| 1. |
- Bokarewa, Maria, 1963, et al.
(författare)
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Staphylococcus aureus: Staphylokinase
- 2006
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Ingår i: Int J Biochem Cell Biol. - 1357-2725. ; 38:4, s. 504-9
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Tidskriftsartikel (refereegranskat)abstract
- Staphylokinase is a 136 aa long bacteriophage encoded protein expressed by lysogenic strains of Staphylococcus aureus. Present understanding of the role of staphylokinase during bacterial infection is based on its interaction with the host proteins, alpha-defensins and plasminogen. alpha-Defensins are bactericidal peptides originating from human neutrophils. Binding of staphylokinase to alpha-defensins abolishes their bactericidal properties, which makes staphylokinase a vital tool for staphylococcal resistance to host innate immunity. Complex binding between staphylokinase and plasminogen results in the formation of active plasmin, a broad-spectrum proteolytic enzyme facilitating bacterial penetration into the surrounding tissues. We have recently shown high levels of staphylokinase expression in clinical isolates of skin and mucosal origin and relative low levels in isolates invading internal organs. These findings are supported by sepsis studies using isogenic S. aureus strains demonstrating increased bacterial load in the absence of staphylokinase production. Our observations indicate that staphylokinase favours symbiosis of staphylococci with the host that makes it an important colonization factor.
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| 2. |
- Jin, Tao, 1973, et al.
(författare)
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Impact of short-term therapies with biologics on prothrombotic biomarkers in rheumatoid arthritis.
- 2009
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Ingår i: Clinical and experimental rheumatology. - 0392-856X. ; 27:3, s. 491-4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Imbalance of haemostasis in patients with rheumatoid arthritis (RA) contributes to future risk of cardiovascular diseases (CVD). Prothrombotic molecules, e.g. fibrinogen, D-dimer, and tPA are elevated in plasma of RA patients, being associated to CVD. There is no imformation about the influence of biological drugs, e.g. anti-CD20 and tumor necrosis factor (TNF) antibodies on these prothrombotic molecules. OBJECTIVE: To assess whether anti-TNF and anti-CD20 therapies modify the profiles of cardiovascular risk factors in patients with RA. METHODS: The expression of prothrombotic molecules in plasma was investigated in 10 RA patients before and after treatment with TNF-alpha antibodies and in another 12 RA patients before and after anti-CD20 treatment. RESULTS: Both anti-TNF and anti-CD20 infusions gave rise to clear clinical improvement. However, only anti-CD20 infusion significantly (p=0.05) reduced concentration of fibrinogen (p=0.05), D-dimer (p<0.001), as well as tPA levels (p<0.01). In contrast, in TNF antibody treated patients only tPA levels were significantly decreased following the treatment (p<0.05). CONCLUSIONS: Infusion of CD20 antibodies to the patients with active RA led to a clearly reduced plasma levels of predictors of CVD indicating that this treatment, apart from its anti-inflammatory properties, may reduce the risk for future CVD in RA.
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| 3. |
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| 4. |
- Jin, Tao, 1973, et al.
(författare)
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Staphylokinase reduces plasmin formation by endogenous plasminogen activators.
- 2008
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Ingår i: European journal of haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 81:1, s. 8-17
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Tidskriftsartikel (refereegranskat)abstract
- Hyperfibrinolysis is a consequence of imbalance between fibrinolytic activators and their inhibitors. Increased levels of circulating plasminogen (Plg) activators such as tissue- or urokinase-type plasminogen activators (tPA or uPA respectively) are the most common causes of hyperfibrinolysis, occasionally causing major hemorrhages. We found that staphylokinase (SAK), a well-known Plg activator of bacterial origin, inhibits Plg activation mediated by endogenous tPA and uPA. Furthermore, mixture of SAK with tPA led to a significantly reduced Plg-dependent fibrinolysis. This inhibitory effect was exerted through direct action of SAK on Plg rather than indirectly on tPA or uPA. Inhibition of Plg activation by SAK is readily abrogated by interaction of SAK with human neutrophil peptides (HNPs). Finally, we show that NH2-terminal residues of SAK are important for the inhibitory effect of SAK on tPA- and uPA-mediated Plg activation. In conclusion, SAK reduces tPA/uPA-mediated Plg activation by means of SAK.Plg complex formation, consequently downregulating tPA/uPA-induced fibrinolysis.
