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  • 1.
    Bengtsson, Torbjörn
    et al.
    Örebro University, School of Medical Sciences.
    Lönn, Johanna
    Department of Oral Biology, Institute of Odontology, Malmö University, Malmö, Sweden; PEAS Research Institute, Linköping, Sweden.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    The lantibiotic gallidermin acts bactericidal against Staphylococcus epidermidis and Staphylococcus aureus and antagonizes the bacteria-induced proinflammatory responses in dermal fibroblasts2018In: MicrobiologyOpen, ISSN 2045-8827, E-ISSN 2045-8827, Vol. 7, no 6, article id e606Article in journal (Refereed)
    Abstract [en]

    Antimicrobial resistance needs to be tackled from new angles, and antimicrobial peptides could be future candidates for combating bacterial infections. This study aims to investigate in vitro the bactericidal effects of the lantibiotic gallidermin on Staphylococcus epidermidis and Staphylococcus aureus, possible cytotoxic effects and its impact on host-microbe interactions. Minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of gallidermin were determined, and cytotoxicity and proinflammatory effects of gallidermin on fibroblasts, red blood cells (RBCs) and in whole blood were investigated. Both MIC and MBC for all four tested strains of S. epidermidis was 6.25 μg/ml. Both MIC and MBC for methicillin-sensitive S. aureus was 12.5 μg/ml and for methicillin-resistant S. aureus (MRSA) 1.56 μg/ml. Gallidermin displayed no cytotoxic effects on fibroblasts, only a high dose of gallidermin induced low levels of CXCL8 and interleukin-6. Gallidermin hemolyzed less than 1% of human RBCs, and did not induce reactive oxygen species production or cell aggregation in whole blood. In cell culture, gallidermin inhibited the cytotoxic effects of the bacteria and totally suppressed the bacteria-induced release of CXCL8 and interleukin-6 from fibroblasts. We demonstrate that gallidermin, expressing low cell cytotoxicity, is a promising candidate for treating bacterial infections caused by S. epidermidis and S. aureus, especially MRSA.

  • 2.
    Fürsatz, Marian
    et al.
    Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden.
    Skog, Mårten
    Department of Physics, Chemistry and Biology, Linkopings universitet, Linköping, Sweden.
    Sivlér, Petter
    Department of Physics, Chemistry and Biology, Linkopings universitet, Linköping, Sweden.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    Aronsson, Christopher
    Department of Physics, Chemistry and Biology, Linkopings universitet, Linköping, Sweden.
    Skallberg, Andreas
    Department of Physics, Chemistry and Biology, Linkopings universitet, Linköping, Sweden.
    Greczynski, Grzegorz
    Department of Physics, Linköping University, Linkoping, Sweden.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Aili, Daniel
    Department of Physics, Chemistry and Biology, Linköping University, Linköping, Sweden.
    Functionalization of bacterial cellulose wound dressings with the antimicrobial peptide ε-poly-L-Lysine2018In: Biomedical Materials, ISSN 1748-6041, E-ISSN 1748-605X, Vol. 13, article id 025014Article in journal (Refereed)
    Abstract [en]

    Wound dressings based on bacterial cellulose (BC) can form a soft and conformable protective layer that can stimulate wound healing while preventing bacteria from entering the wound. Bacteria already present in the wound can, however, thrive in the moist environment created by the BC dressing which can aggravate the healing process. Possibilities to render the BC antimicrobial without affecting the beneficial structural and mechanical properties of the material would hence be highly attractive. Here we present methods for functionalization of BC with ε-Poly-L-Lysine (ε-PLL), a non-toxic biopolymer with broad-spectrum antimicrobial activity. Low molecular weight ε-PLL was cross-linked in pristine BC membranes and to carboxymethyl cellulose (CMC) functionalized BC using carbodiimide chemistry. The functionalization of BC with ε-PLL inhibited growth of S. epidermidis on the membranes but did not affect the cytocompatibility to cultured human fibroblasts as compared to native BC. The functionalization had no significant effects on the nanofibrous structure and mechanical properties of the BC. The possibility to functionalize BC with ε-PLL is a promising, green and versatile approach to improve the performance of BC in wound care and other biomedical applications.

