Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine, that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.
- MeSH
- apoptóza MeSH
- chemokin CCL2 genetika metabolismus MeSH
- lidé MeSH
- lokální recidiva nádoru genetika metabolismus patologie MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši inbrední NOD MeSH
- myši SCID MeSH
- myši MeSH
- nádorové biomarkery genetika metabolismus MeSH
- nádorové buňky kultivované MeSH
- nádorové mikroprostředí MeSH
- nádory plic genetika metabolismus sekundární MeSH
- nádory prsu genetika metabolismus patologie MeSH
- prognóza MeSH
- proliferace buněk MeSH
- protoonkogenní proteiny c-myb genetika metabolismus MeSH
- regulace genové exprese u nádorů * MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Inflammatory changes, both in the arterial wall and adipose tissue, play a crucial role in the development of atherosclerosis. We measured the gene expression of tumor necrosis factor-alpha (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6) in adipose tissue (AT) of living kidney donors (LKD) and patients with peripheral arterial disease (PAD). Quantitative polymerase chain reaction (qPCR) and flow cytometry analyses were performed in subcutaneous (SAT), visceral (VAT), and perivascular adipose tissue (PVAT). Data of PAD patients showed significantly higher expression in VAT in all three genes (TNFalpha 5-fold, p<0.05; MCP-1 3.6-fold, p<0.05; IL-6 18.8-fold, p<0.001). The differences in PVAT and SAT were less significant. Total body pro-inflammatory status was documented by higher TNFalpha concentration in patients (4.86+/-1.4 pg/ml) compared to LKDs (2.14+/-0.9 pg/ml; p<0.001), as was hsCRP (11.8+/-7.0 in PAD; 1.5+/-0.48 in LKDs; p=0.017). We found no age-dependent relationship between gene expression vs. TNFalpha and hsCRP concentrations in both compared groups. No effect of the atherosclerosis score on gene expression and circulating inflammatory markers within the PAD group was observed. Our results suggest that the AT of PAD patients infiltrated with macrophages produces more cytokines involved in the development of inflammation and atherosclerosis.
- MeSH
- ateroskleróza genetika metabolismus patologie MeSH
- biologické markery metabolismus MeSH
- chemokin CCL2 biosyntéza genetika MeSH
- dospělí MeSH
- exprese genu MeSH
- interleukin-6 biosyntéza genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mediátory zánětu metabolismus MeSH
- TNF-alfa biosyntéza genetika MeSH
- tuková tkáň metabolismus patologie MeSH
- žijící dárci MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Our study focused on the ability of epicardial adipocytes to produce bioactive substances and compare the extent of this production with the production of adipokines in visceral adipocytes, which are well known endocrine cells capable of contributing to the development of atherosclerosis. MATERIAL AND METHODS: The gene expression of human cytokines (IL-6, IL-8, IL-18, RANTES and MCP-1) and adipokines (leptin and adiponectin) was measured in primary cell lines of epicardial and visceral adipocytes, both in undifferentiated and mature statuses, after a 21-day-long differentiation protocol. Each condition was assayed in triplicate in two independent primary cell lines obtained from two different donors. RESULTS: The epicardial preadipocytes showed an increased expression of IL-8 (3.25-fold, p<0.05) compared with visceral preadipocytes. The expression of the atheroprotective adiponectin in epicardial preadipocytes was minimal compared with the expression in visceral preadipocytes (p<0.0001). Moreover, the expression of the genes of interest was dependent on the differentiation degree and cell origin. We observed an altered expression of the proinflammatory genes IL-8 (0.016-fold, p<0.01) and MCP-1 (0.19-fold, p<0.05) in differentiated epicardial adipocytes compared with undifferentiated adipocytes. The epicardial adipocytes showed an increased expression of IL-6 (8.13-fold, p<0.05) compared with the visceral adipocytes. CONCLUSION: Our results suggest that epicardial adipocytes substantially differ from visceral adipocytes and might locally contribute to the pathogenesis of coronary atherosclerosis.
