| 1. |
- Al-Omari, Mariam, et al.
(författare)
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Beneficial effects of alpha-1 antitrypsin therapy in a mouse model of colitis-associated colon cancer
- 2023
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Ingår i: BMC Cancer. - 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is widely accepted that chronic inflammatory bowel diseases significantly higher a risk for colorectal cancer development. Among different types of treatments for patients with colon cancer, novel protein-based therapeutic strategies are considered. AIM: To explore the effect of human plasma alpha-1 antitrypsin (AAT) protein in the chemically induced mouse model of colorectal cancer. Methods: BALB/c mice with azoxymethane/dextran sodium sulfate (AOM/DSS)-induced colitis-associated colorectal cancer (CAC), we intraperitoneally treated with commercial preparation of human plasma AAT (4 mg per mouse). Effects of this therapy were evaluated histologically, and by immunohistochemical and gene expression assays. Results: When compared with non-treated controls, AOM/DSS mice receiving AAT therapy exhibited significantly longer colons, and less anal bleeding. Concurrently, AAT-treated mice had significantly fewer polyps, and lower numbers of large colon tumors. Immunohistochemical examinations of colon tissues showed significantly lower neutrophil counts, more granzyme B-positive but fewer MMP9 (gelatinase B)-positive cancer cells and lower numbers of apoptotic cells in mice receiving AAT therapy. The expression levels of IL4 were significantly higher while TNFA was slightly reduced in tumor tissues of AOM/DSS mice treated with AAT than in AOM/DSS mice. Conclusion: Human AAT is an acute phase protein with a broad-protease inhibitory and immunomodulatory activities used as a therapeutic for emphysema patients with inherited AAT deficiency. Our results are consistent with previous findings and support an idea that AAT alone and/or in combination with available anti-cancer therapies may represent a new personalized approach for patients with colitis-induced colon cancer.
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| 2. |
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| 3. |
- Aldonyte, Ruta, et al.
(författare)
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Circulating monocytes from healthy individuals and COPD patients.
- 2003
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 4:1, s. 11-11
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Aldonyte, Ruta, et al.
(författare)
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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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Ingår i: BMC Cell Biology. - : Springer Science and Business Media LLC. - 1471-2121. ; 5
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Baker, Crystal, et al.
(författare)
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Effects of Alzheimer's peptide and alpha 1-antichymotrypsin on astrocyte gene expression
- 2007
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 28:1, s. 51-61
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Tidskriftsartikel (refereegranskat)abstract
- We employed gene array technology to investigate the effects of alpha 1-antichymotrypsin (ACT), soluble or fibrillar Alzheimer's peptide (A beta(1-42)) alone and the combination of ACT/A beta(1-42) on human astrocytes. Using a 1.2-fold change as significance threshold, 398 astrocyte genes showed altered expression in response to these treatments compared to controls. Of the 276 genes affected by the ACT/soluble A beta(1-42) combination, 195 (70.6%) were suppressed. The ACT/fibrillar A beta(1-42) combination affected expression of 64 genes of which 58 (90.5%) were up-regulated. The most prominent gene expression changes in response to the ACT/soluble A beta(1-42), were the down-regulation of at least 60 genes involved in transcription, signal transduction, apoptosis and neurogenesis. The ACT/fibril A beta(1-42) increased the expression of genes involved in transcription regulation and signal transduction. Surprisingly, gene expression of astrocytes exposed to soluble or fibrillar A beta(1-42) alone was largely unaffected. Thus, the molecular forms generated by the combination of ACT/A beta(1-42) alter expression of astrocyte genes more profoundly in breadth and magnitude than soluble or fibrillar A beta(1-42) alone, suggesting that pathogenic effects of A beta(1-42) may occur as a consequence of its association with other proteins. (c) 2005 Elsevier Inc. All rights reserved.
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| 6. |
- Blanco Blanco, Ignacio, et al.
(författare)
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Intravenous Infusions of Purified Alpha-1 Antitripsyn Effectively Controls Symptoms and Reverts Muscle Biopsy Changes in an MZ Alpha-1 Antitripsyn Deficiency and Fibromyalgia Syndrome Patient
- 2010
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Ingår i: Journal of Musculoskeletal Pain. - : Informa UK Limited. - 1540-7012 .- 1058-2452. ; 18:2, s. 167-172
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Tidskriftsartikel (refereegranskat)abstract
- Background: An MZ phenotype alpha-1 antitrypsin [AAT] deficiency and fibromyalgia syndrome [FMS] patient participated in a trial with AAT-intravenous augmentationtherapy [AAT-IV-AT] after failure of conventional therapeutic measures. Three quadricep biopsies were performed at different stages. The first one showed large aggregates of AAT and ubiquitin in myocytes and blood vessels, and moderate muscle atrophy, before AAT-IV-AT. The two remaining biopsies were performed while receiving AAT-IV-AT. Findings: Remarkably good clinical response and histological improvement in the follow-up biopsies. Conclusions: The clinical and histopathological efficacy of AAT-IV-AT evidenced in this patient should open new perspectives of research and management of AAT deficiency and FMS patients.
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| 7. |
- Blanco, Ignacio, et al.
(författare)
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Estimates of the prevalence and number of Fibromyalgia syndrome patients and their alpha-1 antitrypsin phenotypic distribution in ten countries
- 2007
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Ingår i: Journal of Musculoskeletal Pain. - 1540-7012. ; 15:4, s. 41540-41540
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Forskningsöversikt (refereegranskat)abstract
- Objectives: During the last few years, clinical, epidemiological, and pathological evidence has suggested that inherited alpha-1 antitrypsin [AAT] deficiency might play a role in the development of the fibromyalgia syndrome [FMS], probably because of the loss of AAT anti-inflammatory efficacy. The objective of this study was to estimate the prevalence and number of FMS patients, and their AAT phenotypic distribution worldwide. Methods: A critical review selecting reliable studies on the subject. Results: Studies on AAT gene frequencies and FMS prevalence were retrieved for ten countries worldwide, namely Canada, the United States of America [USA], Denmark, Finland, Germany, Italy, the Netherlands, Spain, Sweden, and Pakistan. The severe deficiency Z allele was found in all these countries, with very high frequencies in Denmark and Sweden [23 and 27 per 1,000, respectively], high frequencies in Italy and Spain [16 and 17], intermediate frequencies in Germany, the Netherlands, Canada, and the USA [10 to 14], and a low frequency in Pakistan [nine per 1,000]. The calculated prevalence of AAT deficiency and the number of FMS patients with AAT deficiency were 1/10 and 25,408 in Canada, 1/11 and 478,681 in the US, 1/9 and 3,124 in Denmark, 1/36 and 726 in Finland, 1/16 and 48,523 in Germany, 1/13 and 84,876 in Italy, 1115 and 9,639 in the Netherlands, 1/4 and 114,359 in Spain, 1/11 and 9,065 in Sweden, and 1/25 and 85.965 in Pakistan. Our calculations predict that AAT deficiency would remain undetected in around nine percent of FMS patients, with about eight percent of them carrying moderate deficiency phenotypes [MS, SS, and MZ], and less than one percent with severe deficiency phenotypes [SZ and ZZ]. Conclusions: Therefore, AAT phenotype characterization should be recommended in FMS patients and the possible efficacy of AAT replacement therapy in severe deficiency FMS patients should warrant further Studies.