  • 3.
    Khalaf, Hazem
    et al.
    Örebro University, School of Medical Sciences.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Cellular Response Mechanisms in Porphyromonas gingivalis Infection2017In: Periodontitis: A Useful Reference / [ed] Pachiappan Arjunan, InTech, 2017, p. 45-68Chapter in book (Refereed)
    Abstract [en]

    The pathogenicity of the periodontal biofilm is highly dependent on a few key species, of which Porphyromonas gingivalis is considered to be one of the most important pathogens. P. gingivalis expresses a broad range of virulence factors, of these cysteine proteases (gingipains) are of special importance both for the bacterial survival/proliferation and for the pathological outcome. Several cell types, for example, epithelial cells, endothelial cells, dendritic cells, osteoblasts, and fibroblasts, reside in the periodontium and are part of the innate host response, as well as platelets, neutrophils, lymphocytes, and monocytes/macrophages. These cells recognize and respond to P. gingivalis and its components through pattern recognition receptors (PRRs), for example, Toll-like receptors and protease-activated receptors. Ligation of PRRs induces downstream-signaling pathways modifying the activity of transcription factors that regulates the expression of genes linked to inflammation. This is followed by the release of inflammatory mediators, for example, cytokines and reactive oxygen species. Periodontal disease is today considered to play a significant role in various systemic conditions such as cardiovascular disease (CVD). The mechanisms by which P. gingivalis and its virulence factors interact with host immune cells and contribute to the pathogenesis of periodontitis and CVD are far from completely understood.

  • 4.
    Ljunggren, Stefan
    et al.
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Karlsson, Helen
    Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Johansson Starkhammar, Carin
    Centre for Oral Rehabilitation, Public Dental Health Care County Council of Östergötland, Linköping, Sweden.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    Nayeri, Fariba
    PEAS Institute, Linköping, Sweden.
    Ghafouri, Bijar
    Pain and Rehabilitation Centre, and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Davies, Julia
    Department of Oral Biology, Malmö University, Malmö, Sweden.
    Svensäter, Gunnel
    Department of Oral Biology, Malmö University, Malmö, Sweden.
    Lönn, Johanna
    Örebro University, School of Medical Sciences. PEAS Research Institute, Department of Infection Control, Linköping, Sweden; Department of Oral Biology, Faculty of Odontology, Malmö University, Malmö, Sweden .
    Modified lipoproteins in periodontitis: a link to cardiovascular disease?2019In: Bioscience Reports, ISSN 0144-8463, E-ISSN 1573-4935, Vol. 39, no 3, article id BSR20181665Article in journal (Refereed)
    Abstract [en]

    There is a strong association between periodontal disease and atherosclerotic cardiovascular disorders. A key event in the development of atherosclerosis is accumulation of modified lipoproteins within the arterial wall. We hypothesize that patients with periodontitis have an altered lipoprotein profile towards an atherogenic form. Therefore, this study aims at identifying modifications of plasma lipoproteins in periodontitis. Lipoproteins from ten female patients with periodontitis and gender- and age-matched healthy controls were isolated by density-gradient-ultracentrifugation. Proteins were separated by two-dimensional gel-electrophoresis and identified by map-matching or by nano-liquid chromatography followed by mass spectrometry. ApoA-I methionine oxidation, Oxyblot, total antioxidant capacity and a multiplex of 71 inflammation-related plasma proteins were assessed.Reduced levels of apoJ, phospholipid transfer protein, apoF, complement C3, paraoxonase 3 and increased levels of alpha-1-antichymotrypsin, apoA-II, apoC-III were found in HDL from the patients. In LDL/VLDL, the levels of apoL-1 and platelet-activating factor acetylhydrolase as well as apo-B fragments were increased. Methionine oxidation of apoA-I was increased in HDL and showed a relationship with periodontal parameters. Alpha-1 antitrypsin and alpha-2-HS glycoprotein were oxidised in LDL/VLDL and antioxidant capacity was increased in the patient group. 17 inflammation-related proteins were important for group separation with the highest discriminating proteins identified as IL-21, Fractalkine, IL-17F, IL-7, IL-1RA and IL-2.Patients with periodontitis have an altered plasma lipoprotein profile, defined by altered protein levels as well as posttranslational and other structural modifications towards an atherogenic form, which supports a role of modified plasma lipoproteins as central in the link between periodontal and cardiovascular disease (CVD).