- MeSH
- buněčná diferenciace fyziologie MeSH
- chemokin CCL2 genetika MeSH
- chemokin CCL5 genetika MeSH
- cytokiny genetika MeSH
- dospělí MeSH
- exprese genu fyziologie MeSH
- interleukin-18 genetika MeSH
- interleukin-6 genetika MeSH
- interleukin-8 genetika MeSH
- kultivované buňky MeSH
- lidé MeSH
- nitrobřišní tuk cytologie fyziologie MeSH
- perikard cytologie fyziologie MeSH
- pilotní projekty MeSH
- tukové buňky cytologie fyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
Cíle práce: Formování amyloidových depozit probíhá především v monocytech a makrofázích. Z těchto důvodů lze předpokládat, Že některé polymoďizmy genů pro MCP-1 (monocyte chemoatracttant protein-1) a MIP-1 α (macrophage inflammatory protein-1 alpha) mohou ovlivňovat vznik sekundární (AA) amyloidózy. Cílem práce bylo stanovit vybrané polymorfizmy těchto genů a sérové koncentrace proteinů, které kódují, v populaci českých pacientů s AA amyloidózou a v kontrolních skupinách. Metodika: Byla zjišťována incidence jednotlivých genotypů ve vybraných polymorfizmech genů pro MCP-1 a MIP-1α. Byly stanoveny sérové koncentrace MCP-1 a MlP-1α a zkoumána závislost koncentrací daných cytokinů na polymorfizmech příslušných genů. Stanovení se týkala nemocných s AA amyloidózou (n = 43), pacientů s revmatoidní artritidou (RA) bez amyloidózy (n = 50) a kontrolní skupiny zdravých dobrovolníků (n = 100). Výsledky: Nebyly nalezeny statisticky významné rozdíly v zastoupení zkoumaných genotypů. Významně zvýšená (p < 0,05) byla sérová koncentrace MCP-1 ve skupině nemocných s AA amyloidózou proti skupině nemocných s RA. Zřetelně, i když ne statisticky významně, byly vyšší i koncentrace MIP u obou skupin nemocných proti kontrolní skupině zdravých dobrovolníků. Závěr: Námi zjištěné signifikantně vyšší sérové koncentrace MCP-1 ve skupině nemocných s AA amyloidózou proti skupině nemocných s RA by mohly poukazovat na zvýšenou aktivaci monocytů jako rizikového faktoru pro rozvoj onemocnění. To by mohlo mít i své terapeutické konsekvence - dřívější a razantnější léčbu onemocnění predisponujících ke vzniku AA amyloidózy u pacientů s příslušným genotypem. Potřebné je ale tyto závěry ověřit ve větších souborech nemocných.
Aim of work: Formation of amyloid deposits is localized mainly in monocytes and macrophages. Thus we may suppose influence of some polymorphisms of MCP-1 (monocyte chemoatracttant protein-1) and MIP-1 α (macrophage inflammatory protein-1 alpha) genes. The aim of this work was to determine these polymorphisms and to measure serum levels of proteins which are coded by these gene s in population of Czech patients with AA amyloidosis and control groups. Methods: The incidence of single genotypes MCP-1 and MIP-1 α genes was investigated. Serum levels of MCP-1 and MIP-1a were measured and potential relation between serum levels and genotypes was analyzed. All examinations were performed in patients wi th AA amyloidosis (n = 43), rheumatoid arthritis (n = RA) without amyloidosis and control group of healthy volunteers (n = 100). Results: No statistically significant differences in distribution of the investigated genotypes were found. Serum concentration of MCP- 1 was statistically significantly higher in AA amyloidosis group compared to RA group (p < 0,05). Concentrations of MIP were mark edly (but not statistically significantly) higher in both groups of patients compared to healthy controls. Conclusions: Our findings of significantly higher serum concentrations of MCP-1 in the AA amyloidosis group compared to RA group could advert to increased monocyte activation as a risk factor for development of AA amyloidosis. This could have also therapeu tic consequence – earlier and more assertive therapy of underlying diseases in patients with appropriate genotype in order to preve nt or interfere with occurrence of AA amyloidosis. Further studies in larger populations of patients are warranted.
