• Journal of dental hygiene science
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• v.5 no.3
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• pp.97-103
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• 2005

Irritation fibroma (IF) is the most common tumor-like oral lesion that is evolved by proliferation of collagen in response to chronic irritation. Oral leukoplakia (OL) is considered as precancerous lesion characterized by proliferation of epithelial cells due to chronic irritation, smoking and drinking. TGF-${\beta}1$ and EGFR are important factors that play an essential role in extracellular matrix remodeling during normal wound healing process. The epithelial reaction by chronic irritation may be connected with pathogenesis of IF and OL. In the present study, we examined the expression of TGF-${\beta}1$ and EGFR in the IF and OL using immunohistochemistry. We used 88 cases of IF, 44 cases of OL and 9 cases of normal oral mucosa as normal control. TGF-${\beta}1$ was decreased in the epithelium of IF and OL. As for EGFR, the epithelial cells revealed the increased positive expression in IF and OL. In case of OL, the Spearman correlation coefficient of TGF-${\beta}1$ and EGFR was -0.10 (p< 0.05), which showed weak correlation. In the fibrous tissue, TGF-${\beta}1$ was increased only in IF. The expression difference of TGF-${\beta}1$ and EGFR may be involved in the pathogenesis of IF and OL.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.20 no.2
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• pp.173-183
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• 1998

$TGF-{\beta}$ is one of growth factors that may be involved in the formation of bone and cartilage. Multiple studies demonstrate that $TGF-{\beta}$ is involved in regulating cell proliferation, differentiation and matrix synthesis, events observed in frature healing. The apperance of $TGF-{\beta}$ in the fracture during healing was evaluated by immunohistologic localization of $TGF-{\beta}$ using antibody. Twenty Sprauge-Dawley strain white male rats, each weiging about 150grams were used and divided two groups. The one group, the $2{\times}2mm$ bony defect was formed in the right femur. The other group, $4{\times}2mm$ bony defect was formed in right femur. Both group were sacrificed at 3day, 1, 2, 3, 4 week and femur were harvested, paraffin sections were stained with H & E, MT stain, immunihistochemical staining with $TGF-{\beta}$ antibody and observed under light microscope. The result were as follows: 1. New bone formation and cartilagenous tissue was seen at 3day. And in the $2{\times}2mm$ bony defect group, $TGF-{\beta}$ stained the cell surounding new bone. 2. The osteoclast and trabecular was seen at 1week. $TGF-{\beta}$ stained the osteoblast and in the $2{\times}2mm$ bony defect group was stained more than $4{\times}2mm$ bony defect group. 3. The lamella bone and trabecule was seen from 3, 4week, and $TGF-{\beta}$ stained almost negative. From the above finding, we could concluded that $TGF-{\beta}$ stained the osteoblast at early stage and 1week, the peak stain was seen from 1week, and then decreased, almost negative stain was seen at 3, 4week.

• Molecules and Cells
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• v.38 no.1
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• pp.20-25
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• 2015

TGF-${\beta}$ regulates pleiotropic cellular responses including cell growth, differentiation, migration, apoptosis, extracellular matrix production, and many other biological processes. Although non-Smad signaling pathways are being increasingly reported to play many roles in TGF-${\beta}$-mediated biological processes, Smads, especially receptor-regulated Smads (R-Smads), still play a central mediatory role in TGF-${\beta}$ signaling for epithelial-mesenchymal transition. Thus, the biological activities of R-Smads are tightly regulated at multiple points. Inhibitory Smad (I-Smad also called Smad7) acts as a critical endogenous negative feedback regulator of Smad-signaling pathways by inhibiting R-Smad phosphorylation and by inducing activated type I TGF-${\beta}$ receptor degradation. Roles played by Smad7 in health and disease are being increasingly reported, but the molecular mechanisms that regulate Smad7 are not well understood. In this study, we show that E3 ubiquitin ligase Itch acts as a positive regulator of TGF-${\beta}$ signaling and of subsequent EMT-related gene expression. Interestingly, the Itch-mediated positive regulation of TGF-${\beta}$ signaling was found to be dependent on Smad7 ubiquitination and its subsequent degradation. Further study revealed Itch acts as an E3 ubiquitin ligase for Smad7 polyubiquitination, and thus, that Itch is an important regulator of Smad7 activity and a positive regulator of TGF-${\beta}$ signaling and of TGF-${\beta}$-mediated biological processes. Accordingly, the study uncovers a novel regulatory mechanism whereby Smad7 is controlled by Itch.

