| 1. |
- Forsblad d'Elia, Helena, 1961, et al.
(författare)
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Resistin in serum is associated with higher levels of IL-1Ra in post-menopausal women with rheumatoid arthritis.
- 2008
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 47:7, s. 1082-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of this study was to investigate associations between serum levels of resistin, an adipokine and markers of inflammation, bone metabolism, plasma lipids and kidney function in post-menopausal RA patients and to evaluate if HRT during 2 yrs affected resistin levels. METHODS: Eighty-eight women were randomly allocated to receive HRT, vitamin D(3) and calcium or vitamin D(3) and calcium alone. Serum levels of resistin, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-6, IL-6 soluble receptor, TNF-alpha were measured by ELISA, markers of bone metabolism, carboxyterminal cross-linked telopeptide of type I collagen (ICTP) and carboxyterminal propeptide of type I procollagen by RIA, ESR, CRP, Hb, creatinine and lipids by standard laboratory techniques, BMD and total lean mass (TLM) by DXA and joint destruction by Larsen score. Resistin was also measured in 42 healthy control women. RESULTS: There was no difference in resistin concentration between patients and healthy controls. Resistin was significantly correlated with IL-1Ra, CRP, TNF-alpha, ICTP, glucocorticosteroids and Larsen score and inversely with BMD, hip and with TLM. In multiple regression analysis, IL-1Ra, TLM and use of corticosteroids remained determinants of resistin. Patients treated with HRT displayed significant increase in resistin compared with controls in the first but not the second year. CONCLUSIONS: Resistin was associated with increased inflammation, particularly by the acute-phase reactant IL-1Ra antagonizing IL-1beta, joint destruction, glucocorticosteroids and with reduced BMD and TLM. These findings suggest resistin being a significant mediator in the inflammatory process in RA. Further studies examining the mechanisms behind the relation between resistin and IL-1Ra are encouraged. HRT does not seem to have important long-term effect on resistin.
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| 2. |
- Oltean, Mihai, 1976, et al.
(författare)
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Donor pretreatment with FK506 reduces reperfusion injury and accelerates intestinal graft recovery in rats
- 2007
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Ingår i: Surgery. - : Elsevier BV. - 0039-6060. ; 141:5, s. 667-77
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: FK506 alleviates warm ischemia-reperfusion injury, but it remains unknown if such protection is manifest after cold storage and transplantation. We studied the early outcome after transplantation of intestines from donors pretreated with FK506 compared to grafts from controls treated with saline (154 mM NaCl). METHODS: Sprague-Dawley rats received 0.3 mg/kg FK506 or saline intravenously 6 hours before graft retrieval. The small bowel was harvested, stored for 3 hours, and then transplanted heterotopically. Samples were taken after preservation and at 20 minutes, 6 hours, 12 hours, and 24 hours after reperfusion. Heat shock protein 72 (Hsp72) and iintercellular adhesion molecule (ICAM)-1 expression and nuclear factor kappaB (NF-kappaB) activation were assessed via Western blots and eelectrophoretic mobility shift assay (EMSA), respectively. Dissacharidase activity and enterocyte proliferation rate were also studied. RESULTS: Preservation injury was similar between groups, but pretreated grafts had better morphology already 20 minutes after reperfusion. Control grafts always had thinner mucosa and more PMN infiltration. Hsp72 expression was greater in pretreated grafts. ICAM-1 was absent after harvesting, preservation, and immediately after reperfusion but increased in control grafts at the later time points. Control grafts showed a biphasic NF-kappaB activation pattern, whereas NF-kappaB activation was inhibited effectively in pretreated grafts. Dissacharidase activity decreased during the first 6 hours after reperfusion but recovered within 24 hours in pretreated grafts but not in control grafts. Earlier enterocyte proliferation was observed in pretreated grafts. CONCLUSIONS: FK506 donor pretreatment reduced graft proinflammatory activation and neutrophil inflammation. Pretreated groups revealed a milder reperfusion injury and accelerated morphologic and functional recovery. The mechanisms involved appear to involve Hsp72 upregulation and NF-kappaB inhibition.
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| 3. |
- Oltean, Mihai, 1976, et al.