- MeSH
- amyloidóza genetika krev MeSH
- chemokin CCL2 diagnostické užití genetika krev MeSH
- chemokin CCL3 diagnostické užití genetika krev MeSH
- chemokiny genetika krev MeSH
- dospělí MeSH
- financování organizované MeSH
- lidé středního věku MeSH
- lidé MeSH
- polymorfismus genetický genetika MeSH
- revmatoidní artritida genetika krev MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
The MCP-1/CCL2 as well as RANTES/CCL5 chemokines are potent chemoattractants involved in immunoregulatory and inflammatory processes of rheumatoid arthritis. Recent studies demonstrated elevated levels of MCP-1 and RANTES in plasma, synovial fluid, and the synovial tissue of patients with RA. To examine the relationship among MCP-1 and RANTES single nucleotide polymorphisms and circulating levels and rheumatoid arthritis (RA), a total of 156 RA patients and 125 controls were recruited into the study. An association of -855 C/G MCP-1 polymorphism to IgM RF within the RA patients was observed. The lowest circulating levels of RANTES were observed in the AA variant of RANTES -403 G/A polymorphism. Furthermore, an association of -403 AA variant to circulating levels of IL-15 and IL-10 was found. No associations of factors describing rheumatoid arthritis (RFs, ANA, anti-CCP-positive/negative, DAS 28 score and number of swollen joints) with MCP-1 levels, genotype distribution, allelic frequencies and/or frequencies of haplotypes composed of all three studied polymorphisms in promoter region of MCP-1, and RANTES polymorphism were observed. We conclude that the RANTES promoter polymorphism is associated to circulating levels of RANTES, IL15 and IL10. However, our findings suggest that polymorphisms in the MCP-1 and RANTES gene promoters do not contribute significantly to the interindividual RA susceptibility and/or severity in Caucasians.
- MeSH
- chemokin CCL2 krev genetika imunologie MeSH
- chemokin CCL5 krev genetika imunologie MeSH
- dospělí MeSH
- imunoglobulin M genetika imunologie MeSH
- interleukin-10 krev MeSH
- interleukin-15 krev MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- promotorové oblasti (genetika) MeSH
- revmatoidní artritida genetika imunologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- synoviální membrána metabolismus MeSH
- synoviální tekutina metabolismus MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Quaternary benzo[c]phenanthridine alkaloids sanguinarine and chelerythrine have been used in folk medicine for their wide range of useful properties. One of their major effect is also anti-inflammatory activity, that is not clarified in detail. This study focused on the ability of these alkaloids to modulate the gene expression of pro-inflammatory tumour necrosis factor α (TNF-α), monocyte chemoattractant protein 1 (MCP-1, also known as CCL-2), interleukin (IL)-6, IL-1β and anti-inflammatory cytokines IL-1 receptor antagonist (IL-1RA) and IL-10. The effect of these alkaloids was compared with that of conventional drug prednisone. Human monocyte-derived macrophages were pre-treated with alkaloids or prednisone and inflammatory reaction was induced by lipopolysaccharide. Changes of gene expression at the transcriptional level of mentioned cytokines were measured. In our study mainly affected pro-inflammatory cytokines were CCL-2 and IL-6. Two hours after LPS stimulation, cells influenced by sanguinarine and chelerythrine significantly declined the CCL-2 expression by a factors of 3.5 (p<0.001) and 1.9 (p<0.01); for those treated with prednisone the factor was 5.3 (p<0.001). Eight hours after LPS induction, both alkaloids significantly diminished the CCL-2 expression. The lower expression was found for sanguinarine--lower by a factor of 4.3 than for cells treated with the vehicle (p<0.001). Two hours after LPS stimulation, cells treated with sanguinarine decreased the IL-6 mRNA level by a factor of 3.9 (p<0.001) compared with cells treated with the vehicle. Chelerythrine decreased the level of IL-6 mRNA by a factor of 1.6 (p<0.001). Sanguinarine decreased gene expression of CCL-2 and IL-6 more than chelerythrine and its effect was quite similar to prednisone. Four hours after LPS stimulation, cells pre-treated with sanguinarine exhibited significantly higher expression (a factor of 1.7, p<0.001) of IL-1RA than cells without sanguinarine treatment. Our results help to clarify possible mechanisms of action of these alkaloids in the course of inflammation.
