust allograft tolerance is the ultimate goal for clinical transplantation. Although studies have identified that dendritic cells (DCs) are important for induction of antigen-specific tolerance, the requirements for generating tolerogenic DCs are yet to be elucidated. Recently, it has been demonstrated the modulation of two signaling pathways, Notch and nuclear factor KB (NF-KB) can render DCs tolerogenic. The studies documented here examine (1) whether immature DCs over-expressing Notch-related molecules (Jagged-I, Delta-like-I (Dll-I), Lunatic Fringe (Ung) , and Manic Fringe (Mfng)) act as immunoregulatory DCs and promote allograft survival; and (2) whether DCs deficient in NF-KB signaling inhibit the alloreactive T cell response and promote allograft survival ... Although the potential for Notch signaling to promote alloantigen-specific tolerance remains unresolved, these studies suggest that inhibition of NF-KB signaling in DCs represent a potential approach for promoting allograft survival.; Yes

Variability of RANKL and osteoprotegerin staining in synovial tissue from patients with active rheumatoid arthritis: Quantification using color video image analysis

Crotti, T.; Ahern, M.; Lange, K.; Weedon, H.; Coleman, M.; Roberts-Thomson, P.; Haynes, D.; Smith, M.
Fonte: J Rheumatol Publ Co Publicador: J Rheumatol Publ Co
Tipo: Artigo de Revista Científica
Publicado em //2003 EN
Relevância na Pesquisa
55.82%
OBJECTIVE: To assess the interpatient, interbiopsy, and intrabiopsy variability of receptor activator of nuclear factor kB ligand (RANKL) and osteoprotegerin (OPG) immunostaining within synovial tissue from rheumatoid knee joints with active synovitis, using digital image analysis. METHODS: Synovial biopsy specimens were obtained from patients with rheumatoid arthritis (RA) and active synovitis. Immunohistologic analysis was performed on frozen synovial tissue biopsy specimens from 6 patients using a monoclonal antibody (Mab) to detect RANKL (626) or OPG (805 or 8051). Patients with a minimum of 4 synovial biopsies were included in the study. Sections were evaluated by computer assisted image analysis to assess between-patient, between-biopsy, and intra-biopsy variability of OPG and RANKL protein expression. The study was designed to deliberately maximize the variability. RESULTS: Computerized image analysis of staining with Mab to RANKL and OPG revealed variance for each antibody across the 3 components of the total variability. CONCLUSION: Our study shows that variability in synovial immunostaining of RANKL and OPG protein is a significant and complex problem. We discuss methods to reduce this variability and suggest that the auspices of OMERACT may be employed to advance the study of synovium in collaborative international studies.; Tania N. Crotti...

Receptor activator of nuclear factor-kB ligand expression by human myeloma cells mediates osteoclast formation in vitro and correlates with bone destruction in vivo

Farrugia, A.; Atkins, G.; To, L.; Pan, B.; Horvath, N.; Kostakis, P.; Findlay, D.; Bardy, P.; Zannettino, A.
Fonte: Amer Assoc Cancer Research Publicador: Amer Assoc Cancer Research
Tipo: Artigo de Revista Científica
Publicado em //2003 EN
Relevância na Pesquisa
75.84%
Multiple myeloma (MM) is an incurable B-cell malignancy able to mediate massive destruction of the axial skeleton. The aim of this study was to examine the involvement of the tumor necrosis factor-ligand family member, receptor activator of nuclear factor-B ligand (RANKL), and its naturally occurring antagonist, osteoprotegerin (OPG), in MM biology. Using flow cytometry and two independent anti-RANKL antibodies, we demonstrate RANKL expression in CD38+++CD45+ and CD38+++CD45- myeloma plasma cell (MPC) subpopulations derived from patients with osteolytic MM. In addition, highly purified subpopulations of MPC express mRNA for both transmembrane and soluble RANKL isoforms but lack expression of OPG mRNA and protein. We also show that RANKL expressed by MPC is functional as in vitro coculture of CD38+++CD45+ and CD38+++CD45- MPC subpopulations with peripheral blood mononuclear cells resulted in the formation of multinucleate, tartrate-resistant acid phosphatase-positive osteoclasts-like cells capable of forming typical resorption pits. Furthermore, high expression of membrane-associated RANKL by CD38+++ MPC correlated with the presence of multiple radiological bone lesions in individuals with MM. Together, our data strongly suggest that RANKL expression by MPC confers on them the ability to participate directly in the formation of osteoclast in vivo and extends our knowledge of the involvement of RANKL and OPG in the osteolysis characteristic of this disease.; Amanda N. Farrugia...

