| 1. |
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| 2. |
- Aldonyte, Ruta, et al.
(author)
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Circulating monocytes from healthy individuals and COPD patients.
- 2003
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In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 4:1, s. 11-11
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Journal article (peer-reviewed)abstract
- Background: Chronic obstructive pulmonary disease (COPD) is characterized by incompletely reversible airflow obstruction associated with inflammation in which monocytes/macrophages are the predominant inflammatory cells. The only known genetic factor related to COPD is inherited PiZZ deficiency of alpha1-antitrypsin (AAT), an inhibitor of serine proteases. Methods: We investigated the basal and LPS-stimulated release of pro-inflammatory molecules from blood monocytes isolated from age and gender matched healthy (n = 30) and COPD (n = 20) individuals with and without AAT deficiency. Results: After 18 h of cell culture the basal release of MMP-9 was 2.5-fold, p < 0.02 greater, whereas IL-8 was 1.8-fold (p < 0.01) lower from COPD patient monocytes than from controls. LPS-stimulated release of IL-6 and MCP-1 was greater from COPD patient's monocytes relative to controls, while activation of control cells resulted in enhanced secretion of ICAM-1 and MMP-9 compared to COPD patients. Independent of disease status, monocytes from PiZZ AAT carriers released less TNFalpha (by 2.3-fold, p < 0.03). Conclusions: The basal and LPS-stimulated secretion of specific pro-inflammatory molecules from circulating monocytes differs between healthy and COPD subjects. These findings may be valuable for further studies on the mechanisms involved in recruitment and activation of inflammatory cells in COPD.
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| 3. |
- Aldonyte, Ruta, et al.
(author)
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Concentration-dependent effects of native and polymerised alpha 1-antitrypsin on primary human monocytes, in vitro
- 2004
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In: BMC Cell Biology. - : Springer Science and Business Media LLC. - 1471-2121. ; 5
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Journal article (peer-reviewed)abstract
- Background: alpha1-antitrypsin (AAT) is one of the major serine proteinase inhibitors controlling proteinases in many biological pathways. There is increasing evidence that AAT is able to exert other than antiproteolytic effects. To further examine this question we compared how various doses of the native (inhibitory) and the polymerised (non- inhibitory) molecular form of AAT affect pro-inflammatory responses in human monocytes, in vitro. Human monocytes isolated from different donors were exposed to the native or polymerised form of AAT at concentrations of 0.01, 0.02, 0.05, 0.1, 0.5 and 1 mg/ml for 18 h, and analysed to determine the release of cytokines and to detect the activity of NF-kappaB. Results: We found that native and polymerised AAT at lower concentrations, such as 0.1 mg/ml, enhance expression of TNFalpha (10.9- and 4.8-fold, p < 0.001), IL-6 (22.8- and 23.4-fold, p < 0.001), IL-8 (2.4- and 5.5-fold, p < 0.001) and MCP-1 (8.3- and 7.7-fold, p < 0.001), respectively, compared to buffer exposed cells or cells treated with higher doses of AAT ( 0.5 and 1 mg/ml). In parallel to increased cytokine levels, low concentrations of either conformation of AAT (0.02-0.1 mg/ml) induced NF-kappaB p50 activation, while 1 mg/ml of either conformation of AAT suppressed the activity of NF-kappaB, compared to controls. Conclusions: The observations reported here provide further support for a central role of AAT in inflammation, both as a regulator of proteinase activity, and as a signalling molecule for the expression of pro-inflammatory molecules. This latter role is dependent on the concentration of AAT, rather than on its proteinase inhibitory activity.
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| 4. |
- Gerbod-Giannone, MC, et al.
