epidermal-growth-factor and Gingival-Overgrowth

Little is known about the involvement of saliva in gingival overgrowth (GO). It was hypothesized that, in this situation, the composition of saliva is altered. Thus, proteins, albumin, cytokines, and growth factors in whole and glandular saliva were investigated. Differences between glandular and gingival contributions to the composition of saliva were explored in patients medicated with cyclosporin who exhibited GO (responders), those without GO (non-responders), and non-medicated subjects (controls). In whole saliva, interleukin-1alpha (IL-1alpha), IL-6, IL-8, epidermal growth factor (EGF), nerve growth factor (NGF), and albumin were detected, but in glandular saliva only EGF and NGF were identified. Albumin and IL-6 differed significantly between responders and controls, although the overall profile of salivary proteins remained unchanged. Thus, inflammatory cytokines and albumin are confined to whole saliva and are associated with GO, whereas its content of EGF and NGF appears unaffected by cyclosporin.

Topics: Albumins; Cyclosporine; Cytokines; Epidermal Growth Factor; Gingival Overgrowth; Humans; Interleukins; Male; Nerve Growth Factor; Saliva; Salivary Proteins and Peptides

To understand the roles of epidermal growth factor (EGF) and EGF receptor (EGF-R) in cyclosporin A (CsA)-induced gingival overgrowth, expression of EGF and EGF-R upon CsA treatment was examined in an oral epidermoid carcinoma cell line of humans (OECM-1) and in edentulous gingiva of rats.. In vitro study: after CsA treatment, OECM-1 cells were harvested to evaluate their mRNA and protein expression of EGF and EGF-R with reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, and immunocytochemistry (ICC). In vivo study: 3 weeks after extraction of all maxillary molars, 20 male Sprague-Dawley rats were assigned to a CsA group (30 mg/kg, fed daily) and a control group. Five rats per group were sacrificed at weeks 1 and 4. Edentulous ridge specimens were obtained for evaluating their mRNAs and protein expression with RT-PCR, real-time RT-PCR, and immunohistochemistry (IHC). In both in vitro and in vivo experiments, the proliferating potential of epithelial cells was examined by the presence of proliferating cell nuclear antigen (PCNA).. In vitro: dose-dependently increased mRNA expression of EGF and EGF-R in OECM-1 cells was noted after CsA treatment. Protein expressions of EGF and EGF-R were higher in OECM-1 with CsA treatment than without CsA. In vivo: higher mRNA and protein expressions of EGF and EGF-R were also observed in the gingival tissues of CsA-treated rats. In both in vitro and in vivo experiments, greater PCNA expression after CsA treatment was demonstrated.. Higher expression of EGF and EGF-R upon CsA therapy was observed in OECM-1 epithelial cells of humans and in edentulous gingiva of rats. We suggest that CsA could upregulate gene and protein expression of EGF and EGF-R, and the upregulation may play a role in gingival overgrowth.

Topics: Animals; Cell Line, Tumor; Cyclosporine; Dose-Response Relationship, Drug; Epidermal Growth Factor; ErbB Receptors; Gene Expression; Gingival Overgrowth; Histocytochemistry; Humans; Immunosuppressive Agents; Male; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

Cyclosporin (CsA) and tacrolimus (FK-506) are immunosuppressive drugs that specifically inhibit T-cell activation via calcineurin inhibition. Gingival overgrowth is a common side effect following the administration of CsA. The severity of gingival overgrowth seen in patients taking FK-506 is less than that observed with CsA. Little is known about the involvement of saliva in drug-induced gingival overgrowth. The purpose of this study was to investigate the salivary contents of tumor growth factor beta1 (TGF-beta1), epidermal growth factor (EGF), and interleukin-6 (IL-6) as well as the hystometry of gingival tissue obtained from rats treated with either FK-506 or CsA.. For 30 or 60 days rats received daily subcutaneous injection doses of either CsA or FK-506 (10 mg/kg). The concentrations of TGF-beta1, EGF, and IL-6 in saliva were determined by enzyme-linked immunosorbent assay, and after histological processing, the oral epithelium and connective tissue were assessed at the region of the lower first molars.. The levels of TGF-beta1, EGF, and IL-6 in saliva were not significantly altered by any of the treatments after 30 days. After 60 days of treatment with CsA, gingival overgrowth and significant increase in salivary TGF-beta1, EGF, and IL-6 concentrations were observed; no statistically significant changes were induced by FK-506.. Within the limits of this experimental study, it can be concluded that CsA, but not FK-506, induced gingival overgrowth associated with an increase of the salivary levels of the cytokines TGF-beta1, EGF, and IL-6.

