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Fusobacterium nucleatum Facilitates Apoptosis, ROS Generation, and Inflammatory Cytokine Production by Activating AKT/MAPK and NF-?B Signaling Pathways in Human Gingival Fibroblasts.

ABSTRACT: Fusobacterium nucleatum (F. nucleatum) plays key roles in the initiation and progression of periodontitis. However, the pathogenic effect of F. nucleatum on human oral tissues and cells has not been fully evaluated. In this study, we aimed to analyze the pathogenic effects of F. nucleatum on human gingival fibroblasts (GFs) and clarify the potential mechanisms. RNA-sequencing analysis confirmed that F. nucleatum significantly altered the gene expression of GF as the stimulation time increased. Cell counting and EdU-labeling assays indicated that F. nucleatum inhibited GF proliferation and promoted cell apoptosis in a time- and dose-dependent manner. In addition, cell apoptosis, intracellular reactive oxygen species (ROS) generation, and proinflammatory cytokine production were dramatically elevated after F. nucleatum stimulation. Furthermore, we found that the AKT/MAPK and NF-?B signaling pathways were significantly activated by F. nucleatum infection and that a large number of genes related to cellular proliferation, apoptosis, ROS, and inflammatory cytokine production downstream of AKT/MAPK and NF-?B signaling pathways were significantly altered in F. nucleatum-stimulated GFs. These findings suggest that F. nucleatum inhibits GF proliferation and promotes cell apoptosis, ROS generation, and inflammatory cytokine production partly by activating the AKT/MAPK and NF-?B signaling pathways. Our study opens a new window for understanding the pathogenic effects of periodontal pathogens on the host oral system.

SUBMITTER: Kang W

PROVIDER: S-EPMC6815639 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Fusobacterium nucleatum Facilitates Apoptosis, ROS Generation, and Inflammatory Cytokine Production by Activating AKT/MAPK and NF-κB Signaling Pathways in Human Gingival Fibroblasts.

Kang Wenyan W Jia Zhilong Z Tang Di D Zhang Zhanwei Z Gao Hui H He Kunlun K Feng Qiang Q

Oxidative medicine and cellular longevity 20191013

Fusobacterium nucleatum (F. nucleatum) plays key roles in the initiation and progression of periodontitis. However, the pathogenic effect of F. nucleatum on human oral tissues and cells has not been fully evaluated. In this study, we aimed to analyze the pathogenic effects of F. nucleatum on human gingival fibroblasts (GFs) and clarify the potential mechanisms. RNA-sequencing analysis confirmed that F. nucleatum significantly altered the gene expression of GF a ...[more]

PMID: 31737164

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Project description:Periodontal disease is caused by dental plaque biofilms. Fusobacterium nucleatum is an important periodontal pathogen involved in the development of bacterial complexity in dental plaque biofilms. Human gingival fibroblasts (GFs) act as the first line of defense against oral microorganisms and locally orchestrate immune responses by triggering the production of reactive oxygen species and pro-inflammatory cytokines (IL-6 and IL-8). The frequency and severity of periodontal diseases is known to increase in elderly subjects. However, despite several studies exploring the effects of aging in periodontal disease, the underlying mechanisms through which aging affects the interaction between F. nucleatum and human GFs remain unclear. To identify genes affected by infection, aging, or both, we performed an RNA-Seq analysis using GFs isolated from a single healthy donor that were passaged for a short period of time (P4) 'young GFs' or for longer period of time (P22) 'old GFs', and infected or not with F. nucleatum. Comparing F. nucleatum-infected and uninfected GF(P4) cells the differentially expressed genes (DEGs) were involved in host defense mechanisms (i.e., immune responses and defense responses), whereas comparing F. nucleatum-infected and uninfected GF(P22) cells the DEGs were involved in cell maintenance (i.e., TGF-? signaling, skeletal development). Most DEGs in F. nucleatum-infected GF(P22) cells were downregulated (85%) and were significantly associated with host defense responses such as inflammatory responses, when compared to the DEGs in F. nucleatum-infected GF(P4) cells. Five genes (GADD45b, KLF10, CSRNP1, ID1, and TM4SF1) were upregulated in response to F. nucleatum infection; however, this effect was only seen in GF(P22) cells. The genes identified here appear to interact with each other in a network associated with free radical scavenging, cell cycle, and cancer; therefore, they could be potential candidates involved in the aged GF's response to F. nucleatum infection. Further studies are needed to confirm these observations.

Project description:BackgroundColorectal cancer (CRC) is the third most common malignant tumor. Fusobacterium nucleatum (F. nucleatum) is overabundant in CRC and associated with metastasis, but the role of F. nucleatum in CRC cell migration and metastasis has not been fully elucidated.MethodsDifferential gene analysis, protein-protein interaction, robust rank aggregation analysis, functional enrichment analysis, and gene set variation analysis were used to figure out the potential vital genes and biological functions affected by F. nucleatum infection. The 16S rDNA sequencing and q-PCR were used to detect the abundance of F. nucleatum in tissues and stools. Then, we assessed the effect of F. nucleatum on CRC cell migration by wound healing and transwell assays, and confirmed the role of Matrix metalloproteinase 7 (MMP7) induced by F. nucleatum in cell migration. Furthermore, we dissected the mechanisms involved in F. nucleatum induced MMP7 expression. We also investigated the MMP7 expression in clinical samples and its correlation with prognosis in CRC patients. Finally, we screened out potential small molecular drugs that targeted MMP7 using the HERB database and molecular docking.ResultsF. nucleatum infection altered the gene expression profile and affected immune response, inflammation, biosynthesis, metabolism, adhesion and motility related biological functions in CRC. F. nucleatum was enriched in CRC and promoted the migration of CRC cell by upregulating MMP7 in vitro. MMP7 expression induced by F. nucleatum infection was mediated by the MAPK(JNK)-AP1 axis. MMP7 was highly expressed in CRC and correlated with CMS4 and poor clinical prognosis. Small molecular drugs such as δ-tocotrienol, 3,4-benzopyrene, tea polyphenols, and gallic catechin served as potential targeted therapeutic drugs for F. nucleatum induced MMP7 in CRC.ConclusionsOur study showed that F. nucleatum promoted metastasis-related characteristics of CRC cell by upregulating MMP7 via MAPK(JNK)-AP1 axis. F. nucleatum and MMP7 may serve as potential therapeutic targets for repressing CRC advance and metastasis.

Dataset Information

Fusobacterium nucleatum Facilitates Apoptosis, ROS Generation, and Inflammatory Cytokine Production by Activating AKT/MAPK and NF-?B Signaling Pathways in Human Gingival Fibroblasts.

Publications

<i>Fusobacterium nucleatum</i> Facilitates Apoptosis, ROS Generation, and Inflammatory Cytokine Production by Activating AKT/MAPK and NF-<i>κ</i>B Signaling Pathways in Human Gingival Fibroblasts.

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