(author)
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Suppression of cholesterol 7 alpha-hydroxylase transcription and bile acid synthesis by an alpha(1)-antitrypsin peptide via interaction with alpha(1)-fetoprotein transcription factor
- 2002
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In: Journal of Biological Chemistry. - 1083-351X. ; 277:45, s. 42973-42980
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Journal article (peer-reviewed)abstract
- alpha(1)-Antitrypsin (alpha(1)-AT) is a serum protease inhibitor that is synthesized mainly in the liver, and its rate of synthesis markedly increases in response to inflammation. This increase in alpha(1)-AT synthesis results in an increase in peptides, like its carboxyl-terminal C-36 peptide (C-36), resulting from alpha(1)-AT cleavage by proteases. Atherosclerosis is a form of chronic inflammation, and one of the risk factors is elevated plasma cholesterol levels. Because of the correlation between atherosclerosis, plasma cholesterol content, inflammation, and alpha(1)-AT rate of synthesis, we investigated the effect of the C-36 serpin peptide on hepatic bile acid biosynthesis. We discovered that C-36 is a powerful and specific transcriptional down-regulator of bile acid synthesis in primary rat hepatocytes, through inhibition of the cholesterol 7alpha-hydroxylase/CYP7A1 (7alpha-hydroxylase) promoter. Mice injected with the C-36 peptide also showed a decrease in 7alpha-hydroxylase mRNA. A mutated but very similar peptide did not have any effect on 7alpha-hydroxylase mRNA or its promoter. The sterol 12alpha-hydroxylase/ CYP8B1 (12alpha-hydroxylase) promoter is also down-regulated by the C-36 peptide in HepG2 cells but not by the mutated peptide. The DNA element involved in the C-36-mediated regulation of 7alpha- and 12a-hydroxylase promoters mapped to the alpha(1)-fetoprotein transcription factor (FTF) site in both promoters. The C-36 peptide prevented binding of FTF to its target DNA recognition site by direct interaction with FTF. We hypothesize that the C-36 peptide specifically interacts with FTF and induces a conformational change that results in loss of its DNA binding ability, which results in suppression of 7alpha- and 12alpha-hydroxylase transcription. These results suggest that peptides derived from specific serum proteins may alter hepatic gene expression in a highly specific manner.
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| 5. |
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| 6. |
- Grip, Olof, et al.
(author)
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Atorvastatin activates PPAR-gamma and attenuates the inflammatory response in human monocytes.
- 2002
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In: Inflammation Research. - 1420-908X. ; 51:2, s. 58-62
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To investigate the ability of statins to activate the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR-gamma) in primary human monocytes in culture. MATERIALS AND METHODS: Human peripheral monocytes were incubated with atorvastatin (0.1-10 micromol/1) for up to 24 hours. PPAR-gamma expression was analysed by electrophoretic mobility shift assay. Pro-inflammatory cytokines were measured by enzyme-linked immunosorbent assays, and oxygen consumption was determined polarographically with a Clark-type oxygen electrode. RESULTS: We found that atorvastatin activates PPAR-gamma and inhibits the production of tumour necrosis factor-alpha up to 38% (p < 0.05), monocyte chemoattractant protein-1 up to 85% (p < 0.05), and gelatinase B up to 73% (p < 0.05), in a concentration-dependent manner. Moreover, atorvastatin shows concentration-dependent inhibition of cellular oxygen consumption up to 41%. CONCLUSIONS: These findings contribute to the growing knowledge of the anti-inflammatory effects of statins, and have led us to the suggestion that statins may control inflammatory responses by the regulation of intracellular lipid homeostasis.
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| 7. |
- Grip, Olof, et al.