• Tuberculosis and Respiratory Diseases
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• v.45 no.4
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• pp.861-869
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• 1998

Backgrounds: The injury of a tissue results in the infalmmation, and the imflammed tissue is replaced by the normal parenchymal cells during the process of repair. But, constitutional or repetitive damage of a tissue causes the deposition of collagen resulting in the loss of its function. These lesions are found in the lung of patients with idiopathic pulmonary fibrosis, complicated fibrosis after diffuse alveolar damage (DAD) and inorganic dust-induced lung fibrosis. The tissue from lungs of patients undergoing episodes of active and/or end-stage pulmonary fibrosis shows the accumulation of inflammatory cells, such as mononuclear cells, neutrophils, mast cells and eosinophils, and fibroblast hyperplasia. In this regard, it appears that the inflammation triggers fibroblast activation and proliferation with enhanced matrix synthesis, stimulated by inflammatory mediators such as interleukin-1 (IL-1) and/or tumor necrosis factor (TNF). It has been well known that TGF-$\beta$ enhance the proliferation of fibroblasts and the production of collagen and fibronectin, and inhibit the degradation of collagen. In this regard, It is likely that TGF-$\beta$ undergoes important roles in the pathogenesis of pulmonary fibrosis. Nevertheless, this single cytokine is not the sole regulator of the pulmonary fibrotic response. It is likely that the balance of many cytokines including TGF-$\beta$, IL-1, IL-6 and TNF-$\alpha$ regulates the pathogenesis of pulmonary fibrosis. In this study, we investigate the interaction of TGF-$\beta$, IL-1$\beta$, IL-6 and TNF-$\alpha$ and their effect on the proliferation of fibroblasts. Methods: We used a human fibroblast cell line, MRC-5 (ATCC). The culture of MRC-5 was confirmed by immunofluorecent staining. First, we determined the concentration of serum in cuture medium, in which the proliferation of MRC-5 is supressed but the survival of MRC-5 is retained. Second, we measured optical density after staining the cytokine-stimulated cells with 0.5% naphthol blue black in order to detect the effect of cytokines on the proliferation of MRC-5. Result: In the medium containing 0.5% fetal calf serum, the proliferation of MRC-5 increased by 50%, and it was maintained for 6 days. IL-1$\beta$, TNF-$\alpha$ and IL-6 induced the proliferation of MRC-5 by 45%, 160% and 120%, respectively. IL-1$\beta$ and TNF-$\alpha$ enhanced TGF-$\beta$-induced proliferation of MRC-5 by 64% and 159%, but IL-6 did not affect the TGF-$\beta$-induced proliferation. And lNF-$\alpha$-induced proliferation of MRC-5 was reduced by IL-1$\beta$ in 50%. TGF-$\beta$, TNF-$\alpha$ and both induced the proliferation of MRC-5 to 89%, 135% and 222%, respectively. Conclusions: TNF-$\alpha$, TGF-$\beta$ and IL-1$\beta$, in the order of the effectiveness, showed the induction of MRC-5 proliferation of MRC-5. TNF-$\alpha$ and IL-1$\beta$ enhance the TGF-$\beta$-induced proliferation of MRC-5, but IL-6 did not have any effect TNF-$\alpha$-induced proliferation of MRC-5 is diminished by IL-1, and TNF-$\alpha$ and TGF-$\beta$ showed a additive effect.

• Biomolecules & Therapeutics
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• v.25 no.4
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• pp.417-426
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• 2017