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| 8. |
- Blanco, Ignacio, et al.
(författare)
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Low plasma levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF alpha), and vascular endothelial growth factor (VEGF) in patients with alpha1-antitrypsin deficiency-related fibromyalgia
- 2010
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Ingår i: Clinical Rheumatology. - : Springer Science and Business Media LLC. - 1434-9949 .- 0770-3198. ; 29:2, s. 189-197
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Tidskriftsartikel (refereegranskat)abstract
- Abnormalities in blood inflammatory markers have been associated with clinical manifestations and the pathogenesis of the fibromyalgia syndrome (FMS); a relationship between inherited alpha1-antitrypsin deficiency (AATD) and FMS has also been recently raised. In this study, plasma levels of inflammatory markers in FMS patients with and without AATD have been investigated. Blood samples from 138 age-matched females (79 FMS) and 59 general population (GP), with normal MM [n = 82 (59.4%)] and with MS, MZ, SZ, and ZZ AATD genotypes [n = 56 (40.6%)], were analyzed by ELISA for monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF alpha), soluble TNF alpha receptors I and II, interleukin-8, and vascular endothelial growth factor (VEGF). Plasma levels of MCP-1, VEGF, and TNF alpha were significantly lower in FMS and GP subjects with AATD compared with those with normal MM-AAT genotypes. Moreover, plasma levels of MCP-1, VEGF, and TNF alpha were lower in AATD subjects with FMS than in those without FMS (P = 0.000, 0.000, and 0.046, respectively). No statistical differences were found for the other substances measured. Furthermore, a logistic regression model based on plasma MCP-1 cutoff value of a parts per thousand currency sign130 pg/ml allowed us to discriminate between FMS and GP subjects with a sensitivity of about 93% and a specificity of 79%. Low plasma levels of MCP-1, VEGF, and TNF alpha are related to AATD, although more markedly in FMS patients. Thus, hypotheses considering FMS as an inflammatory condition related to high plasma levels of inflammatory biomarkers cannot be supported.
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| 9. |
- Buchhave, Peder, et al.
(författare)
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Elevated plasma levels of soluble CD40 in incipient Alzheimer's disease.
- 2009
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Ingår i: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 450:1, s. 56-9
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Tidskriftsartikel (refereegranskat)abstract
- CD40 is a member of the tumor necrosis factor receptor super-family and has been suggested to play a role in the metabolism of beta-amyloid (Abeta) in Alzheimer's disease (AD). However, the role of CD40-signalling in incipient AD has not yet been studied. We investigated the plasma levels of soluble CD40 (sCD40) and the soluble CD40 ligand (sCD40L) at baseline in 136 subjects with mild cognitive impairment (MCI) and 30 age-matched controls. Sixty of the 136 MCI cases converted to AD (MCI-AD) during a clinical follow-up period of 4-7 years. The baseline levels of sCD40, but not sCD40L, were elevated in MCI-AD cases when compared to age-matched controls (Mann-Whitney U-test, p=0.02). However, MCI patients who were cognitively stable or developed vascular dementia during follow-up did not have significantly increased levels of sCD40 or sCD40L when compared to controls. The levels of sCD40 correlated to decreased baseline performance on mini-mental state examination (MMSE) in both controls (r(s)=-0.37, p<0.05) and MCI-AD cases (r(s)=-0.29, p<0.05). Finally, the plasma levels of sCD40 correlated with the levels of soluble amyloid precursor protein-alpha (sAPP-alpha) (r(s)=0.28, p<0.01) and sAPP-beta (r(s)=0.23, p<0.05) in cerebrospinal fluid. In conclusion, CD40-signalling might play a role in the pathogenesis of early AD.
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| 10. |
- Buchhave, Peder, et al.
(författare)
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Soluble TNF receptors are associated with Abeta metabolism and conversion to dementia in subjects with mild cognitive impairment.
- 2010
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 31:11, s. 1877-1884
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: There is evidence supporting that tumor necrosis factor receptor (TNFR)-signaling can induce production of beta-amyloid (Abeta) in the brain. Moreover, amyloid-induced toxicity has been shown to be dependent on TNFR-signaling. However, it is still unclear whether TNFRs are involved in the early stages of dementia. METHODS: We analyzed soluble TNFR1 and TNFR2 levels in plasma and cerebrospinal fluid (CSF) at baseline in 137 patients with mild cognitive impairment (MCI) and 30 age-matched controls. The MCI patients were followed for 4-6 years with an incidence of Alzheimer's disease (AD) or vascular dementia (VaD) of 15% per year. RESULTS: The patients with MCI who subsequently developed these forms of dementias had higher levels of sTNFR1 and sTNFR2 in both CSF and plasma already at baseline when compared to age-matched controls (p<0.05). In the CSF of MCI subjects and controls the levels of both sTNFR1 and sTNFR2 correlated strongly with beta-site APP-cleaving enzyme 1 (BACE1) activity (r(s)=0.53-0.68, p<0.01) and Abeta 40 levels (r(s)=0.59-0.71, p<0.001). Similarly, both sTNFRs were associated with Abeta 40 (r(s)=0.39-0.46, p<0.05) in plasma. Finally, the levels of both sTNFRs correlated with the axonal damage marker tau in the CSF of MCI subjects and controls (r(s)=0.57-0.83, p<0.001). CONCLUSION: TNFR-signaling might be involved in the early pathogenesis of AD and VaD, and could be associated with beta-amyloid metabolism.
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| 11. |
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| 12. |
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| 13. |
- Esquinas, Cristina, et al.