(author)
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Circulating monocytes and plasma inflammatory biomarkers in active Crohn's disease : Elevated oxidized low-density lipoprotein and the anti-inflammatory effect of artorvastatin
- 2004
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In: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1078-0998 .- 1536-4844. ; 10:3, s. 193-200
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Journal article (peer-reviewed)abstract
- We investigated inflammatory biomarkers in plasma and in circulating monocytes obtained from patients with Crohn's disease and healthy individuals. Additionally, we assessed the effects of atorvastatin, 10 μM, ex vivo on monocytes cultured for 18 hours from the same subjects. Plasma and blood monocytes from eight patients with active Crohn's disease and eight healthy individuals were analyzed by enzyme-linked immunosorbent and electrophoretic mobility assays. Patients with active Crohn's disease had increased plasma levels of tumor necrosis factor (TNF)-α (7.7-fold;p < 0.05), monocyte chemoattractant protein (MCP)-1 (1.3-fold; p < 0.05), and oxidized low density lipoprotein (oxLDL) (1.2-fold; p < 0.05). Monocytes from patients with Crohn's disease showed enhanced secretion of MCP-1 (4.8-fold; p < 0.05) and a markedly suppressed secretion of macrophage migration inhibitory factor (MIF) (93%; p < 0.001). Transcriptional activation of nuclear factor-kappaB did not differ between the groups. Treating monocytes with atorvastatin resulted in the suppression of MCP-1 (42%; p < 0.05) and TNF-α (45%; p < 0.05) secretion. These results show increased levels of certain proinflammatory biomarkers, including oxLDL, in plasma and indicate that peripheral blood monocytes in active Crohn's disease are sensitized to chemotaxis. Treatment with atorvastatin may be a potential strategy to reduce oxLDL and inhibit monocyte migration to inflamed tissue, thus attenuating the inflammatory response.
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| 8. |
- Grip, Olof, et al.
(author)
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Macrophages in inflammatory bowel disease
- 2003
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In: Current Drug Targets. Inflammation & Allergy. - 1568-010X. ; 2:2, s. 155-160
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Journal article (peer-reviewed)abstract
- Blood monocytes which differentiate into tissue macrophages, are unique in that they can not only initiate immune responses but can also be effector cells which contribute to the resolution of these responses. There is no single activation phenotype, and macrophages can be induced to differentiate into cells that either exacerbate or inhibit acute inflammation. Similarly, these cells can promote, deviate or suppress adaptive immune responses. This review focuses on the mechanisms that have been implicated in the recruitment, activation and differentiation of inflammatory monocytes/macrophages in chronic inflammatory bowel diseases, i.e. ulcerative colitis and Crohn's disease. These mechanisms might provide attractive targets for novel therapies.
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| 9. |
- Grip, Olof, et al.
(author)
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Pravastatin down-regulates inflammatory mediators in human monocytes in vitro
- 2000
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In: European Journal of Pharmacology. - 0014-2999. ; 410:1, s. 83-92
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Journal article (peer-reviewed)abstract
- There is experimental evidence that pravastatin, which is designed to inhibit the rate-limiting enzyme of cholesterol synthesis, can affect cell metabolism and proliferation. We therefore studied the effects of pravastatin on the generation of inflammatory mediators in non-stimulated and stimulated primary human monocytes in vitro. In our experimental model, pravastatin induced a dose-dependent inhibition of monocyte cholesterol synthesis (up to 67%), up-regulation of low density lipoprotein receptor mRNA (by about 35%) and reduction in intracellular cholesterol accumulation. In parallel, exposure of non-stimulated monocytes to various doses of pravastatin resulted in inhibition of monocyte chemoattractant protein-1 protein expression (up to 15-fold), reduction of tumour necrosis factor alpha (TNF-α) levels (up to 2.4-fold) and a total loss of metalloproteinase-9 activity in stimulated cells. Pravastatin at concentrations of 5, 100 and 500 μM caused an inhibition of TNF-α-induced cellular oxygen consumption from 2.4- to 5.5-fold. These data extend the findings of potential anti-inflammatory actions of statins and also suggest the possibility for pravastatin use in a broader spectrum of inflammatory situations.
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| 10. |
- Hollander, Camilla, et al.
(author)
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Human mast cells decrease SLPI levels in type II - like alveolar cell model, in vitro.