- MeSH
- antiflogistika farmakologie terapeutické užití MeSH
- benzofenantridiny farmakologie terapeutické užití MeSH
- buněčné linie MeSH
- chemokin CCL2 genetika metabolismus MeSH
- exprese genu účinky léků MeSH
- fytoterapie MeSH
- genetická transkripce účinky léků MeSH
- interleukin-6 genetika metabolismus MeSH
- isochinoliny farmakologie terapeutické užití MeSH
- lidé MeSH
- lipopolysacharidy MeSH
- makrofágy účinky léků metabolismus MeSH
- mediátory zánětu metabolismus MeSH
- prednison farmakologie terapeutické užití MeSH
- rostlinné extrakty farmakologie terapeutické užití MeSH
- zánět farmakoterapie genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Poznatky získané v posledních letech defi nují aterosklerózu jako chronické systémové zánětlivé onemocnění, které je charakterizováno degenerativními změnami a extracelulární akumulací lipidů. Zánět je důležitým patogenetickým mechanismem aterosklerózy, jejíž klinické projevy zahrnují onemocnění různé lokalizace a závažnosti. V procesu aterogeneze hrají klíčovou úlohu chemotaktické cytokiny a jejich receptory. Expresi a funkci těchto molekul ovlivňuje variabilita (polymorfi smy) genů, které je kódují. Snahou badatelů v translačním výzkumu je na základě nových znalostí patobiologie kardiovaskulárních onemocnění rozšířit současné spektrum vyšetřovaných parametrů o nové ukazatele, které by pomohly upřesnit míru rizika vzniku a progrese onemocnění. Jednou z cest k vytčenému cíli je studium kandidátních molekul uplatňujících se v patogenezi aterosklerózy, diskutovanou kandidátní molekulou je také mononukleární chemoatraktant MCP-1 (CCL2) a jeho receptor CCR2.
Atherosclerosis has been defi ned as systemic, chronic infl ammatory disease characterized by degenerative processes and extracellular accumulation of lipids. Infl ammation is important pathogenetic mechanism of atherosclerosis whose clinical manifestations comprise diseases of distinct location. Chemotactic cytokines and their receptors play key role in atherogenesis. Expression and function of these molecules is infl uenced by variability (polymorphisms) in their encoding genes. Translational research in pathobiology of cardiovascular disorders aims at extending the current spectrum of laboratory parameters with new markers, which could help us to defi ne the patients at risk more precisely and to determine disease course more accurately. Investigation of atherosclerosis candidate molecules is one of the possible routes to this aim. Mononuclear chemoattractant MCP-1 (CCL2) and its receptor CCR2 represent such molecules.
- Klíčová slova
- mononukleární chemoatraktant MCP-1 (CCL2), receptor CCR2,
- MeSH
- angina pectoris MeSH
- ateroskleróza genetika imunologie MeSH
- chemokin CCL2 genetika krev MeSH
- infarkt myokardu MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- mediátory zánětu MeSH
- polymorfismus genetický MeSH
- receptory CCR2 MeSH
- zánět MeSH
- Check Tag
- lidé MeSH
Approximately 5–10% of subjects infected with Mycobacterium tuberculosis develop active tuberculosis. It has been proposed that genetic factors determine the host's vulnerability to tuberculosis. Chemokine (C-C motif) ligand 2 (CCL2), commonly known as monocyte chemoattractant protein-1 (MCP-1), plays a key role in protective immunity against M. tuberculosis. The present study was aimed to determine if there was an association between –2581 A/G single nucleotide polymorphism of CCL2 and pulmonary tuberculosis (PTB) in a sample of Iranian subjects. This case-control study was performed on 142 PTB and 166 healthy subjects. The polymorphism of CCL2 (rs1024611) was determined using tetra amplification refractory mutational system-polymerase chain reaction (tetra ARMS-PCR). There were no significant differences between PTB patients and control subjects regarding –2581 A/G single nucleotide polymorphism of CCL2. In conclusion, our results do not support an association of –2581 A/G polymorphism of CCL2 with PTB susceptibility.