(författare)
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Reduced liver injury and cytokine release after transplantation of preconditioned intestines.
- 2009
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Ingår i: The Journal of surgical research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 154:1, s. 30-7
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The postischemic intestine liberates pro-inflammatory mediators (cytokines, lipopolysaccharide [LPS], free radicals) proportional with the local injury that may trigger a systemic inflammatory response and multi-system organ failure. Previously, intestines from donors receiving Tacrolimus revealed improved morphology and abrogated nuclear factor kappa B (NF-kappaB) activation. Because of its pivotal role in inflammation, we investigated if NF-kappaB intragraft inhibition influences the posttransplant inflammatory response and remote organ injury. MATERIALS AND METHODS: Donor Sprague Dawley rats received tacrolimus (0.3 mg/kg) or saline i.v. 6 h before graft harvest. The intestines were preserved for 3 h and then transplanted heterotopically. Hepatic microcirculation was assessed at 20 min, 6 h, 12 h, or 24 h post-reperfusion (postR) using laser-Doppler flowmetry (n = 10/group). Blood pressure measurements and liver sampling were performed at 6, 12, or 24 h postR. Blood samples were obtained at 1, 3, 6, 12, and 24 h postR. Hepatic intercellular adhesion molecule 1 (ICAM-1) expression, caspase-3 and -9 activity, and circulating tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, and LPS were studied. RESULTS: Pretreated graft (PG) recipients had superior cardiovascular parameters at 6 and 12 h postR, while liver perfusion was similar between groups at all time points. Recipients of PG had lower transaminase levels and ICAM-1 liver expression. Liver caspase 3 and 9 activity were similar at 6 and 12 h but increased at 24 h in both groups. At every time point, circulating tumor necrosis factor alph, IL-1beta, and IL-6 were lower in animals receiving PG. LPS was found increased only at the last time point. CONCLUSIONS: Transplantation of tacrolimus-pretreated intestines triggered a milder inflammatory response and decreased liver injury early posttransplantation compared with untreated grafts. Cytokines, but not neutrophils, hypoperfusion, or LPS may underlie the dysfunction.
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| 4. |
- Pullerits, Rille, 1969, et al.
(författare)
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Decreased levels of soluble receptor for advanced glycation end products in patients with rheumatoid arthritis indicating deficient inflammatory control
- 2005
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Ingår i: Arthritis Res Ther. - : Springer Science and Business Media LLC. - 1478-6362 .- 1465-9905. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily being expressed as a cell surface molecule and binding a variety of ligands. One of these ligands is high-mobility group box chromosomal protein 1, a potent proinflammatory cytokine, expression of which is increased in synovial tissue and in synovial fluid of rheumatoid arthritis (RA) patients. The interaction of high-mobility group box chromosomal protein 1 with cell-surface RAGE leads to an inflammatory response. In contrast, the presence of soluble RAGE (sRAGE) may abrogate cellular activation since the ligand is bound prior to interaction with the surface receptor.Our aim was to analyse to what extent sRAGE is present in patients with chronic joint inflammation (RA) as compared with patients with non-inflammatory joint disease and with healthy subjects, and to assess whether there is an association between sRAGE levels and disease characteristics.Matching samples of blood and synovial fluid were collected from 62 patients with RA with acute joint effusion. Blood from 45 healthy individuals, synovial fluid samples from 33 patients with non-inflammatory joint diseases and blood from six patients with non-inflammatory joint diseases were used for comparison. sRAGE levels were analysed using an ELISA.RA patients displayed significantly decreased blood levels of sRAGE (871 +/- 66 pg/ml, P < 0.0001) as compared with healthy controls (1290 +/- 78 pg/ml) and with patients with non-inflammatory joint disease (1569 +/- 168 pg/ml). Importantly, sRAGE levels in the synovial fluid of RA patients (379 +/- 36 pg/ml) were lower than in corresponding blood samples and correlated significantly with blood sRAGE. Interestingly, a significantly higher sRAGE level was found in synovial fluid of RA patients treated with methotrexate as compared with patients without disease-modifying anti-rheumatic treatment.We conclude that a decreased level of sRAGE in patients with RA might increase the propensity towards inflammation, whereas treatment with methotrexate counteracts this feature.