- 2003
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In: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 3:1
-
Journal article (peer-reviewed)abstract
- Background Mast cells are known to accumulate at sites of inflammation and upon activation to release their granule content, e.g. histamine, cytokines and proteases. The secretory leukocyte protease inhibitor (SLPI) is produced in the respiratory mucous and plays a role in regulating the activity of the proteases. Result We have used the HMC-1 cell line as a model for human mast cells to investigate their effect on SLPI expression and its levels in cell co-culture experiments, in vitro. In comparison with controls, we found a significant reduction in SLPI levels (by 2.35-fold, p < 0.01) in a SLPI-producing, type II-like alveolar cell line, (A549) when co-cultured with HMC-1 cells, but not in an HMC-1-conditioned medium, for 96 hours. By contrast, increased SLPI mRNA expression (by 1.58-fold, p < 0.05) was found under the same experimental conditions. Immunohistochemical analysis revealed mast cell transmigration in co-culture with SLPI-producing A549 cells for 72 and 96 hours. Conclusion These results indicate that SLPI-producing cells may assist mast cell migration and that the regulation of SLPI release and/or consumption by mast cells requires interaction between these cell types. Therefore, a "local relationship" between mast cells and airway epithelial cells might be an important step in the inflammatory response.
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| 11. |
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| 12. |
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| 13. |
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Johansson, Björn, et al.
(author)
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Alpha-1-antitrypsin is present in the specific granules of human eosinophilic granulocytes
- 2001
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In: Clinical and Experimental Allergy. - : Wiley. - 1365-2222 .- 0954-7894. ; 31:3, s. 379-386
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Journal article (peer-reviewed)abstract
- Eosinophils may be found at sites of inflammation, for example in asthma, allergy and helminthic infestation, but their role in human inflammatory disease is unclear. In the present study, we investigated the presence of alpha-1-antitrypsin (AAT), a serine proteinase inhibitor, in human eosinophils. When lysates of highly purified eosinophils were subjected to Western blotting, with a chemiluminescent substrate, immunoreactive bands were seen. An ELISA was developed to measure the AAT content, which was found to be about 100 ng/5 x 106 eosinophils, about 50 ng/5 x 106 neutrophils, and about 25 ng/5 x 106 monocytes. Immunoelectron microscopy showed localization of AAT to the specific granules of eosinophils. During prolonged incubation of eosinophils, no significant increase in the total amount of AAT could be detected by ELISA. However, there was an increased level of AAT in the medium, in parallel with a decrease in the intracellular AAT content, suggesting release of preformed AAT. Apparent complex formation between iodinated elastase and AAT in eosinophil lysates provided evidence that the AAT is functionally active. On the basis of these findings it is suggested that by releasing AAT, eosinophils may, in a microenvironment, play a role in counteracting the tissue damage caused by serine proteinases released by neutrophils in inflammatory conditions.
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| 18. |
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| 19. |
- Schiopu, Alexandru, et al.
(author)
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Recombinant human antibodies against aldehyde-modified apolipoprotein B-100 peptide sequences inhibit atherosclerosis
- 2004
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In: Circulation. - 1524-4539. ; 110:14, s. 2047-2052
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Journal article (peer-reviewed)abstract
- Background-Accumulation and oxidation of LDL are believed to be important initiating factors in atherosclerosis. Oxidized LDL is recognized by the immune system, and animal studies have suggested that these immune responses have a protective effect against atherosclerosis. Aldehyde-modified peptide sequences in apolipoprotein B-100 (apoB-100) are major targets for these immune responses. Methods and Results-Human IgG1 antibodies against 2 malondialdehyde (MDA)-modified apoB-100 peptide sequences were produced through screening of a single-chain antibody-fragment library and subsequent cloning into a pcDNA3 vector. Three weekly doses of these antibodies were injected into male apoE(-/-) mice. Phosphate-buffered saline and human IgG1 antibodies against fluorescein isothiocyanate were used as controls. One of the IgG1 antibodies significantly and dose-dependently reduced the extent of atherosclerosis as well as the plaque content of oxidized LDL epitopes and macrophages. In cell culture studies, human monocytes were incubated with native LDL or oxidized LDL, in the presence of antibodies. The same antibody induced an increase in monocyte binding and uptake of oxidized LDL. Conclusions-These findings suggest that antibodies are important mediators of atheroprotective immune responses directed to oxidized LDL. Thus, passive immunization against MDA-modified apoB-100 peptide sequences may represent a novel therapeutic approach for prevention and treatment of cardiovascular disease.