(författare)
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Gene and miRNA expression profiles in PBMCs from patients with severe and mild emphysema and PiZZ alpha I-antitrypsin deficiency
- 2017
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Ingår i: International Journal of COPD. - 1176-9106. ; 12, s. 3381-3390
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: COPD has complex etiologies involving both genetic and environmental determinants. Among genetic determinants, the most recognized is a severe PiZZ (Glu342Lys) inherited alpha1-antitrypsin deficiency (AATD). Nonetheless, AATD patients present a heterogeneous clinical evolution, which has not been completely explained by sociodemographic or clinical factors. Here we performed the gene expression profiling of blood cells collected from mild and severe COPD patients with PiZZ AATD. Our aim was to identify differences in messenger RNA (mRNA) and microRNA (miRNA) expressions that may be associated with disease severity. Materials and methods: Peripheral blood mononuclear cells from 12 COPD patients with PiZZ AATD (6 with severe disease and 6 with mild disease) were used in this pilot, high-throughput microarray study. We compared the cellular expression levels of RNA and miRNA of the 2 groups, and performed functional and enrichment analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene-ontology (GO) terms. We also integrated the miRNA and the differentially expressed putative target mRNA. For data analyses, we used the R statistical language R Studio (version 3.2.5). Results: The severe and mild COPD-AATD groups were similar in terms of age, gender, exacerbations, comorbidities, and use of augmentation therapy. In severe COPD-AATD patients, we found 205 differentially expressed genes (DEGs) (114 upregulated and 91 downregulated) and 28 miRNA (20 upregulated and 8 downregulated) compared to patients with mild COPD-AATD disease. Of these, hsa-miR-335-5p was downregulated and 12 target genes were involved in cytokine signaling, MAPK/mk2, JNK signaling cascades, and angiogenesis were much more highly expressed in severe compared with mild patients. Conclusions: Despite the small sample size, we identified downregulated miRNA (hsa-miR-335) and the activation of pathways related to inflammation and angiogenesis on comparing patients with severe vs mild COPD-AATD. Nonetheless, our findings warrant further validation in large studies.
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| 14. |
- Frendéus, Katarina H, et al.
(författare)
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Macrophage Responses to Interferon-gamma are Dependent on Cystatin C Levels.
- 2009
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Ingår i: International Journal of Biochemistry and Cell Biology. - : Elsevier BV. - 1878-5875 .- 1357-2725. ; 41, s. 2262-2269
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Tidskriftsartikel (refereegranskat)abstract
- The aim of the present investigation was to elucidate possible effects of cystatin C on inflammatory responses mediated by macrophages. Previously it has been shown that in vitro treatment of murine peritoneal macrophages with interferon-gamma (IFN-gamma) causes a down-regulation of cystatin C secretion. To investigate whether such changes in cystatin C expression in turn can affect inflammatory responses mediated by macrophages, we have compared effects of IFN-gamma on macrophages isolated from wild-type (cysC(+/+)) and cystatin C knockout (cysC(-/-)) mice. It was shown that IFN-gamma-primed cysC(-/-) macrophages exhibit significantly higher interleukin-10 (IL-10) but lower tumor necrosis factor-alpha (TNF-alpha) expression, and reduced nuclear factor (NF)-kappaB p65 activation, compared to similarily primed cysC(+/+) cells. Exogenously added cystatin C enhanced IFN-gamma-induced activation of NF-kappaB p65 and increased mRNA levels for inducible NO synthase (iNOS) in cysC(-/-) macrophages as well as levels of nitric oxide and TNF-alpha in the cell culture medium, in agreement with an enhanced pro-inflammatory response. Accordingly, IFN-gamma-induced IL-10 mRNA expression in cysC(-/-) macrophages was down-regulated by exogenously added cystatin C square. Taken together, our data provide evidence that changes in cystatin C levels alter macrophage responses to IFN-gamma. The latter downregulates the production of cystatin C, which leads to a suppressed inflammatory condition with enhanced IL-10 levels and downregulated TNF-alpha and NF-kappaB. It is concluded that cystatin C through this effect can act as an immunomodulatory molecule.
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| 15. |
- Gerbod-Giannone, MC, et al.
(författare)
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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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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 277:45, s. 42973-42980
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Tidskriftsartikel (refereegranskat)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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| 16. |
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| 17. |
- Gren, Susanne T, et al.
(författare)
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A Single-Cell Gene-Expression Profile Reveals Inter-Cellular Heterogeneity within Human Monocyte Subsets.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- Human monocytes are a heterogeneous cell population classified into three different subsets: Classical CD14++CD16-, intermediate CD14++CD16+, and non-classical CD14+CD16++ monocytes. These subsets are distinguished by their differential expression of CD14 and CD16, and unique gene expression profile. So far, the variation in inter-cellular gene expression within the monocyte subsets is largely unknown. In this study, the cellular variation within each human monocyte subset from a single healthy donor was described by using a novel single-cell PCR gene-expression analysis tool. We investigated 86 different genes mainly encoding cell surface markers, and proteins involved in immune regulation. Within the three human monocyte subsets, our descriptive findings show multimodal expression of key immune response genes, such as CD40, NFⱪB1, RELA, TLR4, TLR8 and TLR9. Furthermore, we discovered one subgroup of cells within the classical monocytes, which showed alterations of 22 genes e.g. IRF8, CD40, CSF1R, NFⱪB1, RELA and TNF. Additionally one subgroup within the intermediate and non-classical monocytes also displayed distinct gene signatures by altered expression of 8 and 6 genes, respectively. Hence the three monocyte subsets can be further subdivided according to activation status and differentiation, independently of the traditional classification based on cell surface markers. Demonstrating the use and the ability to discover cell heterogeneity within defined populations of human monocytes is of great importance, and can be useful in unravelling inter-cellular variation in leukocyte populations, identifying subpopulations involved in disease pathogenesis and help tailor new therapies.
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| 18. |
- Grip, Olof, et al.
(författare)
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Atorvastatin activates PPAR-gamma and attenuates the inflammatory response in human monocytes.
- 2002
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Ingår i: Inflammation Research. - 1420-908X. ; 51:2, s. 58-62
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Tidskriftsartikel (refereegranskat)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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| 19. |
- Grip, Olof, et al.
(författare)
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Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn's disease.
- 2009
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In Crohn's disease high tissue expression and serum levels of chemokines and their receptors are known to correlate with disease activity. Because statins can reduce chemokine expression in patients with coronary diseases, we wanted to test whether this can be achieved in patients with Crohn's disease. METHODOLOGY/PRINCIPAL FINDINGS: We investigated plasma levels of chemokines (CCL2, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26, CXCL8, CXCL10) and endothelial cytokines (sP-selectin, sE-selectin, sICAM-3, thrombomodulin) in ten Crohn's disease patients before and after thirteen weeks' daily treatment with 80 mg atorvastatin. Of the 13 substances investigated, only CXCL10 was found to be significantly reduced (by 34%, p = 0.026) in all of the treated patients. Levels of CXCL10 correlated with C-reactive protein (r = 0.82, p<0.01). CONCLUSIONS/SIGNIFICANCE: CXCL10 is a ligand for the CXCR3 receptor, the activation of which results in the recruitment of T lymphocytes and the perpetuation of mucosal inflammation. Hence the reduction of plasma CXCL10 levels by atorvastatin may represent a candidate for an approach to the treatment of Crohns disease in the future. TRIAL REGISTRATION: (ClinicalTrials.gov) NCT00454545.
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| 20. |
- Grip, Olof, et al.
(författare)
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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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Ingår i: Inflammatory Bowel Diseases. - : Oxford University Press (OUP). - 1078-0998 .- 1536-4844. ; 10:3, s. 193-200
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Tidskriftsartikel (refereegranskat)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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| 21. |
- Grip, Olof, et al.
