transforming-growth-factor-beta and Bacteroidaceae-Infections

Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC). Overabundance of Porphyromonas gingivalis is associated with shorter survival of ESCC patients. We investigated the molecular mechanisms driving aggressive progression of ESCC by P. gingivalis. Intracellular invasion of P. gingivalis potentiated proliferation, migration, invasion, and metastasis abilities of ESCC cells via transforming growth factor-β (TGFβ)-dependent Drosophila mothers against decapentaplegic homologs (Smads)/Yes-associated protein (YAP)/Transcriptional coactivator with PDZ-binding motif (TAZ) activation. Smads/YAP/TAZ/TEA domain transcription factor1 (TEAD1) complex formation was essential to initiate downstream target gene expression, inducing an epithelial-mesenchymal transition (EMT) and stemness features. Furthermore, P. gingivalis augmented secretion and bioactivity of TGFβ through glycoprotein A repetitions predominant (GARP) up-regulation. Accordingly, disruption of either the GARP/TGFβ axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis. P. gingivalis signature genes based on its activated effector molecules can efficiently distinguish ESCC patients into low- and high-risk groups. Targeting P. gingivalis or its activated effectors may provide novel insights into clinical management of ESCC.

Topics: Acyltransferases; Adaptor Proteins, Signal Transducing; Adult; Aged; Animals; Bacteroidaceae Infections; Cells, Cultured; Disease Progression; Drosophila; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Female; Follow-Up Studies; HCT116 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Porphyromonas gingivalis; Signal Transduction; Smad Proteins; Survival Analysis; Transcription Factors; Transforming Growth Factor beta; YAP-Signaling Proteins

Marfan syndrome is an autosomal dominant disease characterized by aneurysm and dilatation of the aortic root, tall stature, and ectopia lentis. These manifestations reflect excessive signaling of transforming growth factor beta (TGF-β). Moreover, cases are frequently associated with severe periodontitis, which is a chronic inflammation of the gingiva, periodontal ligament, and alveolar bone. Recently, angiotensin II receptor blockers (ARBs) were discovered to be an effective drug class that can prevent aortic aneurysm and dilation in Marfan syndrome by inhibiting TGF-β signaling. To investigate the effect of ARB on the progression of periodontitis, the application of a potent ARB, telmisartan, was examined in a mouse model of Marfan syndrome (MgΔ). Six-week-old male heterozygous MgΔ and wild-type mice were challenged with Porphyromonas gingivalis, which causes chronic periodontitis, with and without telmisartan application. After infection, alveolar bone resorption was measured by micro-computed tomography (μCT), and inflammatory cytokine levels were examined. Infection of Porphyromonas gingivalis induced alveolar bone resorption in both MgΔ and wild-type mice. The amount of resorption was significantly larger in the former than the latter. Immunoarray and enzyme-linked immunosorbent assay (ELISA) analyses demonstrated that interleukin-17 (IL-17) and tumor necrosis factor alpha (TNF-α) levels were significantly higher in infected MgΔ mice than infected wild-type mice. Telmisartan treatment significantly suppressed the alveolar bone resorption of infected MgΔ mice. Telmisartan also significantly decreased levels of TGF-β, IL-17, and TNF-α in infected MgΔ mice to levels seen in infected wild-type mice. This study suggests that ARB can prevent the severe periodontitis frequently seen in Marfan syndrome.