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| 20. |
- Sun, Yongxin, et al.
(author)
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Alpha1-antichymotrypsin/Alzheimer's peptide Abeta(1-42) complex perturbs lipid metabolism and activates transcription factors PPARgamma and NFkappaB in human neuroblastoma (Kelly) cells.
- 2002
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In: Journal of Neuroscience Research. - : Wiley. - 1097-4547 .- 0360-4012. ; 67:4, s. 511-522
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Journal article (peer-reviewed)abstract
- Amyloid-beta peptide (A) and the serpin proteinase inhibitor 1-antichymotrypsin (ACT) are components of the amyloid plaques associated with Alzheimer's disease (AD). A exists in soluble monomeric and oligomeric forms and in an insoluble polymerised fibrillar form, but it is not clear which of these plays the most important role in the etiology of AD. In vitro, A1-42 interacts with ACT, and as a result of this, ACT loses its proteinase inhibitor activity and polymerisation of A1-42 is promoted. Here we provide evidence that new molecular forms resulting from incubation of ACT with A1-42 have multiple cellular level effects on neuronal cells. The mixture of soluble A and an ACT/A complex formed by 2 hr incubation at a 10:1 molar ratio of A:ACT strongly induce cellular proliferation and expression of transcription factors peroxisome proliferator-activated receptor-gamma (PPAR) and NFB, and also increase uptake and depress degradation of native and oxidised low-density lipoprotein (LDL) by cells. Similar but less pronounced effects are seen when cells are exposed to the A peptide alone preincubated for 2 hr. A1-42 and to a lesser extent ACT/A1-42 complex mixture prepared by 2 hr incubation both inhibit association of native LDL with cells. Neither ACT alone nor the A1-42 and ACT/A1-42 forms prepared by 24-hr incubation show any significant effects in these assays. We propose that specific molecular forms of A1-42 and ACT/A1-42 complex mixture, both dependent on the abundances of A1-42 and ACT/A1-42 in vivo and on their time of exposure to each other, have cellular effects which are important for the initiation and progression of the pathologies associated with AD.
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| 21. |
- Sun, Yongxin, et al.
(author)
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Glioma cell activation by Alzheimer's peptide Abeta1-42, alpha1-antichymotrypsin, and their mixture.
- 2002
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In: Cellular and Molecular Life Sciences. - 1420-9071. ; 59:10, s. 43-1734
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Journal article (peer-reviewed)abstract
- We compared the effects of Alzheimer’s peptide (Ab1–42), a1-antichymotrypsin (ACT) and an ACT/Ab1–42 mixture on human glioma DK-MG cells. The solution of Ab (5 mM) formed by 2-h incubation at room temperature induced tumour necrosis factor-a (TNF-a) and interleukin (IL)-6 levels by 55 and 45%, respectively, and increased gelatinase B activity by 67%, while exposure of cells to the ACT/Ab1–42 mixture (1:10 molar ratio ACT: Ab1–42) under the same experimental conditions showed no effect on IL-6 levels or gelatinase B activity, but strongly induced TNF-a (by 190%), compared to the con- CMLS, Cell. Mol. Life Sci. 59 (2002) 1734–1743 1420-682X/02/101734-11 © Birkhäuser Verlag, Basel, 2002 CMLS Cellular and Molecular Life Sciences trols. Stimulation of the cells with Ab1–42 alone, but not with ACT, increased by about 20% low-density lipoprotein (LDL) uptake and mRNA levels for LDL receptor and HMG-CoA reductase, while the ACT/Ab1–42 mixture significantly increased LDL uptake (by 50%), up-regulated mRNA levels for LDL receptor and HMG-CoA reductase by 48 and 63%, respectively, and increased lipid accumulation by about 20-fold. These data suggest a possible new role for Ab in Alzheimer’s disease through its interaction with the inflammatory reactant, ACT.
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| 22. |
- Sun, Yongxin, et al.
