| 1. |
- Adlesic, M., et al.
(författare)
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Histamine in rheumatoid arthritis
- 2007
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Ingår i: Scand J Immunol. - : Wiley. - 0300-9475 .- 1365-3083. ; 65:6, s. 530-7
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is an autoimmune disease characterized by a persistent inflammation of the synovium, leading to the erosion of articular cartilage and bone. Synovial mast cells and their effector molecule, histamine, receive increased attention as mediators of joint inflammation. The aim of our study was to analyse levels of free histamine in serum and joint fluid of RA patients and to evaluate the potential inflammatogenic properties of histamine in vivo and in vitro. Histamine levels were measured by an ELISA in synovial fluid and sera of RA patients and of healthy controls. Histamine levels were also assessed in plasma of RA patients undergoing anti-TNF-alpha treatment. In the murine part of the study, histamine was injected intra-articularly in the knee joint of mice and the joints were subsequently analysed with respect to induction of inflammation. RA patients displayed significantly lower levels of histamine in circulation (0.93 +/- 0.16 ng/ml) compared with the healthy controls (1.89 +/- 0.45 ng/ml, P < 0.001). Locally, in synovial fluid the levels of histamine were even lower (0.37 +/- 0.16 ng/ml, P < 0.0006). Long-term anti-TNF-alpha treatment significantly increased circulating levels of histamine in RA patients. Our experiments on animals show that histamine on its own neither induces inflammation in the joint cavity nor influences the course of HMGB1 and peptidoglycan-induced joint inflammation. Based on our experimental and clinical studies we suggest that histamine lacks harmful properties in RA.
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| 2. |
- Bian, Li, et al.
(författare)
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Dichloroacetate alleviates development of collagen II-induced arthritis in female DBA/1 mice
- 2009
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Ingår i: ARTHRITIS RESEARCH and THERAPY. - : BioMed Central. - 1478-6354 .- 1478-6362. ; 11:5
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Dichloroacetate (DCA) has been in clinical use for the treatment of lactacidosis and inherited mitochondrial disorders. It has potent anti-tumor effects both in vivo and in vitro, facilitating apoptosis and inhibiting proliferation. The proapoptotic and anti-proliferative properties of DCA prompted us to investigate the effects of this compound in arthritis. Methods In the present study, we used DCA to treat murine collagen type II (CII)-induced arthritis (CIA), an experimental model of rheumatoid arthritis. DBA/1 mice were treated with DCA given in drinking water. Results Mice treated with DCA displayed much slower onset of CIA and significantly lower severity (P less than 0.0001) and much lower frequency (36% in DCA group vs. 86% in control group) of arthritis. Also, cartilage and joint destruction was significantly decreased following DCA treatment (P = 0.005). Moreover, DCA prevented arthritis-induced cortical bone mineral loss. This clinical picture was also reflected by lower levels of anti-CII antibodies in DCA-treated versus control mice, indicating that DCA affected the humoral response. In contrast, DCA had no effect on T cell-or granulocyte-mediated responses. The beneficial effect of DCA was present in female DBA/1 mice only. This was due in part to the effect of estrogen, since ovariectomized mice did not benefit from DCA treatment to the same extent as sham-operated controls (day 30, 38.7% of ovarectomized mice had arthritis vs. only 3.4% in sham-operated group). Conclusion Our results indicate that DCA delays the onset and alleviates the progression of CIA in an estrogen-dependent manner.
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| 3. |
- Guo, J P, et al.
(författare)
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The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases.
