• Tuberculosis and Respiratory Diseases
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• v.42 no.4
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• pp.492-501
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• 1995

Background: Transforming growth factor- alpha(TGF-$\alpha$) may play important roles in carcinogenesis, tumor growth, and angiogenesis. Transforming growth factor-beta(TGF-$\beta$) are known to be involved in cell-cycle control and regeneration. TGF-$\alpha$ positively acts on growth control of many epithelial cells in contrast to the negative role of TGF-$\beta$. Method: To evaluate the possible role of TGF-$\alpha$ and TGF-$\beta$ in human primary lung cancers, the expression of TGF-$\alpha$ and TGF-$\beta$ were immmunohistochemically investigated in tissue sections from forty seven cases with lung cancers and ten cases with non-cancerous lung tissues. Recombinant cloned monoclonal antibody of TGF-$\alpha$ and neutralizing antibody of TGF-$\beta$ were employed as primary antibodies after dewaxing the formalin-fixed, paraffinized tissue sections. Results: TGF-$\alpha$ was expressed in the cytoplasms of tumor cells in thirty five cases of forty seven(74.5%) primary lung cancers, whereas the control expressed in two of ten brochial epithelial cells. The expression of TGF-$\alpha$ was disclosed in four cases of eleven(36.4 %) small cell carcinomas and thirty one cases of thirty six(86.1%) non-small cell carcinomas of the lung. Expressions of TGF-$\beta$ was discernible in bronchial epithelium in eight of ten non-cancerous lung tissues. The expression of TGF-$\beta$ was noted in the cytoplasms of tumor cells in eight cases of forty seven(17.0%) primary lung cancers. The expression of TGF-$\beta$ disclosed in two cases of eleven(18.2%) small cell carcinomas and six cases of thirty six(16.7%) non- small cell carcinomas of the lung. Conclusion: These findings suggest that up-regulation of TGF-$\alpha$ and down-regulation of TGF-$\beta$ are involved during development and growth of primary lung cancers.

• Korean Journal of Animal Reproduction
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• v.21 no.2
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• pp.177-183
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• 1997

The present study examined the effects of epidermal growth factor(EGF) and transforming growth factor-$\alpha$(TGF-$\alpha$) on in vitro maturation of porcine follicular oocytes. Basic medium used TCM-HEPES, and oocytes cultured for 42 hours in vitro. The results obtained are as follows; 1. The nuclear maturation rates of EGF-treated groups(10ng/ml, 75.9% ; 30ng/ml, 69.2% ; 50ng/ml, 67.2% ; 100ng/ml, 71.0%) on the porcine oocytes cultured in medium without pFF in vitro were significantly(P<0.01) higher than those of non-treated group(57.1%). When the oocytes were cultured in media with 10%(v/v) pFF, the nuclear maturation rates of 30ng EGF/ml(77.1%) treated group were significantly(P<0.01) higher than those of non-(59.2%) and EGF-treated groups(10ng/ml, 65.4% ; 50ng/ml, 65.5% ; 100ng/ml, 70.4%). 2. The nuclear maturation rates of 30ng TGF-$\alpha$/ml treated group(71.9%) in media without pFF in vitro were significatnly(P<0.01) higher than those of non-(57.1%) and TGF-$\alpha$ treated groups(10ng/ml, 60.4% ; 50ng/ml, 65.4% ; 100ng/ml, 60.0%). When the oocytes were cultured in media with 10%(v/v) pFF, the nuclear maturation rates of 30 and 50ng TGF-$\alpha$/ml(77.4% and 79.6%) treated groups(10ng/ml, 64.2% ; 100ng/ml, 61.6%). 3. On the effect of EGF(30ng/ml) and/or TGF-$\alpha$(30ng/ml) treated groups in medium without pFF in vitro, the nuclear maturation rates indicated 57.3, 60.4, 75.9 and 79.7% in media with no EGF & TFG-$\alpha$, TGF-$\alpha$ only, EGF only nad EGF＋TGF-$\alpha$ treated groups, respectively. The nuclear maturation rates in medium with EGF only or EGF＋TGF-$\alpha$ were significantly(P<0.01) higher than those non- and TGF-$\alpha$ treated groups. When the oocytes were cultured in media with 10%(v/v) pFF, the nuclear maturation ratesof EGF＋TGF-$\alpha$ treated group(75.9%) were significantly(P<0.01) higher than those of non-(59.2%), TGF-$\alpha$ only (64.2%) and EGF only(69.4%) treated groups.

• Journal of the Korean Society of Food Science and Nutrition
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• v.23 no.2
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• pp.340-347
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• 1994

The specimens used in this study were obtained from patients with primary gastric carcinoma and adjacent non-malignant mucosa from the same patients. Using the techniques of immunocyto chemicstry and in situ hybridization, transforming growth $factor-{\alpha}(TGF-{\alpha})$ and epiderimal growth factor receptor (EGF-R) nRNAs were identified. $TGF-{\alpha}$ was observed in macrophages and dividing tumor cells but, not in normal cells. EGF-R was observed both in malignant and non-malignant gastric tissues. Although normally, $TGF-{\alpha}$ is not seen in normal gastric tissues, $TGF-{\alpha}$ was discovered in the adjacent non-malignant tissue of histolgically normal, which strongly suggest that $TGF-{\alpha}$ is involved in the differentiation of cancer cells. Immunocytochemicstry using EMB-11 antibody identified the existence of macrophages which express $TGF-{\alpha}$ and EGF-R mRNA. Protein products of EGF-R was identfified using monoclonal antibody. Cancer cells were also identified in the non-malignant normal tissues by the method of immunocytochemicstry using carcino embryonic antigen (CEA)antibody. It is considered that the activity of $TGF-{\alpha}$ increased as tumor cell prolifierates. Immunocytochemistry and in situ hybridization techniques can be used to diagnose gastric cancer along with the use of ${\alpha}-feto$ protein and CEA.