  • 5.
    Lönn, Johanna
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. PEAS Institute, Linköping, Sweden; Clinical Research Center, Örebro University, Örebro, Sweden.
    Johansson, Carin Starkhammar
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; Centre for Oral Rehabilitation, Public Dental Health Care, County Council of Östergötland, Linköping, Sweden.
    Nakka, Sravya
    The Institution for Protein Environment Affinity Surveys (PEAS Institute), Linköping, Sweden.
    Palm, Eleonor
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Nayeri, Fariba
    The Institution for Protein Environment Affinity Surveys (PEAS Institute), Linköping, Sweden ; Div Infect Dis, Linköping Univ Hosp, Linköping, Sweden.
    Ravald, Nils
    Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; Centre for Oral Rehabilitation, Public Dental Health Care, County Council of Östergötland, Linköping, Sweden.
    High Concentration but Low Activity of Hepatocyte Growth Factor in Periodontitis2014In: Journal of Periodontology, ISSN 0022-3492, E-ISSN 1943-3670, Vol. 85, no 1, p. 113-122Article in journal (Refereed)
    Abstract [en]

    Background: High levels of hepatocyte growth factor (HGF), a healing factor with regenerative and cytoprotective effects, are associated with inflammatory diseases, including periodontitis. HGF biological activity requires binding to its receptors, the proto-oncogene c-Met (c-Met) and heparan sulphate proteoglycan (HSPG). Here we investigated HGF expression and its relationship to subgingival microbiota in medically healthy individuals with and without periodontitis.

    Methods: Saliva, gingival crevicular fluid (GCF), and blood samples from 30 patients with severe periodontitis and 30 healthy controls were analyzed for HGF concentration using enzyme-linked immunosorbent assay (ELISA), and binding affinity for HSPG and c-Met using surface plasmon resonance (SPR). The regenerative effects of saliva from three patients and controls were analyzed in an in vitro model of cell injury. Subgingival plaques were analyzed for the presence of 18 bacterial species.

    Results: Patients with periodontitis showed higher HGF concentrations in saliva, GCF, and serum (P < 0.001); however, the binding affinities for HSPG and c-Met were reduced in GCF and saliva (P < 0.002). In contrast to the controls, saliva from patients showed no significant regenerative effect over time on gingival epithelial cells. Compared to controls, patients had a higher prevalence of periodontal-related bacteria.

    Conclusion: Higher circulatory HGF levels indicate a systemic effect of periodontitis. However, the HGF biological activity at local inflammation sites was reduced, and this effect was associated with the amount of periodontal bacteria. Loss of function of healing factors may be an important mechanism in degenerative processes in periodontally susceptible individuals.

  • 6.
    Nakka, Sravya Sowdamini
    et al.
    Örebro University, School of Medical Sciences. The Institution for Protein Environmental Affinity Surveys, PEAS Institut AB, Linköping, Sweden.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Bacteriocin plantaricin NC8 αβ antagonizes Porphyromonas gingivalis infection and induces proliferation of gingival epithelial cellsManuscript (preprint) (Other academic)
  • 7.
    Nakka, Sravya Sowdamini
    et al.
    Örebro University, School of Medical Sciences. The Institution for Protein Environmental Affinity Surveys, PEAS Institut AB, Linköping, Sweden.
    Palm, Eleonor
    Örebro University, School of Medical Sciences.
    Nayeri, Fariba
    The Institution for Protein Environmental Affinity Surveys, PEAS Institut AB, Linköping, Sweden; Division of Infectious Diseases, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medical Sciences.
    Khalaf, Hazem
    Örebro University, School of Medical Sciences.
    Effects of plantaricin NC8 αβ and antibodies on gingival epithelial cells infected by Porphyromonas gingivalisManuscript (preprint) (Other academic)
  • 8.
    Palm, Eleonor
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Inflammatory responses of gingival fibroblasts in the interaction with the periodontal pathogen Porphyromonas gingivalis2015Doctoral thesis, comprehensive summary (Other academic)
    List of papers
    1. Porphyromonas gingivalis downregulates the immune response of fibroblasts
    Open this publication in new window or tab >>Porphyromonas gingivalis downregulates the immune response of fibroblasts
    2013 (English)In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 13, p. 155-Article in journal (Refereed) Published
    Abstract [en]

