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Inflammatory responses of gingival fibroblasts in the interaction with the periodontal pathogen Porphyromonas gingivalis
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Place, publisher, year, edition, pages
Örebro: Örebro university , 2015. , 70 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 113
Keyword [en]
Porphyromonas gingivalis, fibroblasts, CXCL8, TGF-β1, IL-6, SLPI, IDO, c-JUN, PKC, p38, periodontitis
National Category
Medical and Health Sciences Biomedical Laboratory Science/Technology
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-38660ISBN: 978-91-7529-056-0 (print)OAI: oai:DiVA.org:oru-38660DiVA: diva2:763820
Public defence
2015-02-06, Universitetssjukhuset, Bomanssonsalen, Södra Grev Rosengatan, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-11-17 Created: 2014-11-17 Last updated: 2017-10-17Bibliographically approved
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, 155- p.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.

Keyword
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: 2017-12-06Bibliographically 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, 74-85 p.Article 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.

Keyword
CXCL8, gingipain, indoleamine 2, 3-dioxygenase, periodontitis, secretory leucocyte protease inhibitor, transforming growth factor-β
National Category
Microbiology in the medical area
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: 2017-12-04Bibliographically 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: 2017-10-17Bibliographically 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: 2017-10-17Bibliographically approved

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