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| 5. |
- Pullerits, Rille, 1969, et al.
(författare)
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Extracellular cytochrome c, a mitochondrial apoptosis-related protein, induces arthritis
- 2005
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Ingår i: Rheumatology (Oxford). - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 44:1, s. 32-9
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of the study was to assess the role of extracellular cytochrome c as an inducer of joint inflammation and to examine its levels in sera and synovial fluids of rheumatoid arthritis (RA) patients. METHODS: Mice were injected intra-articularly with different doses of cytochrome c and joints were evaluated histopathologically and immunohistochemically 3 and 10 days later. In addition, mouse spleen cells were stimulated with different concentrations of cytochrome c, followed by assessment of NF-kappaB activation and cytokine production. Sera and synovial fluid from RA patients and sera from healthy individuals were assessed with respect to cytochrome c levels by an enzyme-linked immunoassay technique. RESULTS: Histopathological signs of arthritis were evident in 75% of animals following intra-articular injection of cytochrome c. Synovitis was characterized by influx of Mac-1+ cells. In vivo depletion of neutrophils and monocytes led to abrogation of arthritis. Stimulation of mouse spleen cells in vitro with cytochrome c resulted in activation of NF-kappaB and release of proinflammatory cytokines and chemokines. Cytochrome c levels in RA patients' sera were significantly lower than in healthy controls. Further, cytochrome c levels in synovial fluid were significantly lower than in corresponding blood samples. CONCLUSIONS: Our findings demonstrate that extracellular cytochrome c displays direct proinflammatory properties mediated by activation of NF-kappaB and causing neutrophil and monocyte triggered inflammation. We hypothesize that decreased levels of cytochrome c in RA patients reflect consumption of this molecule in the synovial tissue, decreasing apoptosis and shifting the balance towards inflammation.
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| 6. |
- Pullerits, Rille, 1969, et al.
(författare)
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Induction of arthritis by high mobility group box-1 protein is independent of tumour necrosis factor signalling.
- 2008
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Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 10:3
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: INTRODUCTION: TNFalpha and HMGB1 are two potent pro-inflammatory cytokines implicated as important mediators of arthritis. Increased levels of these cytokines are found in the joints of RA patients and they trigger arthritis when applied into the joints of naive mice. HMGB1 is actively released from immune cells in response to TNFalpha and once released, it induces in turn production of several pro-inflammatory cytokines including IL-6 and TNFalpha by macrophages. However, it is unknown whether HMGB1-induced arthritis is mediated via TNFalpha pathway. The purpose of this study was to investigate whether the arthritis-inducing effect of HMGB1 is dependent on TNFalpha expression in vivo and to assess whether TNFalpha deficiency affects a pro-inflammatory cytokine response to HMGB1 in vitro. METHODS: TNFalpha knockout (KO) mice and backcrossed control animals on C57Bl6 background were injected intra-articularly (i.a.) with 5 micrograms of HMGB1. Joints were dissected three days after i.a. injection and evaluated histologically by scoring the frequency and severity of arthritis. For in vitro studies, mouse spleen cultures from TNFalpha KO and control mice were incubated with different doses of HMGB1and cell culture supernatants were collected at different time points for analysis of IL-6. RESULTS: I.a. injection of HMGB1 into healthy mouse joints resulted in overall frequency of 32-39 % arthritic animals. No significant differences were found with respect to severity and incidence of synovitis between mice deficient for TNFalpha (7 out of 18 mice with arthritis) in comparison with control TNFalpha+/+ animals (6 out of 19). No significant differences were detected between spleen cells from TNFalpha+/+ versus TNFalpha-/- mice regarding IL-6 production upon stimulation with highly purified HMGB1 following 24 and 48 hours. However, upon stimulation with suboptimal dose of recombinant HMGB1, the splenocytes from TNFalpha+/+ animals released significantly more IL-6 than cells from the knockout mice (602 +/- 112 and 304 +/- 50 pg/ml, respectively, p< 0.05). CONCLUSIONS: Our data show that HMGB1 triggered joint inflammation is not mediated via TNF pathway. Combined with our previous study, we suggest that HMBG1-triggered arthritis is likely to be mediated through IL-1 activation.