    Background: Porphyromonas gingivalis is a key pathogen in periodontitis, an inflammatory disease leading to destruction of bone and tooth-supporting tissue. P. gingivalis possesses a number of pathogenic properties to enhance growth and survival, including proteolytic gingipains. Accumulating data shows that gingipains are involved in the regulation of host inflammatory responses. The aim of this study was to determine if P. gingivalis infection modulates the inflammatory response of fibroblasts, including the release of chemokines and cytokines. Human gingival fibroblasts or primary dermal fibroblasts were pre-stimulated with tumor-necrosis factor-alpha (TNF-alpha) and cocultured with P. gingivalis. Gingipain inhibitors were used to explore the effect of gingipains. CXCL8 levels were determined with ELISA and the relative levels of various inflammatory mediators were determined by a cytokine assay.

    Results: TNF-alpha-triggered CXCL8 levels were completely abolished by viable P. gingivalis, whereas heat-killed P. gingivalis did not suppress CXCL8. Accumulation of CXCL8 was partially restored by an arginine-gingipain inhibitor. Furthermore, fibroblasts produced several inflammatory mediators, notably chemokines, all of which were suppressed by viable P. gingivalis.

    Conclusion: These findings provide evidence that fibroblast-derived inflammatory signals are modulated by heat-instable gingipains, whereby the bacteria can escape killing by the host immune system and promote its own growth and establishment. In addition, we show that fibroblasts are important mediators of inflammation in response to infection and thereby play a crucial role in determining the nature and magnitude of the invasion of immune cells.

    Keywords
    Porphyromonas gingivalis, Fibroblasts, Chemokines, Cytokines
    National Category
    Microbiology in the medical area
    Research subject
    Medicine
    Identifiers
    urn:nbn:se:oru:diva-30310 (URN)10.1186/1471-2180-13-155 (DOI)000322041700001 ()2-s2.0-84880027349 (Scopus ID)
    Funder
    Swedish Research CouncilSwedish Heart Lung Foundation
    Note

    Funding Agency: Foundation of Olle Engkvist; Mats Kleberg Foundation

    Available from: 2013-08-23 Created: 2013-08-23 Last updated: 2018-01-11Bibliographically approved
    2. Suppression of inflammatory responses of human gingival fibroblasts by gingipains from Porphyromonas gingivalis
    Open this publication in new window or tab >>Suppression of inflammatory responses of human gingival fibroblasts by gingipains from Porphyromonas gingivalis
    2015 (English)In: Molecular Oral Microbiology, ISSN 2041-1006, E-ISSN 2041-1014, Vol. 30, no 1, p. 74-85Article in journal (Refereed) Published
    Abstract [en]

    The interaction between human gingival fibroblasts (HGFs) and Porphyromonas gingivalis plays an important role in the development and progression of periodontitis. Porphyromonas gingivalis possesses several virulence factors, including cysteine proteases, the arginine-specific (Rgp) and lysine-specific (Kgp) gingipains. Studying the mechanisms that P.gingivalis, and its derived virulence, use to propagate and interact with host cells will increase the understanding of the development and progression of periodontitis. In this study, we aimed to elucidate how P.gingivalis influences the inflammatory events in HGFs regarding transforming growth factor-(1) (TGF-(1)), CXCL8, secretory leucocyte protease inhibitor (SLPI), c-Jun and indoleamine 2,3-dioxygenase (IDO). HGFs were inoculated for 6 and 24h with the wild-type strains ATCC 33277 and W50, two gingipain-mutants of W50 and heat-killed ATCC 33277. The P.gingivalis regulated CXCL8 and TGF-(1) in HGFs, and the kgp mutant gave significantly higher immune response with increased CXCL8 (P<0.001) and low levels of TGF-(1). We show that HGFs express and secrete SLPI, which was significantly suppressed by P.gingivalis (P<0.05). This suggests that by antagonizing SLPI, P.gingivalis contributes to the tissue destruction associated with periodontitis. Furthermore, we found that P.gingivalis inhibits the expression of the antimicrobial IDO, as well as upregulating c-Jun (P<0.05). In conclusion, P.gingivalis both triggers and suppresses the immune response in HGFs. Consequently, we suggest that the pathogenic effects of P.gingivalis, and especially the activity of the gingipains on the inflammatory and immune response of HGFs, are crucial in periodontitis.