Molecular profiling of giant cell tumor of bone and the osteoclastic localization of ligand for receptor activator of nuclear factor kB

Morgan, T.; Atkins, G.; Trivett, M.; Johnson, S.; Kansara, M.; Schlicht, S.; Slavin, J.; Simmons, P.; Dickinson, I.; Powell, G.; Choong, P.; Holloway, A.; Thomas, D.
Fonte: Amer Soc Investigative Pathology Inc Publicador: Amer Soc Investigative Pathology Inc
Tipo: Artigo de Revista Científica
Publicado em //2005 EN
Relevância na Pesquisa
75.82%
Giant cell tumor of bone (GCT) is a generally benign, osteolytic neoplasm comprising stromal cells and osteoclast-like giant cells. The osteoclastic cells, which cause bony destruction, are thought to be recruited from normal monocytic pre-osteoclasts by stromal cell expression of the ligand for receptor activator of nuclear factor kappaB (RANKL). This model forms the foundation for clinical trials in GCTs of novel cancer therapeutics targeting RANKL. Using expression profiling, we identified both osteoblast and osteoclast signatures within GCTs, including key regulators of osteoclast differentiation and function such as RANKL, a C-type lectin, osteoprotegerin, and the wnt inhibitor SFRP4. After ex vivo generation of stromal- and osteoclast-enriched cultures, we unexpectedly found that RANKL mRNA and protein were more highly expressed in osteoclasts than in stromal cells, as determined by expression profiling, flow cytometry, immunohistochemistry, and reverse transcriptase-polymerase chain reaction. The expression patterns of molecules implicated in signaling between stromal cells and monocytic osteoclast precursors were analyzed in both primary and fractionated GCTs. Finally, using array-based comparative genomic hybridization, neither GCTs nor the derived stromal cells demonstrated significant genomic gains or losses. These data raise questions regarding the role of RANKL in GCTs that may be relevant to the development of molecularly targeted therapeutics for this disease.; Teresa Morgan...

Receptor activator NF kB ligand (RANKL) and osteoprotegerin (OPG) protein expression in periodontitis

Crotti, T.; Smith, M.; Hirsch, R.; Soukoulis, S.; Weedon, H.; Capone, M.; Ahern, M.; Haynes, D.
Fonte: Munksgaard Int Publ Ltd Publicador: Munksgaard Int Publ Ltd
Tipo: Artigo de Revista Científica
Publicado em //2003 EN
Relevância na Pesquisa
55.82%
Objectives and background: This study investigated the expression of key mediators that regulate differentiation of osteoclasts, receptor activator of nuclear factor κB ligand (RANKL), and its natural inhibitor, osteoprotegerin (OPG), in periodontitis. We aimed to compare the levels of the RANKL and OPG in the granulomatous tissue adjacent to areas of alveolar bone loss from patients with periodontitis to that present in tissue from patients without periodontitis. In addition, we aimed to determine the types of cells expressing these factors in these tissues and to demonstrate the expression of the osteoclastic markers, RANK and tartrate-resistant acid phosphatase (TRAP), in periodontitis. Materials and methods: Frozen biopsy specimens were analysed using specific monoclonal antibodies and were evaluated by semiquantitative analysis and digital image analysis to compare levels of RANKL and OPG protein expression. Double labelling of frozen sections with antibodies to different cell lineage specific markers was used to determine the types of cells expressing these proteins. In situ hybridization was used to detect cells expressing RANK mRNA. Results: Semiquantitative image analysis demonstrated that significantly higher levels of RANKL protein (P < 0.05) were expressed in the periodontitis tissue. Conversely...

Dietary emu oil supplementation suppresses 5-fluorouracil chemotherapy-induced inflammation, osteoclast formation, and bone loss

Raghu Nadhanan, R.; Mashtoub, S.; Su, Y.W.; Scherer, M.; Howarth, G.; Xian, C.
Fonte: Amer Physiological Soc Publicador: Amer Physiological Soc
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
55.78%
Cancer chemotherapy can cause osteopenia or osteoporosis, and yet the underlying mechanisms remain unclear, and currently, no preventative treatments are available. This study investigated damaging effects of 5-fluorouracil (5-FU) on histological, cellular, and molecular changes in the tibial metaphysis and potential protective benefits of emu oil (EO), which is known to possess a potent anti-inflammatory property. Female dark agouti rats were gavaged orally with EO or water (1 ml•day_1•rat_1) for 1 wk before a single ip injection of 5-FU (150 mg/kg) or saline (Sal) was given. The treatment groups were H2O + Sal, H2O + 5-FU, EO + 5-FU, and EO + Sal. Oral gavage was given throughout the whole period up to 1 day before euthanasia (days 3, 4, and 5 post-5-FU). Histological analysis showed that H2O + 5-FU significantly reduced heights of primary spongiosa on days 3 and 5 and trabecular bone volume of secondary spongiosa on days 3 and 4. It reduced density of osteoblasts slightly and caused an increase in the density of osteoclasts on trabecular bone surface on day 4. EO supplementation prevented reduction of osteoblasts and induction of osteoclasts and bone loss caused by 5-FU. Gene expression studies confirmed an inhibitory effect of EO on osteoclasts since it suppressed 5-FU-induced expression of proinflammatory and osteoclastogenic cytokine TNFa...