(författare)
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Macrophages in inflammatory bowel disease
- 2003
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Ingår i: Current Drug Targets. Inflammation & Allergy. - 1568-010X. ; 2:2, s. 155-160
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Tidskriftsartikel (refereegranskat)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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| 22. |
- Grip, Olof, et al.
(författare)
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Pravastatin down-regulates inflammatory mediators in human monocytes in vitro
- 2000
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Ingår i: European Journal of Pharmacology. - 0014-2999. ; 410:1, s. 83-92
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Tidskriftsartikel (refereegranskat)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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| 23. |
- Grip, Olof, et al.
(författare)
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Use of atorvastatin as an anti-inflammatory treatment in Crohn's disease.
- 2008
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Ingår i: British Journal of Pharmacology. - : Wiley. - 1476-5381 .- 0007-1188. ; 155, s. 1085-1092
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose:Experimental and clinical investigations have revealed that statins can downregulate both acute and chronic inflammatory processes. Whether statins express anti-inflammatory activities in the treatment of Crohn's disease is unknown.Experimental approach:Ten patients were given 80 mg atorvastatin once daily for 13 weeks and then followed up for 8 weeks after the treatment. The anti-inflammatory effects of statin were assessed by measuring levels of plasma C-reactive protein (CRP), soluble (s) CD14, tumour necrosis factor (TNF)-alpha, sTNFRI and II, CCL2 and 8 and the mucosal inflammation by faecal calprotectin. Circulating monocytes were subgrouped and their chemokine receptor expression of CCR2 and CX(3)CR1 were analysed.Key results:In 8 of 10 patients, atorvastatin treatment reduced CRP (P=0.008) and sTNFRII (P=0.064). A slight decrease in plasma levels of sCD14, TNF-alpha and sTNFRI was observed in 7/10 patients and faecal calprotectin was reduced in 8/10 patients. We also observed that the treatment diminished expression of CCR2 and CX(3)CR1 on monocyte populations (P=0.014). At the follow-up visit, 8 weeks after the atorvastatin treatment was terminated, CRP levels had returned to those seen before the treatment.Conclusions and implications:Our findings imply that atorvastatin therapy reduces inflammation in patients with Crohn's disease and, therefore, encourage further investigations of statin-mediated protective effects in inflammatory bowel diseases.British Journal of Pharmacology advance online publication, 22 September 2008; doi:10.1038/bjp.2008.369.
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| 24. |
- Gross, B., et al.
(författare)
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New Findings in PiZZ alpha(1)-Antitrypsin Deficiency-Related Panniculitis Demonstration of Skin Polymers and High Dosing Requirements of Intravenous Augmentation Therapy
- 2009
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Ingår i: Dermatology. - : S. Karger AG. - 1421-9832 .- 1018-8665. ; 218:4, s. 370-375
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Tidskriftsartikel (refereegranskat)abstract
- Panniculitis is a recognized but unusual complication of a severe deficiency of alpha(1)-antitrypsin (AAT), with fewer than 100 cases described to date. Like the pathogenesis of emphysema in severe PiZZ deficiency of AAT, panniculitis has been hypothesized to be an inflammatory process, possibly related to Z AAT polymer formation and to an unopposed anti-inflammatory screen in the context of deficient serum levels of AAT. The current report presents a 31-year-old woman with PiZZ AAT deficiency-associated panniculitis. Our case extends current knowledge of AAT-associated panniculitis in 2 ways: (1) we demonstrate Z-type AAT polymers in the skin, which supports the inflammatory pathogenesis of panniculitis and the potential pro-inflammatory role of polymers; (2) we show that a high dose and long- term use of intravenous augmentation therapy (90 mg/kg body weight once weekly during 3 years) can ameliorate the frequency and severity of panniculitis associated with AAT deficiency. Copyright (C) 2009 S. Karger AG, Basel
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| 25. |
- Hadzic, Radinka, et al.
(författare)
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alpha1-Antitrypsin inhibits Moraxella catarrhalis MID protein-induced tonsillar B cell proliferation and IL-6 release.
- 2006
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Ingår i: Immunology Letters. - : Elsevier BV. - 0165-2478 .- 1879-0542. ; 102:2, s. 141-147
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Tidskriftsartikel (refereegranskat)abstract
- alpha 1-Antitrypsin (AAT) is a major circulating and tissues inhibitor of serine proteinases implicated in the regulation of inflammation and host defence. There is now increasing evidence that AAT may also exhibit anti-inflammatory activities independent of its protease inhibitor function. This study was undertaken to investigate the effects of native (inhibitory) and polymerized (non-inhibitory) forms of AAT on MID (Moraxella IgD binding protein)-induced human tonsillar B cell activation in vitro. We found that 0.5 mu g/ml MID induces B cell proliferation and stimulates IL-6 release (p < 0.001) relative to non-stimulated controls. Both native and polymerized AAT (0.5 mg/ml) inhibited MID-stimulated B cell proliferation in a similar manner (by 70%, p < 0.001), whereas MID-induced IL-6 release was more strongly suppressed by polymefized (9.9-fold, p < 0.001) as compared to native AAT (2.8-fold, p < 0.01). Electrophoretic analysis of cell culture media did not indicate any interaction between AAT and MID, and flow cytometry data showed no competition for the same receptor. The effects of AATs were observed whether added together with MID or 2 h after MID-addition to cell cultures. Thus, our data demonstrate that AAT inhibits MID-induced B cell activation in vitro that is unrelated to its protease inhibitory activity and is not dependent on MID binding to the cell surface.
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| 26. |
- Hadzic, Radinka, et al.
(författare)
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α1-Antitrypsin inhibits Moraxella catarrhalis MID protein-induced tonsillar B cell proliferation and IL-6 release
- 2006
-
Ingår i: Immunology Letters. - 0165-2478 .- 1879-0542. ; 102:2, s. 141-147
-
Tidskriftsartikel (refereegranskat)abstract
- α1-Antitrypsin (AAT) is a major circulating and tissues inhibitor of serine proteinases implicated in the regulation of inflammation and host defence. There is now increasing evidence that AAT may also exhibit anti-inflammatory activities independent of its protease inhibitor function. This study was undertaken to investigate the effects of native (inhibitory) and polymerized (non-inhibitory) forms of AAT on MID (Moraxella IgD binding protein)-induced human tonsillar B cell activation in vitro. We found that 0.5 μg/ml MID induces B cell proliferation and stimulates IL-6 release (p < 0.001) relative to non-stimulated controls. Both native and polymerized AAT (0.5 mg/ml) inhibited MID-stimulated B cell proliferation in a similar manner (by 70%, p < 0.001), whereas MID-induced IL-6 release was more strongly suppressed by polymerized (9.9-fold, p < 0.001) as compared to native AAT (2.8-fold, p < 0.01). Electrophoretic analysis of cell culture media did not indicate any interaction between AAT and MID, and flow cytometry data showed no competition for the same receptor. The effects of AATs were observed whether added together with MID or 2 h after MID-addition to cell cultures. Thus, our data demonstrate that AAT inhibits MID-induced B cell activation in vitro that is unrelated to its protease inhibitory activity and is not dependent on MID binding to the cell surface.