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| 5. |
- Jin, Tao, 1973, et al.
(författare)
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The role of urokinase in innate immunity against Staphylococcus aureus
- 2005
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Ingår i: Microbes Infect. - : Elsevier BV. - 1286-4579. ; 7:9-10, s. 1170-5
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase (uPA) is a serine protease that not only displays fibrinolytic function but also promotes host leukocytes to home to inflammatory sites. We have recently demonstrated that staphylokinase (SAK), which is a fibrinolytic protein secreted by Staphylococcus aureus, forms complexes with human neutrophil peptides (HNPs), which are members of the defensin family and have anti-microbial properties, thereby inhibiting the bactericidal effects of the HNPs. The aim of this study was to assess whether endogenous uPA, which has fibrinolytic properties similar to those of SAK, binds to HNPs and interferes with SAK/HNPs interaction. To this end, an ELISA was used to analyze the interactions between uPA and HNPs. HMW uPA had the ability to bind to both HNP types. The biological consequences of the formation of this complex were analyzed with respect to its bactericidal properties. HMW uPA killed S. aureus, albeit at relatively high doses (50-100 mug/ml). In contrast, the binding of HMW uPA to HNPs had no impact on the bactericidal functions of the HNPs. Importantly, the addition of HMW uPA to SAK eliminated the ability of SAK to neutralize HNPs. Our results demonstrate that endogenous HMW uPA inhibits S. aureus growth both directly, by cytolysis, and indirectly, by abrogation of the neutralizing effect of SAK on the bactericidal activities of HNPs. These findings indicate novel functions of HMW uPA in the host defense against staphylococcal infections.
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| 6. |
- Jin, Tao, 1973, et al.
(författare)
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Urokinase-type plasminogen activator, an endogenous antibiotic
- 2005
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Ingår i: J Infect Dis. - 0022-1899. ; 192:3, s. 429-37
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Tidskriftsartikel (refereegranskat)abstract
- Urokinase-type plasminogen activator (uPA) is a serine protease that not only displays fibrinolytic function but also modulates innate and adaptive immune responses. In the present study, we assessed whether uPA acts as an endogenous antibiotic. It has been demonstrated that uPA inhibits growth of Staphylococcus aureus both in vivo and in vitro. Importantly, the bactericidal properties of uPA are associated with the serine protease domain of the molecule but are not dependent on its plasminogen-activation potential and cannot be inhibited by plasminogen activator inhibitor type 1 (PAI-1). In a murine infection model, uPA treatment alleviated staphylococcal sepsis by inhibiting bacterial growth. To further evaluate the changes in uPA levels during the course of staphylococcal infection, total uPA and active uPA levels were analyzed in plasma and in kidney homogenates. Expression of total uPA was constant, but PAI-1 levels were dramatically increased in plasma and in kidney homogenates during the course of staphylococcal infection. After infection with staphylococci, the level of metabolically active uPA was unaltered in plasma but was significantly decreased in kidney homogenates. Active uPA levels were inversely related to PAI-1 levels and to bacterial loads in kidney homogenates. In conclusion, we report that uPA acts as an endogenous antibacterial substance that might constitute the first line of host defense against staphylococcal infection. The decreased active uPA levels in infected organs might be due to the dramatically increased PAI-1 production during S. aureus infection.
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| 7. |
- Kwiecinski, Jakub, 1985, et al.
(författare)
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Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosus.