- 2009
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Ingår i: Genes and immunity. - : Springer Science and Business Media LLC. - 1476-5470 .- 1466-4879. ; 10:3, s. 227-36
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variation in the antigen-presenting lectin-like receptor gene complex (APLEC) associates with autoimmunity and arthritis in rats and humans. We hypothesized that the encoded C-type lectin-like receptors might influence innate immunity and responses to infectious agents. To test this hypothesis, we compared in vivo and in vitro phenotypes in DA rats and APLEC-congenic rats. Survival rates following infection with Staphylococcus aureus and Herpes simplex virus differed significantly between the two strains. Likewise, differential delayed type hypersensitivity (DTH), an immunological reaction involving T lymphocytes and macrophages, was observed in response to provocation with the chemical oxazolone. Unstimulated bone marrow-derived macrophages from the two strains appeared to already have polarized activation states with different mRNA levels of CD163 and Dectin-1 receptors. Following stimulation with a panel of microbial agents, differences in induced mRNA and protein levels were shown for interleukin (IL)-6 and IL-10 following stimulation with lipopolysaccharide, mannan and beta-glucan. Expression levels of APLEC gene mRNAs also differed, and both strains had a notably dichotomous expression of the genes, with general downregulation of all four Dcir genes and upregulation of Mincle and Mcl. We suggest that human APLEC genes may similarly regulate infectious diseases, DTH and general macrophage activation status.
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| 4. |
- Hultgren, Olof H., 1970, et al.
(författare)
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T-box transcription-factor-deficient mice display increased joint pathology and failure of infection control during staphylococcal arthritis.
- 2004
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Ingår i: Microbes and infection / Institut Pasteur. - : Elsevier BV. - 1286-4579. ; 6:6, s. 529-35
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Tidskriftsartikel (refereegranskat)abstract
- To study the impact of T-box transcription factor (T-bet) on initiation and progression of Staphylococcus aureus sepsis and arthritis, T-bet-deficient mice (T-bet(-/-)) and their wild-type controls (T-bet(+/+)) were intravenously inoculated with 8 x 10(6) S. aureus. Already 48 h after inoculation of S. aureus, T-bet-deficient mice displayed increased frequency (62% versus 19%, P = 0.002) as well as severity of arthritis compared with wild-type controls. The bacterial counts were significantly increased in T-bet(-/-) mice compared with T-bet(+/+) as measured in kidneys 72 h after the inoculation (4.3 +/- 1.8 x 10(7) versus 3.2 +/- 3.2 x 10(6) colony-forming units (CFU); P = 0.003). As expected, T-bet-deficient mice displayed significantly decreased production of IFN-gamma (10-15-fold) at 24 and 72 h after bacterial inoculation compared with wild-type mice. Interestingly, in the absence of T-bet, serum IL-4 was decreased at 24 h. IL-6 did not differ at early stage of infection but was sixfold increased in T-bet(-/-) mice over T-bet(+/+) animals at 72 h postinoculation. Ten days after the inoculation, T-bet(-/-) mice still displayed significantly more pronounced weight loss and increased serum IL-6 levels, probably due to increased bacterial burden compared with T-bet(+/+) mice. The cumulative mortality was 19% in T-bet mice (5/27) and 0% (0/27) in control animals (P = 0.05). In conclusion, T-bet plays an important role in early response to S. aureus infection, protecting against bacterial accumulation, cachexia and septic death. Furthermore T-bet downregulates joint inflammation in the early phase of disease.
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| 5. |
- Jochems, Caroline, 1973, et al.
(författare)
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Osteoporosis in experimental postmenopausal polyarthritis: the relative contributions of estrogen deficiency and inflammation
- 2005
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Ingår i: Arthritis Res Ther. - : Springer Science and Business Media LLC. - 1478-6362. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- Generalized osteoporosis in postmenopausal rheumatoid arthritis (RA) is caused both by estrogen deficiency and by the inflammatory disease. The relative importance of each of these factors is unknown. The aim of this study was to establish a murine model of osteoporosis in postmenopausal RA, and to evaluate the relative importance and mechanisms of menopause and arthritis-related osteoporosis. To mimic postmenopausal RA, DBA/1 mice were ovariectomized, followed by the induction of type II collagen-induced arthritis. After the mice had been killed, paws were collected for histology, one femur for bone mineral density (BMD) and sera for analyses of markers of bone resorption (RatLaps; type I collagen cross-links, bone formation (osteocalcin) and cartilage destruction (cartilage oligomeric matrix protein), and for the evaluation of antigen-specific and innate immune responsiveness. Ovariectomized mice displayed more severe arthritis than sham-operated controls. At termination of the experiment, arthritic control mice and non-arthritic ovariectomized mice displayed trabecular bone losses of 26% and 22%, respectively. Ovariectomized mice with arthritis had as much as 58% decrease in trabecular BMD. Interestingly, cortical BMD was decreased by arthritis but was not affected by hormonal status. In addition, markers of bone resorption and cartilage destruction were increased in arthritic mice, whereas markers of bone formation were increased in ovariectomized mice. This study demonstrates that the loss of endogenous estrogen and inflammation contribute additively and equally to osteoporosis in experimental postmenopausal polyarthritis. Markers of bone remodeling and bone marrow lymphocyte phenotypes indicate different mechanisms for the development of osteoporosis caused by ovariectomy and arthritis in this model.