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| 27. |
- Hecker, Andreas, et al.
(författare)
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Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1 beta Release
- 2015
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 195:5, s. 2325-2334
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Tidskriftsartikel (refereegranskat)abstract
- IL-1 beta is a potent proinflammatory cytokine of the innate immune system that is involved in host defense against infection. However, increased production of IL-1 beta plays a pathogenic role in various inflammatory diseases, such as rheumatoid arthritis, gout, sepsis, stroke, and transplant rejection. To prevent detrimental collateral damage, IL-1 beta release is tightly controlled and typically requires two consecutive danger signals. LPS from Gram-negative bacteria is a prototypical first signal inducing pro-IL-1 beta synthesis, whereas extracellular ATP is a typical second signal sensed by the ATP receptor P2X7 that triggers activation of the NLRP3-containing inflammasome, proteolytic cleavage of pro-IL-1 beta by caspase-1, and release of mature IL-1 beta. Mechanisms controlling IL-1 beta release, even in the presence of both danger signals, are needed to protect from collateral damage and are of therapeutic interest. In this article, we show that acetylcholine, choline, phosphocholine, phosphocholine-modified LPS from Haemophilus influenzae, and phosphocholine-modified protein efficiently inhibit ATP-mediated IL-1 beta release in human and rat monocytes via nicotinic acetylcholine receptors containing subunits alpha 7, alpha 9, and/or alpha 10. Of note, we identify receptors for phosphocholine-modified macromolecules that are synthesized by microbes and eukaryotic parasites and are well-known modulators of the immune system. Our data suggest that an endogenous anti-inflammatory cholinergic control mechanism effectively controls ATP-mediated release of IL-1 beta and that the same mechanism is used by symbionts and misused by parasites to evade innate immune responses of the host.
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| 28. |
- Helmers, Sevim Barbasso, et al.
(författare)
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Sera from anti-Jo-1-positive patients with polymyositis and interstitial lung disease induce expression of intercellular adhesion molecule 1 in human lung endothelial cells
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:8, s. 2524-2530
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate whether sera or purified IgG from patients with polymyositis (PM) and patients with dermatomyositis (DM), with or without interstitial lung disease (ILD), can activate endothelial cells (ECs). METHODS: Patients' sera were selected based on the presence or absence of anti-Jo-1, anti-SSA, or anti-U1 small nuclear RNP autoantibodies. The presence of autoantibodies was determined by line blot assays. Cultured human microvascular ECs derived from lung tissue (HMVEC-L) were incubated with sera or purified IgG from 22 patients with PM, 7 patients with DM, and 10 healthy individuals as controls. Assessment of intercellular adhesion molecule 1 (ICAM-1) expression was conducted by immunofluorescence (n=22) and by cell-based enzyme-linked immunosorbent assay (ELISA) (n=20). Serum levels of soluble ICAM-1 (sICAM-1) were determined by ELISA. RESULTS: Sera from PM patients with ILD who were positive for anti-Jo-1 autoantibodies had a significantly stronger effect on the expression of ICAM-1 by HMVEC-L in comparison with sera from healthy controls and patients with other autoantibodies. Purified IgG did not induce ICAM-1 expression. Higher serum levels of sICAM-1 were found in patients with myositis compared with healthy controls. CONCLUSION: EC activation with ICAM-1 expression could contribute to the multiorgan involvement, including the development of myositis and ILD, in patients carrying anti-Jo-1 autoantibodies. The EC-activating factors are not the autoantibodies themselves, but might be systemic factors associated with these autoantibodies.
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| 29. |
- Hollander, Camilla, et al.
(författare)
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Human mast cells decrease SLPI levels in type II - like alveolar cell model, in vitro.
- 2003
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 3:1
-
Tidskriftsartikel (refereegranskat)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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| 30. |
- Hollander, Camilla, et al.
(författare)
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Serum and bronchial lavage fluid concentrations of IL-8, SLPI, sCD14 and sICAM-1 in patients with COPD and asthma
- 2007
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 101:9, s. 1947-1953
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Tidskriftsartikel (refereegranskat)abstract
- Background: Airway inflammation is associated with an increased expression and release of inflammatory reactants that regulate processes of cell migration, activation and degranulation. The purpose of this study was to quantify bronchial lavage (BAL) fluid and serum levels of chemokine (IL-8), secretory leukocyte protease inhibitor (SLPI), soluble intracellular adhesion molecules-1 (sICAM-1) and sCD14, as surrogate markers of inflammatory and immune response in asthma and chronic obstructive pulmonary disease (COPD) patients with similar disease duration time. Methods: Biomarkers in serum and BAL fluid from asthma (n = 13) and COPD (n = 25) patients were measured using commercially available ELISA kits. Results: We found that in asthma and COPD groups the concentrations of IL-8 and SLPI are significantly higher in BAL fluid than in serum, while levels of sICAM-1 and sCD14 in BAL fluid are significantly lower than in serum. Of these 4 measured biomarkers, only the BAL IL-8 was higher in COPD patients when compared to asthma (P < 0.05). In both groups, BAL IL-8 correlated with SLPI (r = 0.577, P < 0.01 and r = 0.589, P < 0.05, respectively). In patients with COPD the BAL sICAM-1 correlated with sCD14 (r = 0.576, P < 0.01), while in asthma patients BAL sICAM-1 correlated with FEV,/FVC (r= 0.418, P < 0.01). Moreover, in asthma patients the serum SLPI correlated with sCD14 (r=0.688, P < 0.01) and serum sICAM-1 negatively correlated with FEV1/FVC (r= -0.582, P < 0.05). Conclusion: Our findings point to the importance of selecting a correct biological fluid when analyzing specific biomarkers, and also show that of 4 measured biomarkers, only the BAL IL-8 was higher in COPD patients when compared to asthma. 2007 Published by Elsevier Ltd.
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| 31. |
- Janciauskiene, Sabina, et al.
(författare)
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A link between sICAM-1, ACE and parietal blood flow in the aging brain.