    Keywords
    CXCL8, gingipain, indoleamine 2, 3-dioxygenase, periodontitis, secretory leucocyte protease inhibitor, transforming growth factor-β
    National Category
    Microbiology in the medical area Medical and Health Sciences
    Research subject
    Microbiology; Medicine
    Identifiers
    urn:nbn:se:oru:diva-42617 (URN)10.1111/omi.12073 (DOI)000347897100007 ()25055828 (PubMedID)2-s2.0-84920913980 (Scopus ID)
    Funder
    Swedish Research CouncilSwedish Heart Lung Foundation
    Note

    Funding Agencies:

    Foundation of Olle Engkvist

    Knowledge Foundation

    Available from: 2015-02-13 Created: 2015-02-13 Last updated: 2018-01-11Bibliographically approved
    3. The role of toll-like and protease-activated receptors in the expression of cytokines by gingival fibroblasts stimulated with the periodontal pathogen Porphyromonas gingivalis
    Open this publication in new window or tab >>The role of toll-like and protease-activated receptors in the expression of cytokines by gingival fibroblasts stimulated with the periodontal pathogen Porphyromonas gingivalis
    (English)Manuscript (preprint) (Other academic)
    National Category
    Microbiology in the medical area
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-43307 (URN)
    Available from: 2015-03-04 Created: 2015-03-04 Last updated: 2018-01-11Bibliographically approved
    4. The role of toll-like and protease-activated receptors and associated intracellular signalling in Porphyromonas gingivalis-infected gingival fibroblasts
    Open this publication in new window or tab >>The role of toll-like and protease-activated receptors and associated intracellular signalling in Porphyromonas gingivalis-infected gingival fibroblasts
    (English)Manuscript (preprint) (Other academic)
    National Category
    Microbiology in the medical area
    Research subject
    Biomedicine
    Identifiers
    urn:nbn:se:oru:diva-43309 (URN)
    Available from: 2015-03-04 Created: 2015-03-04 Last updated: 2018-01-11Bibliographically approved
  • 9.
    Palm, Eleonor
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Demirel, Isak
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    The role of toll-like and protease-activated receptors and associated intracellular signalling in Porphyromonas gingivalis-infected gingival fibroblastsManuscript (preprint) (Other academic)
  • 10.
    Palm, Eleonor
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Demirel, Isak
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    The role of toll-like and protease-activated receptors in the expression of cytokines by gingival fibroblasts stimulated with the periodontal pathogen Porphyromonas gingivalisManuscript (preprint) (Other academic)
  • 11.
    Palm, Eleonor
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine, Örebro University Hospital, Örebro, Sweden.
    Demirel, Isak
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine, Örebro University Hospital, Örebro, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden. Department of Biomedicine, Örebro University Hospital, Örebro, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Biomedicine, Örebro University Hospital, Örebro, Sweden.
    The role of toll-like and protease-activated receptors in the expression of cytokines by gingival fibroblasts stimulated with the periodontal pathogen Porphyromonas gingivalis2015In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 76, no 2, p. 424-432Article in journal (Refereed)
    Abstract [en]

    Porphyromonas gingivalis is a periodontitis-associated pathogen and interactions between the bacterium and gingival fibroblasts play an important role in development and progression of periodontitis, an inflammatory disease leading to degeneration of tooth-supporting structures. Gingival fibroblasts, which expresses protease activated receptors (PARs) as well as toll-like receptors (TLRs), produces inflammatory mediators upon bacterial challenges. In this study, we elucidated the importance of PAR1, PAR2, TLR2 and TLR4 for the expression and secretion of CXCL8, interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-beta 1) and secretory leukocyte inhibitor (SLPI). Human gingival fibroblasts were transfected with small-interfering RNA against the target genes, and then stimulated with P. gingivalis wild-type W50 and W50-derived double rgp mutant E8 and kgp mutant K1A. TLR2-silencing reduced P. gingivalis-induced CXCL8 and IL-6. IL-6 was also reduced after PAR1-silencing. No effects were observed for TGF-beta 1. SLPI was suppressed by P. gingivalis and silencing of PAR1 as well as TLR2, gave additional suppression at the mRNA level. TLR4 was not involved in the regulation of the investigated mediators. CXCL8 and IL-6 are important for progression and development of periodontitis, leading to a chronic inflammation that may contribute to the tissue destruction that follows an exacerbated host response. Therefore, regulating the expression of TLR2 and subsequent release of CXCL8 and IL-6 in periodontitis could attenuate the tissue destruction seen in periodontitis.