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| 6. |
- Jonsson, Ing-Marie, 1949, et al.
(författare)
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Ethanol prevents development of destructive arthritis
- 2007
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Ingår i: Proc Natl Acad Sci U S A. - Washington, DC : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 104:1, s. 258-63
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Tidskriftsartikel (refereegranskat)abstract
- Environmental factors are thought to play a major role in the development of rheumatoid arthritis. Because the use of ethanol is widespread, we assessed the role of ethanol intake on the propensity to develop chronic arthritis. Collagen type II-immunized mice were given water or water containing 10% (vol/vol) ethanol or its metabolite acetaldehyde. Their development of arthritis was assessed, as well as the impact of ethanol on leukocyte migration and activation of intracellular transcription factors. Mice exposed daily to this dose of ethanol did not display any liver toxicity, and the development of erosive arthritis was almost totally abrogated. In contrast, the antibody-mediated effector phase of collagen-induced arthritis was not influenced by ethanol exposure. Also, the major ethanol metabolite, acetaldehyde, prevented the development of arthritis. This antiinflammatory and antidestructive property of ethanol was mediated by (i) down-regulation of leukocyte migration and (ii) up-regulation of testosterone secretion, with the latter leading to decreased NF-kappaB activation. We conclude that low but persistent ethanol consumption delays the onset and halts the progression of collagen-induced arthritis by interaction with innate immune responsiveness.
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| 7. |
- Jonsson, Ing-Marie, 1949, et al.
(författare)
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Role of fibrinogen-binding adhesin expression in septic arthritis and septicemia caused by Streptococcus agalactiae
- 2005
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Ingår i: J Infect Dis. - 0022-1899. ; 192:8, s. 1456-64
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Streptococcus agalactiae (group B streptococcus) is an important human pathogen that causes neonatal pneumonia, sepsis, septic arthritis, and meningitis, as well as severe infections in immunocompromised adult patients. The streptococci produce several molecules important for virulence. METHODS: We used a murine model of sepsis and septic arthritis to assess the role of FbsA, a fibrinogen-binding adhesin of S. agalactiae as a virulence determinant. NMRI mice were inoculated intravenously with S. agalactiae strains isogenic for the expression of FbsA. RESULTS: Inoculation with wild-type (wt) streptococci resulted in significantly higher mortality, more-pronounced weight decrease, and more-severe arthritis, compared with inoculation with the FbsA mutant isogenic strain. Neither active nor passive immunization with FbsA or FbsA-specific antibodies, respectively, resulted in any protection against subsequent infection with the S. agalactiae wt strain. CONCLUSION: Our results clearly indicate that the expression of FbsA by Streptococcus agalactiae is a significant virulence determinant in septic arthritis and septicemia. However, because blocking of the fibrinogen binding properties did not protect the host against the action of FbsA-expressing streptococci, we believe that the FbsA molecule has some other presently unknown biological in vivo properties.
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| 8. |
- Osborn, Teresia M, et al.
(författare)
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Decreased levels of the gelsolin plasma isoform in patients with rheumatoid arthritis.