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| 7. |
- Pullerits, Rille, 1969, et al.
(författare)
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Soluble receptor for advanced glycation end products triggers a proinflammatory cytokine cascade via beta2 integrin Mac-1
- 2006
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Ingår i: Arthritis Rheum. - : Wiley. - 0004-3591. ; 54:12, s. 3898-907
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Receptor for advanced glycation end products (RAGE) is a cell surface molecule that binds a variety of ligands, including high mobility group box chromosomal protein 1 (HMGB-1), a potent proinflammatory cytokine. RAGE-ligand interaction leads to an inflammatory response. A truncated form of the receptor, soluble RAGE (sRAGE), has been suggested to function as a decoy abrogating cellular activation, but its endogenous activity is not fully understood. We undertook this study to assess the properties of sRAGE in vivo and in vitro and to analyze the role of sRAGE in HMGB-1-induced arthritis. METHODS: Mice were injected intraarticularly with HMGB-1 and treated systemically with sRAGE prior to histologic joint evaluation. All animals were subjected to peritoneal lavage to assess the local effect of sRAGE treatment. For in vitro studies, mouse splenocytes were incubated with sRAGE followed by assessment of NF-kappaB activation and cytokine production. The chemotactic properties of sRAGE were investigated using in vitro migration assay. RESULTS: Soluble RAGE was determined to have proinflammatory properties since it gave rise to production of interleukin-6, tumor necrosis factor alpha, and macrophage inflammatory protein 2. This effect was triggered by interaction with leukocyte beta2 integrin Mac-1 and was mediated via NF-kappaB. Systemic treatment with sRAGE significantly down-regulated HMGB-1-triggered arthritis, but the observed effect was due to a deviation of the inflammatory response from the joint to the peritoneal cavity rather than a genuine antiinflammatory effect. Apart from its proinflammatory properties, sRAGE was proven to act as a chemotactic stimulus for neutrophils. CONCLUSION: We conclude that sRAGE interacts with Mac-1, thereby acting as an important proinflammatory and chemotactic molecule.
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| 8. |
- Pullerits, Rille, 1969, et al.
(författare)
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Synovial fluid expression of autoantibodies specific for RAGE relates to less erosive course of rheumatoid arthritis
- 2007
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Ingår i: Rheumatology. - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 46:8, s. 1367-1371
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. The receptor for advanced glycation end products (RAGE) is expressed by many cells in joints of rheumatoid arthritis (RA) patients and interacts with a variety of pro-inflammatory ligands that are enriched in inflamed joint. The RAGE-ligand interaction leads to a sustained inflammatory response. Also, secreted form of the receptor, called soluble RAGE (sRAGE), the levels of which are decreased in RA patients, modulates inflammatory responses. We sought to determine whether RA patients display increased occurrence of autoantibodies against RAGE and whether such an autoantibody production is related to disease characteristics. Methods. Matching samples of blood and synovial fluid were collected from 50 patients with RA with acute joint effusion. Blood from 43 healthy individuals and synovial fluid samples from 32 patients with non-inflammatory joint diseases were used for comparison. Anti-RAGE antibody levels were analysed using an ELISA. Results. RA patients displayed significantly higher blood and synovial fluid levels of anti-RAGE antibodies, both of IgG as well as of IgM class as compared with healthy controls and with patients with non-inflammatory joint diseases. Patients with seropositive RA had significantly less IgG antibodies in their synovial fluid as compared to seronegative patients. Furthermore, the presence of IgG class of anti-RAGE antibodies locally in the joint was found to be related to less aggressive, i.e. non-erosive disease. Conclusion. These results suggest that RAGE-specific B cell response protect patients with RA from destructive course of the disease.
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| 9. |
- Pullerits, Rille, 1969, et al.
(författare)
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The decrease of soluble RAGE levels in rheumatoid arthritis patients following hormone replacement therapy is associated with increased bone mineral density and diminished bone/cartilage turnover: a randomized controlled trial.
- 2009
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324.