  • 12.
    Palm, Eleonor
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Porphyromonas gingivalis downregulates the immune response of fibroblasts2013In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 13, p. 155-Article in journal (Refereed)
    Abstract [en]

    Background: Porphyromonas gingivalis is a key pathogen in periodontitis, an inflammatory disease leading to destruction of bone and tooth-supporting tissue. P. gingivalis possesses a number of pathogenic properties to enhance growth and survival, including proteolytic gingipains. Accumulating data shows that gingipains are involved in the regulation of host inflammatory responses. The aim of this study was to determine if P. gingivalis infection modulates the inflammatory response of fibroblasts, including the release of chemokines and cytokines. Human gingival fibroblasts or primary dermal fibroblasts were pre-stimulated with tumor-necrosis factor-alpha (TNF-alpha) and cocultured with P. gingivalis. Gingipain inhibitors were used to explore the effect of gingipains. CXCL8 levels were determined with ELISA and the relative levels of various inflammatory mediators were determined by a cytokine assay.

    Results: TNF-alpha-triggered CXCL8 levels were completely abolished by viable P. gingivalis, whereas heat-killed P. gingivalis did not suppress CXCL8. Accumulation of CXCL8 was partially restored by an arginine-gingipain inhibitor. Furthermore, fibroblasts produced several inflammatory mediators, notably chemokines, all of which were suppressed by viable P. gingivalis.

    Conclusion: These findings provide evidence that fibroblast-derived inflammatory signals are modulated by heat-instable gingipains, whereby the bacteria can escape killing by the host immune system and promote its own growth and establishment. In addition, we show that fibroblasts are important mediators of inflammation in response to infection and thereby play a crucial role in determining the nature and magnitude of the invasion of immune cells.

  • 13.
    Palm, Eleonor
    et al.
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Khalaf, Hazem
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Bengtsson, Torbjörn
    Örebro University, School of Medicine, Örebro University, Sweden.
    Suppression of inflammatory responses of human gingival fibroblasts by gingipains from Porphyromonas gingivalis2015In: Molecular Oral Microbiology, ISSN 2041-1006, E-ISSN 2041-1014, Vol. 30, no 1, p. 74-85Article in journal (Refereed)
    Abstract [en]

    The interaction between human gingival fibroblasts (HGFs) and Porphyromonas gingivalis plays an important role in the development and progression of periodontitis. Porphyromonas gingivalis possesses several virulence factors, including cysteine proteases, the arginine-specific (Rgp) and lysine-specific (Kgp) gingipains. Studying the mechanisms that P.gingivalis, and its derived virulence, use to propagate and interact with host cells will increase the understanding of the development and progression of periodontitis. In this study, we aimed to elucidate how P.gingivalis influences the inflammatory events in HGFs regarding transforming growth factor-(1) (TGF-(1)), CXCL8, secretory leucocyte protease inhibitor (SLPI), c-Jun and indoleamine 2,3-dioxygenase (IDO). HGFs were inoculated for 6 and 24h with the wild-type strains ATCC 33277 and W50, two gingipain-mutants of W50 and heat-killed ATCC 33277. The P.gingivalis regulated CXCL8 and TGF-(1) in HGFs, and the kgp mutant gave significantly higher immune response with increased CXCL8 (P<0.001) and low levels of TGF-(1). We show that HGFs express and secrete SLPI, which was significantly suppressed by P.gingivalis (P<0.05). This suggests that by antagonizing SLPI, P.gingivalis contributes to the tissue destruction associated with periodontitis. Furthermore, we found that P.gingivalis inhibits the expression of the antimicrobial IDO, as well as upregulating c-Jun (P<0.05). In conclusion, P.gingivalis both triggers and suppresses the immune response in HGFs. Consequently, we suggest that the pathogenic effects of P.gingivalis, and especially the activity of the gingipains on the inflammatory and immune response of HGFs, are crucial in periodontitis.

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