- 2008
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Ingår i: Arthritis research & therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Gelsolin is an intracellular actin-binding protein involved in cell shape changes, cell motility, and apoptosis. An extracellular gelsolin isoform, plasma gelsolin circulates in the blood of healthy individuals at a concentration of 200 +/- 50 mg/L and has been suggested to be a key component of an extracellular actin-scavenging system during tissue damage. Levels of plasma gelsolin decrease during acute injury and inflammation, and administration of recombinant plasma gelsolin to animals improves outcomes following sepsis or burn injuries. In the present study, we investigated plasma gelsolin in patients with rheumatoid arthritis. METHODS: Circulating and intra-articular levels of plasma gelsolin were measured in 78 patients with rheumatoid arthritis using a functional (pyrene-actin nucleation) assay and compared with 62 age- and gender-matched healthy controls. RESULTS: Circulating plasma gelsolin levels were significantly lower in patients with rheumatoid arthritis compared with healthy controls (141 +/- 32 versus 196 +/- 40 mg/L, P = 0.0002). The patients' intra-articular plasma gelsolin levels were significantly lower than in the paired plasma samples (94 +/- 24 versus 141 +/- 32 mg/L, P = 0.0001). Actin was detected in the synovial fluids of all but four of the patients, and immunoprecipitation experiments identified gelsolin-actin complexes. CONCLUSIONS: The plasma isoform of gelsolin is decreased in the plasma of patients with rheumatoid arthritis compared with healthy controls. The reduced plasma concentrations in combination with the presence of actin and gelsolin-actin complexes in synovial fluids suggest a local consumption of this potentially anti-inflammatory protein in the inflamed joint.
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| 9. |
- Pizzolla, A., et al.
(författare)
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Reactive Oxygen Species Produced by the NADPH Oxidase 2 Complex in Monocytes Protect Mice from Bacterial Infections
- 2012
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 188:10, s. 5003-5011
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Tidskriftsartikel (refereegranskat)abstract
- Chronic granulomatous disease (CGD) is an inherited disorder characterized by recurrent life-threatening bacterial and fungal infections. CGD results from defective production of reactive oxygen species by phagocytes caused by mutations in genes encoding the NADPH oxidase 2 (NOX2) complex subunits. Mice with a spontaneous mutation in Ncf1, which encodes the NCF1 (p47(Phox)) subunit of NOX2, have defective phagocyte NOX2 activity. These mice occasionally develop local spontaneous infections by Staphylococcus xylosus or by the common CGD pathogen Staphylococcus aureus. Ncf1 mutant mice were more susceptible to systemic challenge with these bacteria than were wild-type mice. Transgenic Ncf1 mutant mice harboring the wild-type Ncf1 gene under the human CD68 promoter (MN+ mice) gained the expression of NCF1 and functional NOX2 activity specifically in monocytes/macrophages, although minimal NOX2 activity was also detected in some CD11b(+)Ly6G(+) cells defined as neutrophils. MN+ mice did not develop spontaneous infection and were more resistant to administered staphylococcal infections compared with MN- mice. Most strikingly, MN+ mice survived after being administered Burkholderia cepacia, an opportunistic pathogen in CGD patients, whereas MN- mice died. Thus, monocyte/macrophage expression of functional NCF1 protected against spontaneous and administered bacterial infections. The Journal of Immunology, 2012, 188: 5003-5011.
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| 10. |
- 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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| 11. |
- Pullerits, Rille, 1969, et al.
(författare)
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High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis.
- 2003
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Ingår i: Arthritis and Rheumatism. - 1529-0131. ; 48:6, s. 1693-1700
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis. METHODS: Mice were injected intraarticularly with 1 microg or 5 microg of HMGB-1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed. In addition, spleen cells were cultured in the presence of HMGB-1, and nuclear factor kappaB (NF-kappaB) activation was detected by electrophoretic mobility shift assay. RESULTS: Injection of recombinant HMGB-1 (rHMGB-1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac-1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB-1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin-1 (IL-1) receptor did not develop inflammation upon challenge with HMGB-1. In vitro data corroborate this finding, showing that rHMGB-1 activated NF-kappaB, a major pathway leading to IL-1 production. CONCLUSION: Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-kappaB activation.
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| 12. |
- Strandberg, Louise, 1981, et al.
(författare)
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Mice chronically fed high-fat diet have increased mortality and disturbed immune response in sepsis.