(author)
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Inflammatory markers in matched plasma and cerebrospinal fluid from patients with Alzheimer's disease.
- 2003
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In: Dementia and Geriatric Cognitive Disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 16:3, s. 136-144
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Journal article (peer-reviewed)abstract
- It has been suggested that a number of molecules associated with inflammation are involved in the pathogenesis of Alzheimer's disease (AD). We measured the levels of alpha1-antichymotrypsin (ACT), alpha1-antitrypsin (AAT), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and oxidised low-density lipoprotein (oxLDL) in matched cerebrospinal fluid (CSF) and plasma of 141 patients with probable AD. We found a significant relationship between CSF and plasma levels of ACT (r = 0.4, p < 0.001), IL-6 (r = 0.74, p < 0.001), MCP-1 (r = 0.71, p < 0.001), and a borderline relationship between CSF and plasma oxLDL (r = 0.22, p < 0.05). In addition, linear regression analysis revealed a positive correlation between levels of CSF-ACT and oxLDL (p < 0.001), but an inverse relation between levels of CSF ACT, CSF AAT and MCP-1 (p < 0.001). A significant correlation was also found between levels of CSF ACT, oxLDL and the ratio of CSF to serum albumin, which is used as a measure of the blood-brain barrier function. Our data extend previous reports regarding the inflammatory markers in the plasma and CSF of patients with AD and provide good evidence that levels of ACT, IL-6, MCP-1 and oxLDL in plasma and CSF might be candidates as biomarkers for monitoring the inflammatory process in AD.
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| 23. |
- Sun, Yongxin, et al.
(author)
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Pravastatin inhibits pro-inflammatory effects of Alzheimer's peptide Abeta(1-42) in glioma cell culture in vitro.
- 2003
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In: Pharmacological Research. - 1096-1186 .- 1043-6618. ; 47:2, s. 119-126
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Journal article (peer-reviewed)abstract
- Statins are known to exert a number of biological effects apart from reducing cholesterol synthesis. The results of recent studies indicate that patients treated with pravastatin have a lower prevalence of diagnosed Alzheimer’s disease (AD). These observations prompted us to examine the effects of pravastatin on Alzheimer’s peptide (Aβ1–42)-induced pro-inflammatory activation in the human glioma cell line in vitro. Cells alone or cells pre-treated with pravastatin (0.1 mg ml−1) for 24 h were stimulated with 5 μM of freshly dissolved Aβ1–42 for the next 24 h. The pre-treatment of cells with pravastatin diminished the capacity of Aβ to induce metalloproteinases, cytokine IL-6 and free radical levels. Although both pravastatin and Aβ1–42 separately increased PPARγ activity, the combination of Aβ1–42 and pravastatin resulted in no effect on PPARγ expression. These data indicate that soluble forms of Aβ1–42, which are a potent stimulus of pro-inflammatory activation of glioma cells in vitro, could be a good target for pravastatin.
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| 24. |
- Zelvyté, Inga, et al.
(author)
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Diverse responses between human pancreatic cancer cell lines to native alpha 1-antitrypsin and its C-terminal fragment.
- 2003
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In: Anticancer research. - 1791-7530. ; 23:3B, s. 2267-2273
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Journal article (peer-reviewed)abstract
- BACKGROUND: Previous studies imply that human pancreatic cancer cells have a wide heterogeneity and their exposure to various agents may give unpredictable results in clinical situations. MATERIALS AND METHODS: The cell lines LPC-3, -5 and -10, established from primary cultures of pancreatic adenocarcinoma, were exposed to 5 microM of AAT or its C-terminal peptide C-36 for 24 hours and analysed for cytokines by an enzyme-linked immunosorbent assay and for NF kappa B by the electrophoretic mobility shift assay. RESULTS: Native AAT lowers TGF-beta 1 levels and increases NF-kappa B activity in LPC-3 cells, while C-36 increases TGF-beta 1 levels and up-regulates NF-kappa B in LPC-5 cells. In LPC-10 cells AAT lowers TGF-beta 1. However, both AAT and C-36 fail to cause a change in NF-kappa B expression. For LPC-10 cells treated with C-36 IL-6 and TNF-alpha levels also increase. CONCLUSION: Our findings provide evidence that human cancer cell lines originating from primary pancreatic tumors do not have a uniform response to the same stimulus which shows a great heterogenicity among pancreatic cancer cells. Serine proteinase inhibitor, AAT, dependent on its molecular form, is also found to exert diverse effects on the properties of tumour cells confirming the complexity of cell-protein interaction.