- 2009
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 30:9, s. 1504-1511
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Tidskriftsartikel (refereegranskat)abstract
- A connection between Alzheimer's disease (AD) and endothelium pathology has been inferred from measured decreases in both blood flow and metabolism in the parietal and temporal cortex. However, it is not known whether these alterations are seen in normal aging. We performed regional cerebral blood flow (rCBF) measurements in 22 AD patients and in 44 non-demented subjects during a simple test of information processing speed. Cerebrospinal fluid (CSF) levels of angiotensin-converting enzyme (ACE) and the soluble form of intercellular adhesion molecule-1 (sICAM-1) were analyzed in non-demented subjects. We found correlations between sICAM-1 and ACE (p=0.004), and sICAM (but not ACE) and CSF/plasma albumin ratio (p<0.0001). Higher concentrations of sICAM-1 (>893ng/L) and ACE (>5.22microg/L) were exclusively associated with lower parietal blood flow (p<0.001). The rCBF patterns in the AD and non-demented subjects with biomarker levels above median showed similar reductions in the temporoparietal areas. Our findings provide evidence that elevated CSF sICAM-1 and ACE are associated with lower perfusion levels in the parietal cortex of cognitively intact elderly.
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| 32. |
- Janciauskiene, Sabina, et al.
(författare)
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Adhesion molecules in dementia
- 2016
-
Ingår i: Adhesion Molecules. - 9781138117891 - 9781439840603 ; , s. 477-495
-
Bokkapitel (refereegranskat)abstract
- During the past decade it has become evident that immunological, infl ammatory and vascular processes play an important role in the etiology and pathogenesis of various neuro-degenerative diseases. Alzheimer's disease (AD) is a complex and genetically heterogeneous disease that is the most common form of dementia and aff ects up to 15 million individuals worldwide. Th e presenting pathology of AD includes extacellular neuritic plaques composed of beta-amyloid peptide (Aß) and intracellular neurofi brillary tangles composed of hyperphosphorylated tau, with neuronal loss in specifi c brain regions. A large body of evidence suggests that some form(s) of the polymorphic Aß are neurotoxic and induce neuronal death, tau hyperphosphorylation and neuronal death. However, the mechanisms underlying these pathological changes are still largely unknown. Th e early stages of symptomatic AD are characterized by memory impairment and subtle behavioral changes that are associated with changes in synaptic function. Th e loss of synapses strongly correlates with cognitive decline in AD and is now thought to result from the interactions of toxic forms of Aß peptide with molecules that are essential for neuronal integrity and synaptic connections. A combination of cell culture and animal studies has recently shown that adhesion molecules play important roles in synapse initiation, maturation, and function. Functional studies of individual adhesion molecules have begun to provide information on their role in synapse assembly and synaptic plasticity. In this chapter, we review the roles of diff erent families of adhesion molecules, including the immunoglobulins, integrins, cadherins and selectins, in normal brain and in dementia, particularly Alzheimer's disease.
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| 33. |
- Janciauskiene, Sabina, et al.
(författare)
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Allergen-specific immunotherapy increases plasma gelsolin levels
- 2014
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Ingår i: American Journal of Rhinology & Allergy. - : SAGE Publications. - 1945-8924 .- 1945-8932. ; 28:3, s. 136-140
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Tidskriftsartikel (refereegranskat)abstract
- Background: It has been observed that patients with allergic asthma/rhinitis have increased apoptosis of peripheral blood cells. This study was designed to explore the idea that the markers of apoptosis may help predict the response of allergen immunotherapy. Methods: The Allergy Department of University Hospital, Malmo, Sweden, recruited a total of 58 young adults (<35 years) with a history of birch pollen/grass pollen-induced allergic rhinitis. Their diagnoses were verified by positive skin-prick tests and the presence of serum-specific immunoglobulin E antibodies toward birch and/or grass pollen. Plasma samples were obtained from 34 patients before the start of immunotherapy and 24 patients after treatment. The control group consisted of 38 nonallergic individuals. The levels of plasma gelsolin, soluble forms of Fas (sFas) and Fas ligand (Fas-L), the chemokine CCL17 (thymus- and activation-regulated chemokine), and tissue inhibitor of metalloprotease (TIMP) 1, were measured by enzyme-linked immunosorbent assay. Results: In patients receiving immunotherapy plasma gelsolin levels were higher relative to those without immunotherapy (the median level was 23.97 mu g/mL [range, 18-35.8 mu g/mL] versus 21.2 mu g/mL [range, 13.9-29.8 mu g/mL]; p = 0.012) and were similar to those of healthy controls (24.7 mu g/mL [range, 17.4-35.3 mu g/mL]). Plasma levels of sFas, Fas-L, CCL17, and TIMP-1 did not differ between study groups. Only in controls did the plasma gelsolin levels inversely correlate to the levels of soluble Fas. Conclusion: Allergen-specific immunotherapy increases plasma levels of gelsolin, an antioxidant and antiapoptotic protein.
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| 34. |
- Janciauskiene, Sabina, et al.
(författare)
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{alpha}1-antitrypsin Inhibits the Activity of the Matriptase Catalytic Domain in vitro.
- 2008
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1535-4989. ; 39:6, s. 631-637
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Tidskriftsartikel (refereegranskat)abstract
- Matriptase is a type II transmembrane protease which is characterized by an N-terminal transmembrane and multiple extracellular domains, in addition to the conserved extracellular serine protease catalytic domain. The expression pattern of matriptase suggests that this protease may play broad roles in the biology of surface lining epithelial cells. In this study we report that alpha1-antitrypsin (AAT), an endogenous inhibitor of serine proteases, inhibits the catalytic domain of human recombinant matriptase in vitro. Co-incubation of alpha1-antitrypsin with matriptase (at a molar ratio 1:2) resulted in the formation of heat stable complexes, clearly seen in sodium dodecyl sulfate (SDS) electrophoresis and Western blots. AAT was found to be a slow, tight-binding inhibitor of the catalytic domain of matriptase with a second order reaction rate constant of 0.31 x10(3) M(-1)s(-1). Notably, the oxidised form of AAT, which lacks serine protease inhibitor activity, failed to generate matriptase complexes and to inhibit matriptase activity. Since matriptase is involved in a number of physiological processes including activation of epithelial sodium channels, our findings offer considerable new insights into new regulatory function of AAT in vivo.
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| 35. |
- Janciauskiene, Sabina, et al.
(författare)
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alpha(1)-Antitrypsin, old dog, new tricks - alpha 1-Antitrypsin exerts in vitro anti-inflammatory activity in human monocytes by elevatin cAMP
- 2007
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 282:12, s. 8573-8582
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Tidskriftsartikel (refereegranskat)abstract
- Regulation of serine protease activity is considered to be the sole mechanism for the function of alpha(1)-antitrypsin (AAT). However, recent reports of the anti-inflammatory effects of AAT are hard to reconcile with this classical mechanism. We discovered that two key activities of AAT in vitro, namely inhibition of endotoxin-stimulated tumor necrosis factor-a and enhancement of interleukin-10 in human monocytes, are mediated by an elevation of cAMP and activation of cAMP-dependent protein kinase A. As expected with this type of mechanism, the AAT mediated rise in cAMP and the impact on endotoxin-stimulated tumor necrosis factor-a and interleukin-10 was enhanced when the catabolism of cAMP was blocked by the phosphodiesterase inhibitor rolipram. These effects were still observed with modified forms of AAT lacking protease inhibitor activity.