- 2009
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sepsis is a potentially deadly disease that often is caused by gram-positive bacteria, in particular Staphylococcus aureus (S. aureus). As there are few effective therapies for sepsis, increased basic knowledge about factors predisposing is needed. METHODOLOGY/PRINCIPAL FINDINGS: The purpose of this study was to study the effect of Western diet on mortality induced by intravenous S. aureus inoculation and the immune functions before and after bacterial inoculation. Here we show that C57Bl/6 mice on high-fat diet (HFD) for 8 weeks, like genetically obese Ob/Ob mice on low-fat diet (LFD), have increased mortality during S. aureus-induced sepsis compared with LFD-fed C57Bl/6 controls. Bacterial load in the kidneys 5-7 days after inoculation was increased 10-fold in HFD-fed compared with LFD-fed mice. At that time, HFD-fed mice had increased serum levels and fat mRNA expression of the immune suppressing cytokines interleukin-1 receptor antagonist (IL-1Ra) and IL-10 compared with LFD-fed mice. In addition, HFD-fed mice had increased serum levels of the pro-inflammatory IL-1beta. Also, HFD-fed mice with and without infection had increased levels of macrophages in fat. The proportion and function of phagocytosing granulocytes, and the production of reactive oxygen species (ROS) by peritoneal lavage cells were decreased in HFD-fed compared with LFD-fed mice. CONCLUSIONS: Our findings imply that chronic HFD disturb several innate immune functions in mice, and impairs the ability to clear S. aureus and survive sepsis.
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| 13. |
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| 14. |
- Tarkowski, Andrej, 1951, et al.
(författare)
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Current status of pathogenetic mechanisms in staphylococcal arthritis.
- 2002
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Ingår i: FEMS microbiology letters. - 0378-1097. ; 217:2, s. 125-32
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Forskningsöversikt (refereegranskat)abstract
- Interactions between staphylococci and the joint tissues of the host lead typically to rapidly progressing and highly destructive processes. Staphylococci possess a vast arsenal of components and products that contribute to the pathogenesis of joint infection. Occasionally these compounds have overlapping activities and act either in concert or alone. Host responsiveness to staphylococcal infection displays an even more complex pattern. Most of the cells and molecules that participate in the innate immune system protect the host against bacteria. However, the staphylococci have developed systems that counteract endogenous protective mechanisms. Interestingly, certain cells and molecules of the acquired immune system potentiate the severity of infection by triggering exaggerated responses to the staphylococcal danger signals. This review deals with the intricate host-bacterium interactions that occur during experimental septic arthritis, and outlines potential preventive and treatment modalities.
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| 15. |
- Verdrengh, Margareta, 1942, et al.
(författare)
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Addition of bisphosphonate to antibiotic and anti-inflammatory treatment reduces bone resorption in experimental Staphylococcus aureus-induced arthritis
- 2007
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Ingår i: J Orthop Res. - 0736-0266. ; 25:3, s. 304-10
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial arthritis is a disease with high morbidity leading to rapidly progressive bone resorption. We have shown earlier that treatment with antibiotics in combination with corticosteroids decreases joint inflammation and mortality but does not significantly affect bone/cartilage destruction of the joints. This study was performed to assess the effect of treatment with bisphosphonate [zoledronic acid (ZA)] in combination with antibiotics and corticosteroids, on the course and outcome of Staphlococcus aureus-induced arthritis. Three days after intravenous inoculation with S. aureus, mice were treated with antibiotics alone, ZA alone, ZA and antibiotics, or ZA combined with antibiotics and corticosteroids, respectively. One group served as controls and received PBS. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. One femur from each mouse was collected for bone mineral density (BMD) analysis. In addition, serum levels of type I collagen fragments (RatLaps), and osteocalcin, markers for osteoclastic and osteoblastic activity, respectively, were analyzed. Mice treated with ZA and antibiotics or with ZA in combination with antibiotics and corticosteroids lost significantly less in trabecular bone density compared to infected control mice. Furthermore, the addition of corticosteroids to animals treated with ZA and antibiotics, significantly decreased serum levels of RatLaps and osteocalcin, compared to animals treated with ZA and antibiotics or ZA alone. Treatment with bisphosphonates in combination with antimicrobial agents and corticosteroids significantly decreases the activity of osteoclasts in septic arthritis, thereby reducing the risk of skeletal destruction.