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| 25. |
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| 26. |
- Zelvyté, Inga, et al.
(author)
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Increased plasma levels of serine proteinase inhibitors in lung cancer patients.
- 2004
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In: Anticancer research. - 1791-7530. ; 24:1, s. 7-241
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Journal article (peer-reviewed)abstract
- BACKGROUND: Tumor growth and invasiveness occur through infiltration of tumor cells into the host cells and by angiogenesis, which is modulated by proteinases and antiproteinases released from tumor cells that carry out tissue remodelling. A number of studies have revealed variations in the plasma levels of serine proteases and their inhibitors among tumor types. PATIENTS AND METHODS: By immunological methods we analysed the levels of serine protease inhibitors AAT, ACT and SLPI in newly diagnosed lung cancer patients (n=14) compared to non-smoker and smoker, age- and gender-matched control groups (n=16), and also in an expanded group of lung cancer patients with local tumors (n=14) and with metastasis (n=18). RESULTS: Our data show that plasma levels of AAT, ACT and SLPI were elevated in lung cancer patients by 1.43-fold, p<0.01, 2.57-fold, p<0.01 and 1.6-fold, p<0.001, respectively when compared to controls. In addition, we found that levels of AAT and ACT were higher by 1.47-fold, p<0.001 and 2.27-fold, p<0.001, respectively in lung cancer cases with metastasis compared to localized tumor. CONCLUSION: These inhibitor levels may provide measures of cancer progression in individual patients and possibly offer useful information for an understanding of the mechanisms of metastasis.
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| 27. |
- Zelvyté, Inga, et al.
(author)
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Modulation of inflammatory mediators and ppargammaand nfkappab expression by pravastatin in response to lipoproteins in human monocytes in vitro.
- 2002
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In: Pharmacological Research. - : Elsevier BV. - 1096-1186 .- 1043-6618. ; 45:2, s. 147-154
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Journal article (peer-reviewed)abstract
- Statins are inhibitors of the rate-limiting step of cellular cholesterol synthesis. In vitro and in vivo studies suggest that statins have anti-inflammatory properties independent of their cholesterol-lowering effects. These observations prompted us to examine the effects of pravastatin (50 mgr; M) and native or oxidized low density lipoprotein (nLDL or oxLDL) (50 mgr; g ml(minus sign1)) on primary human monocytes. We found that cells treated with pravastatin prior to nLDL and cells pre-treated with oxLDL prior to pravastatin showed increased activity of peroxisome proliferator-activated receptor gamma (PPAR gamma). Treatment of cells with drug either before incubation with oxLDL or afterwards suppressed nuclear factor kappa B (NF kappa B) expression and reduced uptake of(125)I-oxLDL by 1.7- and 1.5-fold, respectively. Pravastatin also increased PPAR gamma levels and abolished NF kappa B activity in non-stimulated monocytes. Statin added to monocytes prior to or after treatment with nLDL or oxLDL significantly inhibited generation of matrix metalloproteinases (MMPs), monocyte chemotactic protein-1 (MCP-1) and tumor necrosis factor alpha (TNF- alpha). These data corroborate previous findings of the pleiotropic role of statins and also suggest the involvement of transcription factors such as PPAR gamma and NF kappa B in the modulation of the inflammatory processes by statins. Copyright 2002 Elsevier Science Ltd.
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| 28. |
- Zelvyté, Inga, et al.