4-O-methylhonokiol, a neolignan compound from Magnolia Officinalis, has been reported to have various biological activities including hair growth promoting effect. However, although transforming growth factor-${\beta}$ (TGF-${\beta}$) signal pathway has an essential role in the regression induction of hair growth, the effect of 4-O-methylhonokiol on the TGF-${\beta}$ signal pathway has not yet been elucidated. We thus examined the effect of 4-O-methylhonokiol on TGF-${\beta}$-induced canonical and noncanonical pathways in HaCaT human keratinocytes. When HaCaT cells were pretreated with 4-O-methylhonokiol, TGF-${\beta}1$-induced G1/G0 phase arrest and TGF-${\beta}1$-induced p21 expression were decreased. Moreover, 4-O-methylhonokiol inhibited nuclear translocation of Smad2/3, Smad4 and Sp1 in TGF-${\beta}1$-induced canonical pathway. We observed that ERK phosphorylation by TGF-${\beta}1$ was significantly attenuated by treatment with 4-O-methylhonokiol. 4-O-methylhonokiol inhibited TGF-${\beta}1$-induced reactive oxygen species (ROS) production and reduced the increase of NADPH oxidase 4 (NOX4) mRNA level in TGF-${\beta}1$-induced noncanonical pathway. These results indicate that 4-O-methylhonokiol could inhibit TGF-${\beta}1$-induced cell cycle arrest through inhibition of canonical and noncanonical pathways in human keratinocyte HaCaT cell and that 4-O-methylhonokiol might have protective action on TGF-${\beta}1$-induced cell cycle arrest.

• Tuberculosis and Respiratory Diseases
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• v.43 no.2
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• pp.164-172
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• 1996

Background : Transforming growth factor-$\beta$(TGF-$\beta$) may play a role in a variety of fibroproliferative disorders including pulmonary fibrosis via the induction of extracellular matrix accumulation. TGF-$\beta$ not only stimulates extracellular matrix production, but also decreases matrix degradation. Interstial lung diseases have demonstrated marked expression of TGF-$\beta$. Methods : To evaluate the possible role of TGF-$\beta$ in human pulmonary fibrosis, by using neutralizing antibody of TGF-$\beta$ we investigated immunohistochemically the expression of TGF-$\beta$ in the formalin-fixed, paraffin-embedded tissue sections of the 5 normal cases for the control, and a couple of pieces of tissues taken out of 3 cases with idiopathic pulmonary fibrosis, 3 cases with ILD from bleomycin toxicity, 3 cases with ILD from sarcoidosis, and 3 cases with ILD from eosinophilic granuloma. Results : In the 5 normal cases for the control, the TGF-$\beta$ was expressed in bronchial and alveolar epithelial cells. Up-regulation of the TGF-$\beta$ expression was showed in the interstitial fibroblast cells of alveolar septa in 5 pieces and proliferated alveolar pneumocytes in 1 piece among 6 pieces tissues taken out of 3 cases with idiopathic pulmonary fibrosis. Also up-regulation of the TGF-$\beta$ expression was showed in alveolar lining pneumocytes, intra-alveolar mononuclear cells, and epithelioid cells in most of cases of ILD from bleomycin toxicity, sarcoidosis and eosinophilic granuloma. Conclusion : These findings suggest that up-regulation of the TGF-$\beta$are involved in pathogenesis of interstitial lung fibrosis from variety of causes.

• The Korean Journal of Physiology and Pharmacology
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• v.5 no.4
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• pp.353-357
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• 2001

The pathogenesis of the nasal polyp is multifactorial and choanal polyps can be defined by its origin of genesis: antrochoanal (maxillochoanal), ethmochoanal and sphenochoanal polyp. Transforming growth $factor-{\beta}\;(TGF-{\beta})$ has various biologic activities, including the regulation of epithelial proliferation, the promotion of extracellular matrix formation and the induction of angiogenesis, hence closely related to pathogenesis of nasal polyp. Twenty cases of choanal polyps (13 antrochoanal, 4 ethmochoanal and 3 sphenochoanal polyps) were included in this study. Each polyp was subdivided into its origin, pedicle and choanal part. Hematoxylin and eosin stain for routine histopathology and immunohistochemistry were employed to detect expression of $TGF-{\beta}1.$ According to polyp type, edematous type is common at origin part and fibrous type at choanal part, and showed no difference at pedicle part in frequency. In ethmochoanal and sphenochoanal polyps, glandulocystic and edematous type is more common than fibrous type. $TGF-{\beta}1$ was expressed in epithelial cells, endothelial cells, eosinophils and lymphocytes. There was no different expression of $TGF-{\beta}1$ in each kind of choanal polyps and separate parts in each polyp. But histologic finding of choanal polyp is different between origin, pedicle and choanal part. Also infiltration of inflammatory cells including eosinophils has no difference between origin site. The expression of $TGF-{\beta}1$ was observed at all the choanal polyps and no difference between origin site and each portions was noted.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.165.1-165.1
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• 2003