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| 16. |
- Verdrengh, Margareta, 1942, et al.
(författare)
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IL-1 receptor-associated kinase 1 mediates protection against Staphylococcus aureus infection.
- 2004
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Ingår i: Microbes and infection / Institut Pasteur. - : Elsevier BV. - 1286-4579. ; 6:14, s. 1268-72
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Tidskriftsartikel (refereegranskat)abstract
- The interleukin-1 receptor-associated kinase-1 (IRAK-1) mediates signal transduction from Toll-like/IL-1/IL-18 receptors. Though a critical protective role against Staphylococcus aureus infection has been previously attributed to myeloid differentiation factor 88 (MyD88) and IRAK-4, both also involved in TLR/IL-1/IL-18 signaling, the role of IRAK-1 is unknown. IRAK-1-deficient (IRAK-1-/-) and wild-type mice were inoculated i.v. with 2 x 10(7) or 1 x 10(6) S. aureus per mouse to evaluate the role of IRAK-1 in S. aureus sepsis. Since IRAK-1 transduces IL-1R signals, IL-1R-/- mice were also included in experiments. IRAK-1-/- mice are susceptible to a high dose of S. aureus compared to wild-type controls. In contrast to the high mortality and extensive weight loss seen in IL-1R-deficient mice in response to 1 x 10(6) S. aureus, IRAK-1-/- mice are resistant to this low dose of S. aureus. Thus IRAK-1 plays an important role in the host response to staphylococcal sepsis.
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| 17. |
- Verdrengh, Margareta, 1942, et al.
(författare)
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Inhibition of septic arthritis by local administration of taurine chloramine, a product of activated neutrophils
- 2005
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Ingår i: J Rheumatol. - 0315-162X. ; 32:8, s. 1513-7
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Taurine is an amino acid able to react with hypochlorous acid, produced endogenously by neutrophils, resulting in the more stable and less toxic taurine chloramine (Tau-Cl). Since Tau-Cl has been shown to down-regulate the production of proinflammatory mediators and to exert anti-bacterial properties, we investigated the efficacy of Tau-Cl treatment for infectious arthritis. METHODS: The murine model of hematogenous septic arthritis involved intravenous injection of a single dose of Staphylococcus aureus. Tau-Cl was administered by daily intraperitoneal injections. In another experiment S. aureus and Tau-Cl were injected intra-articularly. Evaluation of arthritis was performed clinically and histologically. The effect of Tau-Cl on bacterial growth in vitro was also assessed. RESULTS: Growth of staphylococci, including the methicillin-resistant strain 67-0, was inhibited by Tau-Cl. Mice injected with bacteria and Tau-Cl locally in the joint exhibited significantly fewer arthritic lesions. In contrast, there were no obvious differences between Tau-Cl-treated animals and controls with regard to clinical or histological signs of arthritis when bacteria and Tau-Cl were administered systemically. CONCLUSION: Our results show that Tau-Cl exerts an inhibitory effect on the development of bone and cartilage damage in the infected joint when administered intra-articularly.