(author)
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Multiple effects of alpha(1)-antitrypsin on breast carcinoma MDA-MB 468 cell growth and invasiveness
- 2003
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In: European Journal of Cancer Prevention. - 1473-5709. ; 12:2, s. 117-124
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Journal article (peer-reviewed)abstract
- The degradation of extracellular matrix during cancer invasion results from the action of several protease and protease inhibitor systems. alpha(1)-Antitrypsin (AAT) is a serine proteinase inhibitor produced by various tumour cells, and its plasma concentration rises during inflammation, infection and malignant diseases. AAT is found in a native, inhibitory active form, but also in other, non-inhibitory forms including cleaved and/or degraded. To test a hypothesis that AAT dependent on its molecular form may have multiple effects on tumour cell behaviour, breast cancer cells, MDA-MB 468, were cultured alone or stimulated with a native AAT or its C-terminal fragment (C-36) at a concentration of 5mumol/l = for 2, 24 and 48 hours. Native AAT added to the cells for 2 hours enhanced transforming growth factor beta 1 (TGFbeta1) levels by 50%, but inhibited cell proliferation (by 61%), reduced interleukin 6 (IL-6) levels (by 87%) and activity (by about 66%), compared with non-stimulated cells. Native AAT showed similar, but less pronounced, effects when added to the cells for 24 and 48 hours. Under the same experimental conditions the cells exposed to the C-36 peptide significantly increased in proliferation, invasiveness and showed higher IL-6 levels. In addition, cells treated with the C-36 for 48 hours increased in NFkappaB (nuclear factor kappa B) activity. These results indicate that AAT, dependent on its molecular form, can both suppress and induce breast tumour cell biological activity in vitro. (C) 2003 Lippincott Williams Wilkins.
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| 29. |
- Zelvyte, Inga, et al.
(author)
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αl-antitrypsin and its C-terminal fragment attenuate effects of degranulated neutrophil-conditioned medium on lung cancer HCC cells, in vitro
- 2004
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In: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 4
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Journal article (peer-reviewed)abstract
- Background: Tumor microenvironment, which is largely affected by inflammatory cells, is a crucial participant in the neoplastic process through promotion of cell proliferation, survival and migration. We measured the effects of polymorphonuclear neutrophil (PMN) conditioned medium alone, and supplemented with serine proteinase inhibitor α-1 antitrypsin (AAT) or its C-terminal fragment (C-36 peptide), on cultured lung cancer cells. Methods: Lung cancer HCC cells were grown in a regular medium or in a PMN-conditioned medium in the presence or absence of AAT (0.5 mg/ml) or its C-36 peptide (0.06 mg/ml) for 24 h. Cell proliferation, invasiveness and release of IL-8 and VEGF were analyzed by [ 3H]-thymidine incorporation, Matrigel invasion and ELISA methods, respectively. Results: Cells exposed to PMN-conditioned medium show decreased proliferation and IL-8 release by 3.9-fold, p < 0.001 and 1.3-fold, p < 0.05, respectively, and increased invasiveness by 2-fold (p < 0.001) compared to non-treated controls. In the presence of AAT, PMN-conditioned medium loses its effects on cell proliferation, invasiveness and IL-8 release, whereas VEGF is upregulated by 3.7-fold (p < 0.001) compared to controls. Similarly, C-36 peptide abolishes the effects of PMN-conditioned medium on cell invasiveness, but does not alter its effects on cell proliferation, IL-8 and VEGF release. Direct HCC cell exposure to AAT enhances VEGF, but inhibits IL-8 release by 1.7-fold (p < 0.001) and 1.4-fold (p < 0.01) respectively, and reduces proliferation 2.5-fold (p < 0.01). In contrast, C-36 peptide alone did not affect these parameters, but inhibited cell invasiveness by 51.4% (p < 0.001), when compared with non-treated controls. Conclusions: Our data provide evidence that neutrophil derived factors decrease lung cancer HCC cell proliferation and IL-8 release, but increase cell invasiveness. These effects were found to be modulated by exogenously present serine proteinase inhibitor, AAT, and its C-terminal fragment, which points to a complexity of the relationships between tumor cell biological activities and local microenvironment.
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