Transforming growth factor (TGF)-$\beta$, a hormonally active polypeptide found in normal and transformed tissue, is a potent regulator of cell growth and differentiation. In this study, we examined the effect of TGF-$\beta$ on invasion and motility of MCF10A human breast epithelial cells. TGF-$\beta$-induced migration and invasive phenotype of the parental MCF10A cells in a dose-dependent manner. Activity of MMP-2 promoter was increased by TGF-b, suggesting that the TGF-$\beta$-induced invasive phenotype may possibly be mediated by MMP-2 rather than MMP-9. (omitted)

• IMMUNE NETWORK
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• v.9 no.6
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• pp.248-254
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• 2009

[ $TGF-{\beta}1$ ]is well known to induce Ig germ-line ${\alpha}$ ($GL{\alpha}$) transcription and subsequent IgA isotype class switching recombination (CSR). Homeodomain protein TG-interacting factor (TGIF) and E3-ubiquitin ligases TGIF interacting ubiquitin ligase 1 (Tiul1) are implicated in the negative regulation of $TGF-{\beta}$ signaling. In the present study, we investigated the roles of Tiul1 and TGIF in $TGF{\beta}1$-induced IgA CSR. We found that over-expression of Tiul1 decreased $TGF{\beta}1$-induced $GL{\alpha}$ promoter activity and strengthened the inhibitory effect of Smad7 on the promoter activity. Likewise, overexpression of TGIF also diminished $GL{\alpha}$ promoter activity and further strengthened the inhibitory effect of Tiul1, suggesting that Tiul1 and TGIF can down-regulate $TGF{\beta}1$-induced $GL{\alpha}$ expression. In parallel, overexpression of Tiul1 decreased the expression of endogenous IgA CSR-predicitive transcripts ($GLT_{\alpha},\;PST_{\alpha},\;and\;CT_{\alpha}$) and $TGF{\beta}1$-induced IgA secretion, but not $GLT_{\gamma3}$ and IgG3 secretion. Here, over-expressed TGIF further strengthened the inhibitory effect of Tiul1. These results suggest that Tiul1 and TGIF act as negatively regulators in $TGF{\beta}1$-induced IgA isotype expression.

• Journal of Periodontal and Implant Science
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• v.47 no.2
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• pp.66-76
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• 2017

Purpose: Oral wound healing requires gingival fibroblasts to respond to local growth factors. Epigenetic silencing through DNA methylation can potentially decrease the responsiveness of gingival fibroblasts to local growth factors. In this study, our aim was to determine whether the inhibition of DNA methylation sensitized gingival fibroblasts to transforming growth factor-${\beta}1$ (TGF-${\beta}1$). Methods: Gingival fibroblasts were exposed to 5-aza-2'-deoxycytidine (5-aza), a clinically approved demethylating agent, before stimulation with TGF-${\beta}1$. Gene expression changes were evaluated using quantitative polymerase chain reaction (PCR) analysis. DNA methylation was detected by methylation-sensitive restriction enzymes and PCR amplification. Results: We found that 5-aza enhanced TGF-${\beta}1$-induced interleukin-11 (IL11) expression in gingival fibroblasts 2.37-fold (P=0.008). 5-aza had no significant effects on the expression of proteoglycan 4 (PRG4) and NADPH oxidase 4 (NOX4). Consistent with this, 5-aza caused demethylation of the IL11 gene commonly next to a guanosine (CpG) island in gingival fibroblasts. The TGF-${\beta}$ type I receptor kinase inhibitor SB431542 impeded the changes in IL11 expression, indicating that the effects of 5-aza require TGF-${\beta}$ signaling. 5-aza moderately increased the expression of TGF-${\beta}$ type II receptor (1.40-fold; P=0.009), possibly enhancing the responsiveness of fibroblasts to TGF-${\beta}1$. As part of the feedback response, 5-aza increased the expression of the DNA methyltransferases 1 (DNMT1) (P=0.005) and DNMT3B (P=0.002), which are enzymes responsible for gene methylation. Conclusions: These in vitro data suggest that the inhibition of DNA methylation by 5-aza supports TGF-${\beta}$-induced IL11 expression in gingival fibroblasts.