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      Tetra- and Penta-Acylated Lipid A Structures of Porphyromonas gingivalis LPS Differentially Activate TLR4-Mediated NF-κB Signal Transduction Cascade and Immuno-Inflammatory Response in Human Gingival Fibroblasts

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          Abstract

          Background

          Porphyromonas gingivalis is a major pathogen of periodontal disease that affects a majority of adults worldwide. Increasing evidence shows that periodontal disease is linked to various systemic diseases like diabetes and cardiovascular disease, by contributing to increased systemic levels of inflammation. Lipopolysaccharides (LPS), as a key virulent attribute of P. gingivalis, possesses significant amount of lipid A heterogeneity containing tetra- (LPS 1435/1449) and penta-acylated (LPS 1690) structures. Hitherto, the exact molecular mechanism of P. gingivalis LPS involved in periodontal pathogenesis remains unclear, due to limited understanding of the specific receptors and signaling pathways involved in LPS-host cell interactions.

          Methodology/Principal Findings

          This study systematically investigated the effects of P. gingivalis LPS 1435/1449 and LPS 1690 on the expression of TLR2 and TLR4 signal transduction and the activation of pro-inflammatory cytokines IL-6 and IL-8 in human gingival fibroblasts (HGFs). We found that LPS 1435/1449 and LPS 1690 differentially modulated TLR2 and TLR4 expression. NF-κB pathway was significantly activated by LPS 1690 but not by LPS 1435/1449. In addition, LPS 1690 induced significant expression of NF-κB and p38 MPAK pathways-related genes, such as NFKBIA, NFKB1, IKBKB, MAP2K4 and MAPK8. Notably, the pro-inflammatory genes including GM-CSF, CXCL10, G-CSF, IL-6, IL-8 and CCL2 were significantly upregulated by LPS 1690 while down-regulated by LPS 1435/1449. Blocking assays confirmed that TLR4-mediated NF-κB signaling was vital in LPS 1690-induced expression of IL-6 and IL-8 in HGFs.

          Conclusions/Significance

          The present study suggests that the tetra- and penta-acylated lipid A structures of P. gingivalis LPS differentially activate TLR4-mediated NF-κB signaling pathway, and significantly modulate the expression of IL-6 and IL-8 in HGFs. The ability to alter the lipid A structure of LPS could be one of the strategies carried-out by P. gingivalis to evade innate host defense in gingival tissues, thereby contributing to periodontal pathogenesis.

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          Most cited references70

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          Periodontitis: a polymicrobial disruption of host homeostasis.

          Periodontitis, or gum disease, affects millions of people each year. Although it is associated with a defined microbial composition found on the surface of the tooth and tooth root, the contribution of bacteria to disease progression is poorly understood. Commensal bacteria probably induce a protective response that prevents the host from developing disease. However, several bacterial species found in plaque (the 'red-complex' bacteria: Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola) use various mechanisms to interfere with host defence mechanisms. Furthermore, disease may result from 'community-based' attack on the host. Here, I describe the interaction of the host immune system with the oral bacteria in healthy states and in diseased states.
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            Innate immune sensing and its roots: the story of endotoxin.

            How does the host sense pathogens? Our present concepts grew directly from longstanding efforts to understand infectious disease: how microbes harm the host, what molecules are sensed and, ultimately, the nature of the receptors that the host uses. The discovery of the host sensors--the Toll-like receptors--was rooted in chemical, biological and genetic analyses that centred on a bacterial poison, termed endotoxin.
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              Series introduction: the transcription factor NF-kappaB and human disease.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                12 March 2013
                : 8
                : 3
                : e58496
                Affiliations
                [1 ]Faculty of Dentistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
                [2 ]School of Dentistry, University of Washington, Seattle, Washington, United States of America
                [3 ]School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America
                [4 ]Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
                University of California Merced, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TDKH CJS LJJ. Performed the experiments: TDKH CJS. Analyzed the data: TDKH CJS LJJ. Contributed reagents/materials/analysis tools: RPD CYW YW LJJ. Wrote the paper: TDKH CJS RPD LJJ.

                Article
                PONE-D-12-35231
                10.1371/journal.pone.0058496
                3595299
                23554896
                598ea3f0-f64d-4374-844a-82f6665276b6
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 13 November 2012
                : 5 February 2013
                Page count
                Pages: 17
                Funding
                This study was supported by the Hong Kong Research Grants Council (HKU766909M, HKU768411M and HKU767512M to LJJ) ( http://www.ugc.edu.hk/eng/rgc/index.htm) and the Modern Dental Laboratory/HKU Endowment Fund to LJJ. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Genomics
                Immunology
                Immunity
                Inflammation
                Microbiology
                Immunity
                Inflammation
                Molecular Cell Biology
                Signal Transduction
                Signaling in Selected Disciplines
                Immunological Signaling
                Medicine
                Clinical Immunology
                Immunity
                Inflammation
                Immune Response
                Infectious Diseases
                Oral Medicine
                Oral Diseases

                Uncategorized
                Uncategorized

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