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| 36. |
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| 37. |
- Janciauskiene, Sabina, et al.
(författare)
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Detection of Alzheimer peptides and chemokines in the aqueous humor
- 2011
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Ingår i: European Journal of Ophthalmology. - 1120-6721. ; 21:1, s. 104-111
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. Alzheimer disease (AD) and age-related ocular diseases are characterized by inflammation and accumulation of insoluble proteins. We aimed to investigate the detectability and clinical relevance of a panel of AD-related markers, such as Alzheimer peptides and chemokines, in the aqueous humor (AH) samples taken from patients with cataract only, or cataract and 1 other ocular disease. METHODS. The AH samples were obtained during cataract surgery from patients with cataract only (n=162), cataract and glaucoma (n=21), cataract and exfoliation (PEX) (n=31), cataract and macular degeneration (n=36), and cataract and diabetic retinopathy (n=16). The AD peptides (A beta(1-42), A beta(1-40), A beta(1-38)) and chemokines (eotaxin, eotaxin 3, interleukin [IL]-8, inducible protein-10, monocyte chemotactic protein [MCP]-1, MCP-4, macrophage-derived chemokine, macrophage inflammatory protein-1 beta, thymus and activation-egulated chemokine) were quantified by using multiplex immunoassays. RESULTS. The levels of the AH peptides (A beta(1-38), A beta(1-40), A beta(1-42)) did not differ between disease groups. Independently of disease group, the A beta(1-38) levels correlated with A beta(1-40) and A beta(1-42) (p<0.001, n=277). Notably, the ratio A beta(1-42) to A beta(1-38) differed between PEX and macular degeneration (mean 95% confidence interval [CI] =8.12 [11.3-3.99] vs 2.23 [2.67-0.52], p=0.003). Among chemokines examined, only MCP-1 and IL-8 were detected in about 90% to 46% of all analyzed (n=266) samples. Higher levels of AH IL-8 were found in the glaucoma group than in cataract only (p=0.011). Independently of disease group, a correlation was observed between AH MCP-1 and IL-8 (rho=0.275, p<0.001, n=266) and between MCP-1 and A beta(1-40) (rho=0.239, p<0.001, n=266). CONCLUSIONS. Our findings highlight pathologic similarities between AD and eye diseases, and show the potential of modern technologies to detect AD biomarkers in age-related eye diseases.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
- Janciauskiene, Sabina
(författare)
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Hydrophobic interactions of serpins
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The proteins of the serpin family are primarily but not exclusively proteinase inhibitors, which share a common, similar structure. It is known that this structure undergoes major conformational changes upon cleavage in the serpin reactive site loop, and that these changes include rearrangements within the hydrophobic core of the molecule. AAT and the free C-terminal peptide dissociated from cleaved AAT are found in human bile, where they are exposed to high concentrations of hydrophobic compounds, such as cholesterol and denaturing bile salts. ACT has been identified in the amyloid deposits of Alzheimer`s disease, where it is exposed to the hydrophobic peptide, Ab, from which neurotoxic amyloid fibrils are formed. The present studies were designed to determine the effects of such hydrophobic components on AAT and ACT. The interactions of AAT with hydrophobic bile acids and with its own hydrophobic C-terminal peptide were studied. The effects of these small molecules on the structure and biochemical properties of AAT were determined. The interaction of ACT with Ab was characterized, and the effects of ACT on fibril formation were determined. The binding of small sterol ligands in the hydrophobic core of AAT alters the conformation and aggregation properties of AAT. Large scale changes of AAT structure also occur in bile, which result in alteration of antigenicity and loss of activity of AAT. The C-terminal peptide from AAT has been found to polymerize into amyloid fibrils, which can be disrupted by intact AAT. The heterogeneous fibrils formed from the immunoglobulin lambda light chain were also found to be disaggregated by intact AAT. A specific interaction of ACT with Ab was found to be dependent on the concentrations of both interacting components and to affect the fibrillogenic property of the peptide and the heat stability and inhibitory activity of ACT. Available structural information and solution stability data enabled a model of the complex between ACT and Ab to be designed and a mechanism proposed of the action of ACT in fibril formation. Interaction of AAT and ACT with specific hydrophobic molecules and milieus results in conformational transitions of the serpin structure, with attendant changes in physicochemical properties which may be relevant to disease states.
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| 42. |
- Janciauskiene, Sabina, et al.
(författare)
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Indirect effect of alpha-1-antitrypsin on endotoxin-induced IL-1β secretion from human PBMCs
- 2022
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Ingår i: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Human alpha-1-antitrypsin (AAT) encoded by the SERPINA1 gene, is an acute phase glycoprotein that regulates inflammatory responses via both protease inhibitory and non-inhibitory activities. We previously reported that AAT controls ATP-induced IL-1β release from human mononuclear cells by stimulating the release of small bioactive molecules. In the current study, we aimed to elucidate the identity of these putative effectors released from human PBMCs in response to AAT, which may inhibit the LPS-induced release of IL-1β. We pre-incubated human PBMCs alone or with different preparations of AAT (4 mg/ml) for 30 min at 37°C, 5% CO2, and collected cell supernatants filtered through centrifugal filters (cutoff 3 kDa) to eliminate AAT and other high molecular weight substances. Supernatants passed through the filters were used to culture PBMCs isolated from the autologous or a heterologous donors with or without adding LPS (1 μg/ml) for 6 h. Unexpectedly, supernatants from PBMCs pre-incubated with AAT (Zemaira®), but not with other AAT preparations tested or with oxidized AAT (Zemaira®), lowered the LPS-induced release of IL-1β by about 25%–60% without affecting IL1B mRNA. The reversed-phase liquid chromatography coupled with mass spectrometry did not confirm the hypothesis that small pro-resolving lipid mediators released from PBMCs after exposure to AAT (Zemaira®) are responsible for lowering the LPS-induced IL-1β release. Distinctively from other AAT preparations, AAT (Zemaira®) and supernatants from PBMCs pre-treated with this protein contained high levels of total thiols. In line, mass spectrometry analysis revealed that AAT (Zemaira®) protein contains freer Cys232 than AAT (Prolastin®). Our data show that a free Cys232 in AAT is required for controlling LPS-induced IL-1β release from human PBMCs. Further studies characterizing AAT preparations used to treat patients with inherited AAT deficiency remains of clinical importance.
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| 43. |
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| 44. |
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| 45. |
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| 46. |
- Janciauskiene, Sabina, et al.
(författare)
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Performance of enhanced liver fibrosis plasma markers in asymptomatic individuals with ZZ α1-antitrypsin deficiency.