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| 18. |
- Verdrengh, Margareta, 1942
(författare)
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Innate immunity in Staphylococcus aureus arthritis and sepsis
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Bacterial arthritis is a severe, rapidly progressing erosive disease with high morbidity and mortality. Staphylococcus aureus is the most common causative bacterium. Granulocytes together with cells from the monocyte/macrophage lineage, are the earliest leukocytes entering the synovial tissue in response to invading staphylococci. The recruitment of leukocytes from the vasculature and their extravasation into tissues is critical for a successful host response to infectious agent, but excessive acculmulation of leukocytes may also cause pathology. The role of granulocytes and macrophages in a model of haematogenously acquired S. aureus arthritis and sepsis was investigated. Phagocytosis by neutrophils recruited in the initial stage of S. aureus infection was found to be critical to the outcome of staphylococcal infection, since mice depleted of granulocytes prior to bacterial inoculation exhibited high mortality rate and severe arthritis. Cells of the monocytic lineage exerted a dual role in staphylococcal infection. Induced monocytopenia in S. aureus-infected mice resulted in (a) less severe arthritis, probably due to lower production of proinflammatory cytokines and (b) increased mortality, as a result of a diminished capacity to eliminate bacteria. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine promoting synthesis and maturation of phagocytic cells. GM-CSF treatment of S. aureus infected mice did not ameliorate arthritis. Our results indicate that excessive amount of GM-CSF is not beneficial in septic arthritis, possibly due to exaggerated in situ activation of phagocytic cells resulting in increased joint inflammation. The interactions between adhesion molecules on endothelial cells and their ligands on leukocytes are critical for their subsequent extravasation leading to joint inflammation. Blocking the adhesion molecules ICAM-1, and P-and L-selectins in infected mice resulted in delayed recruitment of leukocytes, leading to less severe and frequent arthritis. However, the same treatment gave rise to a less efficient phagocytosis and clearance of bacteria, resulting in higher mortality rates. This thesis provides an insight into how specific components of the innate immune system act in inflammatory diseases such as arthritis and how prophylactic and therapeutic treatments might be developed to reduce mortality and joint destruction in infected individuals.
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| 19. |
- Verdrengh, Margareta, 1942, et al.
(författare)
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Phytoestrogen genistein as an anti-staphylococcal agent
- 2004
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Ingår i: Microbes Infect. - : Elsevier BV. - 1286-4579. ; 6:1, s. 86-92
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Tidskriftsartikel (refereegranskat)abstract
- The soybean-derived isoflavone genistein has been shown to exert beneficial effects on many disorders, including cancer and cardiovascular diseases. The effects of genistein on mammalian cells are mediated by its abilities to inhibit topoisomerase II and protein tyrosine kinase. In order to examine the potential antibacterial activities of genistein, we incubated the bacteria with various concentrations of this compound for different periods of time and assessed the viable counts. Exposure to genistein exhibited an inhibitory effect on all staphylococcal strains tested, including methicillin-resistant strains. Furthermore, the growth of Streptococcus pasteurianus, Bacillus cereus, and Helicobacter pylori was clearly inhibited by genistein, whereas Escherichia coli growth was not suppressed. Daidzein, which is structurally similar to genistein, but deficient in topoisomerase II inhibitory activity, also inhibited the growth of Staphylococcus aureus, albeit with lower potency than genistein. Our results indicate that genistein exerts potent antibacterial properties in vitro, which are possibly mediated by the stabilization of the covalent topoisomerase II-DNA cleavage complex.
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| 20. |
- Verdrengh, Margareta, 1942, et al.
(författare)
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RANKL-targeted therapy inhibits bone resorption in experimental Staphylococcus aureus-induced arthritis.
- 2010
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Ingår i: Bone. - 1873-2763. ; 46:3, s. 752-758
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Bacterial arthritis causes rapidly progressing joint destruction in humans. We have shown that addition of bisphosphonates or corticosteroids to conventional antimicrobial agents decreases the activity of osteoclasts, thereby reducing bone destruction. Here we assess the effect of RANKL-targeted treatments using soluble receptor decoy and osteprotegerin (OPG) on the course and outcome of staphylococcal arthritis. Methods: Treatment was initiated 3 days after Staphylococcus aureus inoculation and included RANK-Fc, OPG-Fc, and OPG-Fc in combination with antibiotics. Control groups were treated with antibiotics, huFc, and PBS. Joints were evaluated for clinical signs of arthritis and histologically for bone and cartilage destruction. Bone mineral density (BMD) was evaluated using a peripheral quantitative computed tomography. Circulating markers of bone metabolism, inflammatory cytokines, and chemokines were analyzed in each group. Results: Mice treated with RANK-Fc or OPG-Fc in combination with antibiotics preserved total BMD and trabecular bone as compared to huFc or antibiotics. Treatment with RANK-Fc or OPG-Fc diminished the levels of bone resorption markers (osteocalcin, CTX-I, and TRACP5b). Neither RANK-Fc nor OPG-Fc influenced significantly the frequency and severity of arthritis. Conclusions: Inhibition of RANKL signalling efficiently prevents bone loss in the mouse model of bacterial arthritis even when started in the overt phase of infection.