- MeSH
- chemokin CCL2 genetika MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- jednonukleotidový polymorfismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- plicní tuberkulóza genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Geografické názvy
- Írán MeSH
Flavonoids are commonly studied for their anti-inflammatory effects; however, this is the first paper describing the possible antiphlogistic activity of a geranylated flavanone. This study focused on the ability of diplacone to modulate the gene expression of pro-inflammatory tumour necrosis factor alpha and monocyte chemoattractant protein 1, and of anti-inflammatory zinc finger protein 36. The action of diplacone was also compared with that of conventional drug indomethacin. Human monocyte-derived macrophages of the human monocytic leukaemia cell line were pretreated with diplacone or indomethacin. Subsequently, inflammatory reaction was induced by lipopolysaccharide, and changes of tumour necrosis factor alpha, monocyte chemoattractant protein 1 and zinc finger protein 36 gene expression at the transcriptional level were measured. In this model, diplacone significantly down-regulated the expression of tumour necrosis factor alpha and monocyte chemoattractant protein 1 and up-regulated the zinc finger protein 36 expression. This makes diplacone a promising molecule for treatment of the inflammatory stage of diseases. The effect of diplacone in decreasing lipopolysaccharide-induced inflammatory gene expression is in many ways similar to that of the conventional drug indomethacin.
OBJECTIVE: The number of patients with end-stage renal disease (ESRD) is rising and these patients are at higher risk of cardiovascular disease. We studied the role of hormonal production of adipose tissue in the development of chronic inflammation in patients with ESRD before kidney transplantation. METHODS: Fifteen women with ESRD and 17 healthy women (control) underwent single blood drawing and visceral and subcutaneous adipose tissue sampling during surgery (kidney transplantation in the ESRD group or cholecystectomy in the control group). Serum concentrations of C-reactive protein, interleukin-6, tumor necrosis factor-alpha, leptin, adiponectin, resistin, monocyte chemoattractant protein-1 were measured. Messenger RNA expression of the same hormones, adiponectin receptors 1 and 2 and immunocompetent cell marker CD68 in subcutaneous and visceral samples were measured using real-time polymerase chain reaction. Adipose tissue was examined immunohistochemically for CD68-positive cells. RESULTS: Serum concentrations of C-reactive protein, adiponectin, resistin, interleukin-6, tumor necrosis factor-alpha, and monocyte chemoattractant protein-1 were significantly higher in the ESRD versus control group. Subcutaneous and visceral mRNA expressions of tumor necrosis factor-alpha and CD68 were significantly increased in the ESRD versus control group. Adiponectin receptor-1 and monocyte chemoattractant protein-1 mRNA expressions were significantly higher in visceral but not in subcutaneous adipose tissue of the ESRD group. Messenger RNA expressions of resistin, leptin, adiponectin, interleukin-6, and adiponectin receptor-2 in both fat depots did not significantly differ between groups. Increased infiltration of subcutaneous and visceral adipose tissue with CD68-positive immunocompetent cells was found in the ESRD group by histologic examination. CONCLUSION: Subcutaneous and visceral adipose tissues in ESRD express higher amounts of proinflammatory cytokines and may play a role in the development of systemic inflammation.
- MeSH
- adiponektin genetika metabolismus MeSH
- antigeny diferenciační myelomonocytární metabolismus MeSH
- C-reaktivní protein metabolismus MeSH
- CD antigeny metabolismus MeSH
- chemokin CCL2 genetika metabolismus MeSH
- chronické selhání ledvin metabolismus MeSH
- cytokiny metabolismus MeSH
- interleukin-6 genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mediátory zánětu metabolismus MeSH
- messenger RNA biosyntéza MeSH
- nitrobřišní tuk metabolismus MeSH
- podkožní tuk metabolismus MeSH
- receptory adiponektinu biosyntéza genetika MeSH
- resistin genetika metabolismus MeSH
- TNF-alfa krev MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