Early exposure of interferon-γ inhibits signal transducer and activator of transcription-6 signalling and nuclear factor κB activation in a short-term monocyte-derived dendritic cell culture promoting 'FAST' regulatory dendritic cells; Early exposure of interferon-gamma inhibits signal transducer and activator of transcription-6 signalling and nuclear factor kappaB activation in a short-term monocyte-derived dendritic cell culture promoting 'FAST' regulatory dendritic cells

Rojas-Canales, D.; Krishnan, R.; Jessup, C.; Coates, P.
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Publicado em //2012 EN
Relevância na Pesquisa
55.9%
Early exposure of interferon-γ inhibits signal transducer and activator of transcription-6 signalling and nuclear factor κB activation in a short-term monocyte-derived dendritic cell culture promoting ‘FAST’ regulatory dendritic cellsInterferon (IFN)-γ is a cytokine with immunomodulatory properties, which has been shown previously to enhance the generation of tolerogenic dendritic cells (DC) when administered early ex vivo in 7-day monocyte-derived DC culture. To generate tolerogenic DC rapidly within 48 h, human monocytes were cultured for 24 h with interleukin (IL)-4 and granulocyte–macrophage colony-stimulating factor (GM-CSF) in the presence (IFN-γ-DC) or absence of IFN-γ (500 U/ml) (UT-DC). DC were matured for 24 h with TNF-α and prostaglandin E2 (PGE2). DC phenotype, signal transducer and activator of transcription-6 (STAT-6) phosphorylation and promotion of CD4+CD25+CD127neg/lowforkhead box P3 (FoxP3)hi T cells were analysed by flow cytometry. DC nuclear factor (NF)-κB transcription factor reticuloendotheliosis viral oncogene homologue B (RELB) and IL-12p70 protein expression were also determined. Phenotypically, IFN-γ-DC displayed reduced DC maturation marker CD83 by 62% and co-stimulation molecules CD80 (26%) and CD86 (8%). IFN-γ treatment of monocytes inhibited intracellular STAT6...

Distinct NF-kB activation pathways engaged by T-cell receptor and co-receptor CD28 on T-cells

Thaker, Youg Raj; Rudd, Christopher E
Fonte: Smart Science & Technology Publicador: Smart Science & Technology
Tipo: Article; published version
EN
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This is the final version of the article. It first appeared from Smart Science & Technology via http://dx.doi.org/10.14800/ics.613; The transcription factor nuclear factor-kB (NF-kB) is critical for the induction of inflammatory responses in T-cells, survival and differentiation. Antigen receptor (TCR) and co-receptor CD28 are the central regulators of NF-kB activation in T-cells. Progress in understanding NF-kB activation in T-cells has occurred over the years with the identification of individual adapters such as ADAP and GRB-2 and enzymes such as PKC-? that regulate NF-kB. However, little is known whether the engagement of distinct modules by the TCR and CD28 account for the cooperative effects of the two receptors in activating NF-kB. In this review, we discuss recent advances in our understanding of NF-kB regulation by TCR and CD28.; This work was supported by Wellcome Trust Program Grant (PG) PKAG/504 to Principal Research Fellow (PRF) C.E. Rudd.

Insights into the regulation of TNF-a production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition

Deree, Jessica; Martins, Joilson O.; Melbostad, Heidi; Loomis, William H.; Coimbra, Raul
Fonte: Universidade de São Paulo. Faculdade de Medicina Publicador: Universidade de São Paulo. Faculdade de Medicina
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; ; Formato: application/pdf
Publicado em 01/01/2008 ENG
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OBJECTIVE: The objective of this study was to determine the effect of nonspecific phosphodiesterase inhibition on transcription factor activation and tumor necrosis factor-alpha (TNF-a) production in lipopolysaccharide (LPS)-stimulated human mononuclear cells. INTRODUCTION: The production of TNF-a following LPS stimulation is one of the key steps in bacterial sepsis and inflammation. The mechanism by which phosphodiesterase inhibition alters TNF-a production in the presence of LPS remains unclear. METHODS: Human mononuclear cells were stimulated with LPS (1 µg/mL), in the presence and absence of Pentoxifylline (PTX; 20 mM), a nonspecific phosphodiesterase inhibitor. Western blotting of phosphorylated cytoplasmic I-kBa, nuclear factor-kB p65 (NF-kB), and nuclear cAMP-response element binding protein (CREB) was performed. DNA binding of NF-kB and CREB was verified by electrophoretic mobility shift assay. TNF-a levels were determined in the supernatant of stimulated cells in the presence and absence Protein kinase A inhibition by an enzyme-linked immunosorbent assay (ELISA). RESULTS: PTX was demonstrated to significantly reduce cytoplasmic I-kBa phosphorylation, nuclear p65 phosphorylation, and the DNA binding activity of NF-kB. In contrast...