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of the study was to prospectively investigate the effects of HRT on serum soluble receptor for advanced glycation end product (sRAGE) levels in RA patients and to determine whether sRAGE production is related to bone/cartilage metabolism. Methods. Eighty-eight post-menopausal RA patients were randomized to receive vitamin D3 and calcium supplementation with or without HRT (oestradiol plus noretisterone acetate). The levels of total sRAGE in sera were measured before, 1 and 2 years after treatment initiation. Potential associations between sRAGE levels, bone/cartilage metabolic markers and BMD were investigated. Results. Patients receiving HRT displayed significantly decreased levels of serum sRAGE at 1 and 2 years as compared with levels at study entry. The increase in serum oestradiol was associated with the decline in sRAGE levels. Importantly, sRAGE levels at baseline significantly correlated with bone/cartilage turnover markers including C-terminal propeptide of type I procollagen, carboxyterminal telopeptide of type I collagen and cartilage oligomeric matrix protein, and the decrease of sRAGE levels paralleled with diminished concentration of these molecules. BMD in hip and femoral neck and progression of Larsen score at 1 year were associated with baseline sRAGE levels. The decline in sRAGE levels significantly correlated with an increase in total BMD following 2 years of treatment in patients receiving HRT but not in the control group. Conclusion. Our findings suggest that HRT decreases the levels of endogenous sRAGE in post-menopausal RA patients implicating its role in sRAGE regulation. In addition, serum sRAGE was associated with BMD and markers of bone/cartilage metabolism. These data suggest that sRAGE is involved directly or indirectly in bone metabolism. Trial registration. Current Controlled Trials, ISRCTN46523456, http://www.controlled-trials.com/isrctn/search.html?srch=ISRCTN46523456.
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| 10. |
- Pullerits, Rille, 1969
(författare)
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The inflammatory and immunogenic properties of the receptor for advanced glycation end products and its ligand, high mobility group box chromosomal protein 1
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA) is a chronic systemic inflammatory joint disease, the pathogenesis of which is complex, involving a wide range of molecules. High mobility group box chromosomal protein 1 (HMGB1) is a nuclear protein recently recognised as a pro-inflammatory cytokine which levels are increased in RA patients. The interaction of HMGB1 with one of its receptors, receptor for advanced glycation end products (RAGE), leads to an inflammatory response. In contrast, the presence of soluble RAGE (sRAGE) has been suggested to function as a decoy by binding RAGE ligands and abrogating cellular activation. The aims of this thesis were to (I) investigate the role of HMGB1 in the development of arthritis; (II) to assess the properties of soluble RAGE in vivo as well as in vitro and to determine the role of sRAGE treatment in HMGB1 triggered arthritis; (III) to determine to what extent sRAGE is present in patients with RA, and to assess the association between sRAGE levels and disease characteristics; (IV) to investigate the immune response to sRAGE in RA patients. To evaluate the role of HMGB1 in arthritis, we administered recombinant HMGB1 into the knee joints of healthy mice. The results demonstrated that HMGB1 triggered joint inflammation. In vitro studies show that sRAGE in contrast to what was previously believed, exerts pro- rather than anti-inflammatory properties giving a dose-dependent rise to production of pro-inflammatory cytokines. Further, we demonstrated that this effect is at least partly triggered by interaction with Mac-1 and mediated via NF-ƒÛB pathway. Intra-peritoneal administration of sRAGE down regulated HMGB1-triggered arthritis, but the observed effect was due to a deviated inflammatory response from joint to peritoneal cavity. Finally, we demonstrated that sRAGE also acted as a chemotactic stimulus for neutrophils in vitro. Matching samples of blood and synovial fluid from RA patients were analysed regarding 1) sRAGE levels and 2) the immune response to sRAGE. RA patients displayed significantly decreased blood levels of sRAGE and higher blood and synovial fluid levels of anti-RAGE antibodies, as compared to healthy controls and patients with non-inflammatory joint disease. The presence of antibodies against sRAGE was associated with a more benign course of RA. Taken together, these results indicate that HMGB1 and sRAGE are pro-inflammatory molecules participating in the development of arthritis. The endogenous antibodies directed against sRAGE might neutralise the pro-inflammatory impact of this molecule, thereby affecting the clinical outcome of arthritis.
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