Topics: Alveolar Bone Loss; Angiotensin Receptor Antagonists; Animals; Bacteroidaceae Infections; Benzimidazoles; Benzoates; Bone Resorption; Disease Models, Animal; Inflammation; Interleukin-17; Male; Marfan Syndrome; Mice; Osteoclasts; Periodontitis; Porphyromonas gingivalis; Telmisartan; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Periodontitis is a polymicrobial oral infection characterized by the destruction of tooth-supporting structures that can be linked to systemic diseases such as cardiovascular disease, diabetes or rheumatoid arthritis. Porphyromonas gingivalis, a bacterium implicated in the etiology of periodontitis, has shown variation in inducing T-cell responses among different strains. Therefore, in this study we investigated the strain-specific immune response using a murine experimental model of periodontitis. Periodontitis was induced by P. gingivalis strains A7A1-28, W83 and W50, and later confirmed by the presence of P. gingivalis in the oral microflora and by alveolar bone resorption. Splenocytes were evaluated for gene expression, cellular proteins and cytokine expression. Dendritic cells were stimulated in vitro for T helper cell-cytokine profiling. Results showed that P. gingivalis had the ability to alter the systemic immune response after bacterial exposure. Strains W50 and W83 were shown to induce alveolar bone loss, whereas the A7A1-28 strain did not significantly promote bone resorption in mice. Splenocytes derived from mice infected with strains W50 and W83 induced expression of high levels of interleukin-4 (IL-4) but A7A1-28 stimulated increased IL-10. Stimulation of dendritic cells in vitro showed a similar pattern of cytokine expression of IL-12p40, IL-6 and transforming growth factor-β among strains. A distinct systemic response in vivo was observed among different strains of P. gingivalis, with IL-10 associated with the least amount of alveolar bone loss. Evaluation of pathogen-driven systemic immune responses associated with periodontal disease pathogenesis may assist in defining how periodontitis may impact other diseases.

Topics: Alveolar Bone Loss; Animals; Bacteroidaceae Infections; Cytokines; Dendritic Cells; Disease Models, Animal; Flow Cytometry; Gene Expression Regulation, Bacterial; Interleukin-10; Interleukin-12 Subunit p40; Interleukin-4; Interleukin-6; Male; Mice; Mice, Inbred DBA; Mice, Inbred Strains; Periodontitis; Porphyromonas gingivalis; Spleen; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; Transforming Growth Factor beta; X-Ray Microtomography

Periodontitis is a chronic inflammatory disease characterized by a progression that is very much dependent on host response. The gingiva can be considered to be in a constant state of wounding (pathologic wounding by bacterial plaque) and a constant state of maintenance/repair. In this context, any metabolic disturbance in the host which compromises tissue repair/wound healing will exacerbate the progression of periodontitis. Diabetes presents an interesting example because two major complications of diabetes are delayed wound healing and periodontitis. Our previous studies indicate that delayed wound healing and periodontitis may be manifestations of a general systemic deficit in diabetes involving alteration of macrophage cytokine gene expression. The present study was designed to determine whether: 1) diabetes-induced metabolic alterations affect gingival cytokine levels; and 2) diabetes-induced metabolic alterations modify the gingival cytokine profile in periodontitis. Sprague-Dawley rats (N=12/group) were injected with streptozotocin (65 mg/kg) into the tail vein to induce diabetes (defined by blood glucose levels > 250 mg/dl) or received the injection vehicle or no treatment as controls. Periodontitis was induced in additional groups of diabetic and control rats by gavage with Porphyromonas gingivalis A7436. After 90 days, serum glucose was analyzed to document diabetes; alveolar bone level was measured to document severity of periodontitis; gingiva was harvested circumferentially from the first and second molars; and cytokines in gingival homogenates were assayed by ELISA using commercial kits. Cytokine levels were expressed as mean+/-SEM pg/microg protein. Diabetes alone did not alter the gingival cytokine profile for platelet-derived growth factor B (PDGF-B), interleukin 1-beta (IL-1beta), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha). Periodontitis alone demonstrated a significant increase (P < 0.05) in levels of PDGF-B and IL-1beta. Diabetes superimposed on periodontitis prevented these increases. Thus, diabetes-induced metabolic alterations do not affect gingival cytokine levels per se; however, they do alter the normal host response to periodontitis through blockage of periodontitis-induced increases in PDGF-B and IL-1beta.

Topics: Alveolar Bone Loss; Animals; Bacteroidaceae Infections; Blood Glucose; Dental Plaque; Diabetes Mellitus, Experimental; Disease Models, Animal; Disease Progression; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation; Gingiva; Interleukin-1; Macrophages; Male; Periodontitis; Pharmaceutical Vehicles; Platelet-Derived Growth Factor; Porphyromonas gingivalis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-sis; Random Allocation; Rats; Rats, Sprague-Dawley; Streptozocin; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Wound Healing