Topics: Animals; Cyclosporine; Cytokines; Epidermal Growth Factor; Gingival Overgrowth; Immunosuppressive Agents; Interleukin-6; Male; Rats; Rats, Sprague-Dawley; Saliva; Tacrolimus; Transforming Growth Factor beta; Transforming Growth Factor beta1

The purpose of this study was to investigate the presence of epidermal growth factor (EGF) in patients receiving cyclosporin therapy who had gingival overgrowth and to determine whether there were any differences between these patients and normal healthy controls. Seventeen patients with cyclosporin-induced gingival overgrowth and seventeen age- and sex-matched controls who were taking cyclosporin but had healthy gingiva were used for this study. Unstimulated whole saliva was collected from all individuals by expectoration. Gingival crevicular fluid (GCF) was also collected from all individuals. Blood was additionally collected from all subjects and serum was separated by keeping the samples overnight at 4 degrees C. EGF levels in all cases were measured by an ELISA assay. EGF concentrations were found to be significantly higher in the saliva of patients with cyclosporin-induced gingival overgrowth compared to the control group (401.2 +/- 31.1 pg/ml and 144.3 +/- 31.4 pg/ml, respectively), whereas the results were reversed in the serum (67.0 +/- 15.6 pg/ml and 141.6 +/- 17.7 pg/ml, respectively). EGF was not detected in the samples of GCF in either group. This study thus demonstrated an increase in EGF levels in the saliva and a decrease of EGF in the serum of patients with cyclosporin-induced gingival overgrowth.

Topics: Case-Control Studies; Cyclosporine; Dental Plaque Index; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Gingival Crevicular Fluid; Gingival Hemorrhage; Gingival Overgrowth; Humans; Immunosuppressive Agents; Male; Periodontal Attachment Loss; Periodontal Index; Periodontal Pocket; Saliva; Statistics as Topic; Statistics, Nonparametric

The formation of the biologically active metabolite 5 alpha-dihydrotestosterone (DHT) from testosterone in response to phenytoin (Ph), interleukin-1 (IL-1), and epidermal growth factor (EGF) was investigated. The androgen DHT stimulates matrix synthesis in connective tissue and bone. Duplicate incubations were performed with confluent human gingival fibroblasts, 14C-testosterone, and optimal stimulatory concentrations of IL-1 (5 IU/ml), EGF (10 ng/ml), Ph (5 micrograms/ml), Ph + EGF, and Ph + IL-1 respectively for 24 hours in Eagle's MEM at 37 degrees C. The medium was then analyzed for radioactive metabolites. Similar incubations were performed with human gingival tissue using 14C-4-androstenedione as substrate in the presence or absence of EGF, Ph, and EGF + Ph. In the cell lines studied, EGF stimulated DHT and 4-androstenedione synthesis by 20% (n = 5; P < 0.01; Wilcoxon signed rank statistic for paired observations). IL-1 stimulated DHT and 4-androstenedione synthesis by 2-fold (n = 6; P < 0.01). Ph stimulated DHT and 4-androstenedione synthesis by 2-fold increases (n = 3; P < 0.01). Combinations of phenytoin and EGF stimulated DHT and 4-androstenedione synthesis by 33% and 37% greater than the effect of phenytoin alone (n = 3; P < 0.01). Combinations of Ph and IL-1 caused a 45% increase in the amount of DHT formed and a 66% increase in 4-androstenedione when compared to the effect of phenytoin alone (n = 3; P < 0.01). 14C-4-androstenedione was converted to DHT and testosterone by human gingival tissue. There were 2-fold, 4-fold, and 2.5-fold increases in DHT synthesis and 5-fold, 2-fold, and 6-fold increases in the formation of testosterone in response to EGF, Ph, and EGF + Ph respectively (n = 3; P < 0.01). EGF and IL-1 present in inflammatory exudate may have implications on phenytoin-induced overgrowth via the steroid metabolic pathway.

Topics: 17-Hydroxysteroid Dehydrogenases; Androstenedione; Bone and Bones; Carbon Radioisotopes; Cells, Cultured; Connective Tissue; Culture Media; Dihydrotestosterone; Drug Combinations; Epidermal Growth Factor; Extracellular Matrix; Fibroblasts; Gingiva; Gingival Overgrowth; Humans; Interleukin-1; Phenytoin; Radiopharmaceuticals; Testosterone