- 2011
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Ingår i: European Journal of Gastroenterology and Hepathology. - 1473-5687. ; 23:8, s. 716-720
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Alpha1-antitrypsin deficiency (AATD) is a common genetic cause of chronic liver disease. According to retrospective studies, up to 25% of those with homozygous ZZ (Glu 342 to Lys) AATD suffer from liver cirrhosis and/or liver cancer in late adulthood. We hypothesized that the plasma markers for liver fibrosis, necrosis, and apoptosis may identify AATD individuals at higher risk for liver diseases. METHODS: The study cohort included 52 clinically healthy ZZ AATD individuals of 34 years of age, identified in the Swedish neonatal screening of 1972-1974, and 81 age-matched controls with normal MM AAT variant. We analyzed plasma levels of the enhanced liver fibrosis (ELF) panel, including plasma tissue inhibitor of metalloprotease-1, amino-terminal propeptide of type III collagen and hyaluronic acid (HA), and the M30 and M65 antigens, markers for apoptosis/necrosis. RESULTS: Higher levels of tissue inhibitor of metalloprotease-1 (52%, P<0.001), amino-terminal propeptide of type III collagen (12%, P<0.05), HA (17% not significant), and M65 (13.4%, P=0.043) were found in ZZ than in MM patients. In the ZZ group, plasma levels of AAT correlated with M65 (P<0.01) and with HA (P<0.05). On the basis of the ELF panel, M30 and M65, a logistic regression model enabled us to correctly classify 81.2% of the originally grouped ZZ and MM cases with a sensitivity of 73.1% and a specificity of 86.4%. CONCLUSION: The ELF markers are associated with ZZ AATD at early adulthood, and can be considered as a useful tool to identify ZZ cases at an increased risk of developing liver diseases later in life.
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| 47. |
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| 48. |
- Janciauskiene, Sabina, et al.
(författare)
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Secreted leukocyte protease inhibitor is present in aqueous humours from cataracts and other eye pathologies.
- 2006
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Ingår i: Experimental Eye Research. - : Elsevier BV. - 0014-4835. ; 82:3, s. 505-511
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies identified serine, cysteine and metalloproteases in normal aqueous humours (AH) and suggested that a balance between proteases and their inhibitors may play a role in the modulation of the AH outflow. We aimed to determine whether secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor, is present in AH of patients with cataract and other eye pathologies. AH was collected from 117 cataract patients of which 55 were diagnosed with more when one eye disease: cataract only (n = 62), pseudoexfoliation (PEX) (n = 26), glaucoma (n = 6), diabetes retinopathy (n = 4), iritis-uveitis (n = 4) and macular degeneration (n = 28). The total protein in AH was determined by a Bradford assay and SLPI was analyzed by Western blot and ELISA methods. The average concentration of total protein and SLPI in AH samples was 160 +/- 15 mu g/ml (n = 117, +/- SEM) and 500 +/- 94 pg/ml (n = 105), respectively. The cataract patients with additional eye disease(s) showed higher protein levels (201 + 35 mu g/ml) than cataract (controls) (128 31 pg/ml), P < 0.01. It is noteworthy that no correlation was found between SLPI and the total protein concentrations in AH, but SLPI was positively correlated with age (r = 0.2, P < 0.05). No statistical difference in SLPI levels was found between controls (cataract) and other pathologies, while patients with iritis/uveitis had higher SLPI levels compared to those with diabetes (P < 0.05). We show here for the first time that SLPI is present in AH and may play a role as well as serve as a marker in pathological states. (c) 2005 Elsevier Ltd. All rights reserved.
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| 49. |
- Janols, Helena, et al.
(författare)
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A high frequency of MDSCs in sepsis patients, with the granulocytic subtype dominating in gram-positive cases.
- 2014
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Ingår i: Journal of Leukocyte Biology. - 1938-3673. ; 96:5, s. 685-693
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Tidskriftsartikel (refereegranskat)abstract
- The causative microorganisms dictate the type of MDSC generated in sepsis patients, and a large proportion of PMN-MDSCs in gram-positive sepsis includes immunosuppressive myeloid blasts. MDSCs constitute a heterogeneous population of immature myeloid cells that potently suppress immune responses. They were identified originally in cancer patients and have since been reported to occur also in chronic inflammation, autoimmunity, and even bacterial infections. Human MDSCs are commonly divided into Mo-MDSCs and granulocytic (PMN-MDSCs) subtypes. To what extent the bona fide cancer MDSCs are representative of the proposed MDSCs found in other diseases is not well known. PMN-MDSCs have been found previously to be enriched among LDGs in density gradient-centrifuged blood. In this study, we analyzed potential MDSCs in sepsis patients with different causative microorganisms, using total peripheral blood compared with density gradient-centrifuged blood. We found a high frequency of typical CD14(+)HLA-DR(low) Mo-MDSCs in all sepsis patients, whereas the typical PMN-MDSCs, as well as a prominent CD14(low) PMN-MDSC-like population, appeared preferentially in gram-positive cases. The CD14(low) PMN-MDSC variant was demonstrated to suppress T cell proliferation in vitro via a ROS-dependent mechanism, to display an increased IL-10:TNF-α ratio, and to present with signs of immaturity: blast morphology and low cytokine levels. We conclude that a spectrum of cells with MDSC features is enriched in sepsis and that the microbial origin of sepsis contributes to the substantial interindividual patient variation in the MDSC pattern.
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| 50. |
- Janols, Helena, et al.
(författare)
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Heterogeneity among septic shock patients in a set of immunoregulatory markers.
- 2014
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Ingår i: European Journal of Clinical Microbiology & Infectious Diseases. - : Springer Science and Business Media LLC. - 1435-4373 .- 0934-9723. ; 33:3, s. 313-324
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Tidskriftsartikel (refereegranskat)abstract
- Immune activation is a regular feature of sepsis, but the incidence and nature of the ensuing inflammation-resolving and immunosuppressive component is less well understood. In this study, we compared immunoregulatory markers on blood leukocytes from patients with Gram-negative or Gram-positive sepsis or septic shock, and compared this to blood from patients with severe virosis or healthy controls. To this end, blood from 32 patients with sepsis, including ten cases with shock, and 12 patients with severe virosis were analysed by flow cytometry for the expression levels of monocyte HLA-DR, CD11c, CD14 and CD40, and for frequencies of CD163(+)-suppressive monocytes, HLA-DR(+) or CD40(+)-activated T cells and Tregs. Plasma cytokine levels were analysed as a functional measurement. Signs of immunosuppression dominated in the septic shock and Gram-positive sepsis groups, whereas monocyte activation was common in Gram-negative sepsis patients without shock. However, the main finding was the large inter-individual variation of immune activation and immunosuppression, with no correlation to prognosis among the shock patients. The pronounced inter-individual variation in the analysed monocyte and lymphocyte markers forms a strong argument that, when immunomodulatory treatment is considered in a sepsis patient, it should be personalised and guided by a detailed immune status assessment.
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