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| 21. |
- Verdrengh, Margareta, 1942, et al.
(författare)
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Rapid systemic bone resorption during the course of Staphylococcus aureus-induced arthritis
- 2006
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Ingår i: J Infect Dis. - 0022-1899. ; 194:11, s. 1597-600
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Tidskriftsartikel (refereegranskat)abstract
- Bacterial arthritis is the most rapidly progressing destructive joint disease in humans. To evaluate bone resorption and formation, mice were injected with Staphylococcus aureus and killed after 3 and 14 days. Both total and trabecular bone mineral density were, compared with those in uninfected controls, already significantly reduced 3 days after bacterial inoculation. Serum levels of type I collagen fragments were significantly increased and osteocalcin levels decreased in mice infected with S. aureus, compared with those in noninfected mice, 3 and 14 days after bacterial inoculation. This study shows that there is a rapid and easily measurable systemic bone resorption during S. aureus-induced arthritis.
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| 22. |
- Verdrengh, Margareta, 1942, et al.
(författare)
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Riboflavin in innate and acquired immune responses
- 2005
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Ingår i: Inflamm Res. - : Springer Science and Business Media LLC. - 1023-3830. ; 54:9, s. 390-3
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE AND DESIGN: Riboflavin, also known as vitamin B2, is a micronutrient with a key role in maintaining human health. It has also been shown to enhance host resistance to bacterial infections in mice. The aim of this study was to assess the role of vitamin B2 treatment in inflammatory conditions. SUBJECTS AND METHODS: Three models of inflammatory states were assessed. One of them encompasses neutrophil mediated but T cell/macrophage independent cutaneous inflammation. Another one is delayed type hypersensitivity reaction (DTH), a T cell/macrophage dependent but neutrophil independent inflammatory response. The third one is collagen- induced arthritis, having components from both of the above described reactions. Mice were treated with vitamin B2, administered by peritoneal injections, throughout the course of the experiments. RESULTS: The granulocyte dependent reaction to olive oil was significantly reduced in vitamin B2 treated mice. In contrast, DTH reactivity and collagen II arthritis were not affected by the treatment. CONCLUSION: Riboflavin administration affects neutrophil migration but does not alter acquired immune responsiveness.
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| 23. |
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| 24. |
- Verdrengh, Margareta, 1942, et al.
(författare)
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Topoisomerase II inhibitors, irrespective of their chemical composition, ameliorate experimental arthritis
- 2005
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Ingår i: Rheumatology (Oxford). - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 44:2, s. 183-6
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease, characterized by a chronic inflammation in the joints. The model of collagen-induced arthritis (CIA) has been extensively used to elucidate the pathogenic mechanisms relevant to human RA and is widely employed for the evaluation of potential anti-rheumatic agents. Etoposide and mitoxantrone are immunosuppressive drugs, both acting by inhibiting the topoisomerase II function. We have previously demonstrated an ameliorating effect of etoposide in CIA. The aims of this study were (1) to assess the optimal ameliorating dose of etoposide and (2) to ascertain that topoisomerase II inhibition, irrespective of the chemical composition of the drug, affects the course of autoimmunity. METHODS: Male DBA/1 mice were treated with 12.5 mg/kg body weight of etoposide five times, twice, once per week or once every second week. Mitoxantrone was administered as high dose (1 mg/kg body weight five times after immunization or after booster with collagen II) or low dose (3 microg/mouse, 5 days/week starting after collagen II immunization or after booster). RESULTS: Treatment with 12.5 mg/kg body weight five times or twice weekly with etoposide completely inhibited development of arthritis. Low-dose treatment with mitoxantrone after collagen II immunization or high-dose treatment after collagen II booster delayed the onset of arthritis. These results were observed clinically as well as histologically. In addition, serum levels of anti-collagen II antibodies were significantly lower in mice displaying less severe arthritis. CONCLUSION: Treatment of collagen-induced arthritis with topoisomerase II inhibitors ameliorates the development of disease.
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