- 2009
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Ingår i: Arthritis and rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:7, s. 2094-101
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: A homeostatic imbalance between coagulation and fibrinolysis might occur intrathecally in neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no published data on levels of fibrinolytic factors in the cerebrospinal fluid (CSF) of patients with NPSLE. The present study was undertaken to assess CSF levels of fibrinolytic molecules, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), D-dimer, and plasminogen activator inhibitor 1 (PAI-1), in SLE patients with clinically verified neuropsychiatric involvement and to compare these levels with those in SLE patients without neuropsychiatric involvement and in healthy subjects. METHODS: Levels of uPA, tPA, and PAI-1 were assessed in CSF from 94 patients with SLE (33 who had NPSLE, 56 who did not have NPSLE, and 5 who were positive for antiphospholipid antibody [not included in the NPSLE or non-NPSLE group]) and from 53 age-matched controls. Patients were evaluated clinically, with magnetic resonance imaging of the brain, analyses of neuronal/glial degradation products in CSF, and neuropsychiatric testing. RESULTS: In the group of patients with NPSLE, intrathecal PAI-1 levels were significantly elevated compared with levels in SLE patients without overt neuropsychiatric involvement (P < 0.05) and in healthy controls (P < 0.001). In contrast, intrathecal levels of uPA did not differ significantly. Intrathecal levels of PAI-1 correlated significantly with CSF levels of interleukin-6 (IL-6) (r = 0.34, P < 0.001) and IL-8 (r = 0.33, P < 0.001). Importantly, increased PAI-1 and D-dimer levels were observed in SLE patients who had pathologically elevated levels of glial fibrillary acidic protein, neurofilament triplet protein, and tau protein in CSF. CONCLUSION: Intrathecal release of PAI-1 is increased in patients with NPSLE. This results in impaired fibrinolysis, which might contribute to neuronal and astrocytic damage in NPSLE.
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| 8. |
- Zare, Fariba, 1972, et al.
(författare)
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Single-stranded polyinosinic acid oligonucleotides trigger leukocyte production of proteins belonging to fibrinolytic and coagulation cascades.
- 2008
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Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 84:3, s. 741-7
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Tidskriftsartikel (refereegranskat)abstract
- The present study assessed the inductory effects of ds- and ssRNA on the leukocyte production of proteins belonging to fibrinolytic and coagulation cascades. Murine splenocytes were stimulated with dsRNA [polyinosinic:polycytidylic acid (polyIC)] and ssRNA sequences [polyinosinic acid (polyI), polycytidylic acid (polyC), and polyuridylic acid (polyU)]. The expression of plasminogen (Plg), tissue factor (TF), IL-6, and IFN-alpha was assessed. Intracellular transduction mechanisms activated by oligonucleotides were evaluated using specific inhibitors of signaling pathways and genetically modified mice. polyIC efficiently and dose-dependently induced the expression of Plg, IL-6, and IFN-alpha, whereas TF was not induced by polyIC. polyI was unable to trigger IFN-alpha production, and it was efficiently inducing Plg and TF. IFN-alphaR and dsRNA-dependent protein kinase signaling were not required for the polyI-induced production of Plg or TF. Neither polyU nor polyC induced the expression of Plg or TF. Importantly, the presence of U- and C-nucleotide strands in the dsRNA significantly reduced expression of Plg and TF compared with polyI alone. Exposure of splenocytes to polyI activated the NF-kappaB pathway followed by the expression of TF and IL-6. In contrast, Plg production did not require NF-kappaB, was only partly down-regulated by p38 MAPK inhibitor, and was efficiently inhibited by insulin, indicating a different mechanism for its induction. ssRNA exerts its TF-generating properties through NF-kappaB activation in an IFN-alpha-independent manner. The expression of fibrinolytic versus coagulation proteins is regulated through distinctly different transduction pathways. As fibrinolytic and coagulation cascades are important components of inflammatory homeostasis, these findings might have importance for development of new, targeted therapies.
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