• Tuberculosis and Respiratory Diseases
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• v.45 no.4
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• pp.823-834
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• 1998

Background: Chronic inhalation of silica induces the lung fiborsis. The alveolar macrophages ingest the inhaled silica; they liberate the pro-inflammatory cytokines such as IL-1$\beta$, IL-6, TNF-$\alpha$ and fibrogenic cytokines, TGF-$\beta$ and PDGF. Cytokines liberated from macrophage have pivotal role in pulmonary fibrosis. There is a complex cytokine network toward fibrosis. However, the exact roles and the interaction among the proinflammatory cytokines and TGF-$\beta$, a fibrogenic cytokine, have not been defined, yet. In this study, we investigated silica induced IL-1$\beta$, IL-6, TNF-$\alpha$ and TGF-$\beta$ production and the effect of IL-1$\beta$, IL-6, TNF-$\alpha$ on the production of TGF-$\beta$ from lung macrophages of Balb/C mice. Method: We extracted the lung of Balb/C mice and purified monocytes by Percoll gradient method. Macrphages were stimulated by silica ($SiO_2$) in the various concentration for 2, 4, 8, 12, and 24 hours. The supernatants were used for the measurement of protein levels by bioassay, and cells for the levels of mRNA by in situ hybridization. Results: The production of IL-6 was not observed till 4 hours, and reached the peak levels at 8 hours after stimulation of silica. The production of TNF-$\alpha$ increased from 2 hours and reached the peak levels at 4 hours after stimulation of silica. The spontaneous TGF-$\beta$ production reached the peak levels at 24 hours. TNF-$\alpha$ upregulated the silica induced TGF-$\beta$ production. Silica induced TGF-$\beta$ production was blocked by pretreated anti-TNF-$\alpha$ antibody. In situ hybridization revealed the increased positive signals at 4 hours in IL-6, at 4 hours TNF-$\alpha$ and 12 hours in TGF-$\beta$. Conclusion: The results above suggest that silica induced the sequential production of IL-6, 1NF-$\alpha$ and TGF-$\beta$ from macrophages and TNF-$\alpha$ upregultaes the production of TGF-$\beta$ from silica-induced macrophages.

• Molecules and Cells
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• v.24 no.2
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• pp.283-287
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• 2007

$TGF-{\beta}1$ induces Ig germ-line ${\alpha}$ ($GL{\alpha}$) transcription and subsequent class switching recombination (CSR) to IgA. In the present study, we investigated the roles of two E3-ubiquitin ligases, Smurfs (HECT type) and Arkadia (RING finger type) on $TGF{\beta}1$-induced IgA CSR. We found that over-expression of Smurf1 and Smurf2 decreased $TGF{\beta}1$-induced $GL{\alpha}$ promoter activity and strengthened the inhibitory effect of Smad7 on the promoter activity. Further, over-expression of Smurf1 and Smurf2 decreased both Smad3/4-mediated and Runx3-mediated $GL{\alpha}$ promoter activities, suggesting that the Smurfs can down-regulate the major $TGF-{\beta}1$ signaling pathway and decrease $GL{\alpha}$ gene expression. In parallel, the over-expressed Smurf1 decreased the expression of endogenous IgA CSR-predictive transcripts ($GLT_{\alpha}$, $PST_{\alpha}$, and $CT_{\alpha}$) and also $TGF{\beta}1$-induced IgA secretion. Conversely over-expression of Arkadia abolished the inhibitory effect of Smad7 on $TGF{\beta}1$-induced $GLT_{\alpha}$ expression and IgA secretion. Similar results were obtained in the presence of over-expressed Smad7 and Smurf1. These results indicate that Arkadia can amplify $TGF{\beta}1$-induced IgA CSR by degrading Smad7, which interacts with Smurf1. We conclude that Smurf and Arkadia have opposite roles in the regulation of $TGF{\beta}1$-induced IgA isotype expression.

• IMMUNE NETWORK
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• v.14 no.6
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• pp.321-327
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• 2014

TGF-${\beta}$ induces IgA class switching by B cells. We previously reported that Smad3 and Smad4, pivotal TGF-${\beta}$ signal-transducing transcription factors, mediate germline (GL) ${\alpha}$ transcription induced by TGF-${\beta}1$, resulting in IgA switching by mouse B cells. Post-translational sumoylation of Smad3 and Smad4 regulates TGF-${\beta}$-induced transcriptional activation in certain cell types. In the present study, we investigated the effect of sumoylation on TGF-${\beta}1$-induced, Smad3/4-mediated $GL{\alpha}$ transcription and IgA switching by mouse B cell line, CH12F3-2A. Overexpression of small ubiquitin-like modifier (SUMO)-1, SUMO-2 or SUMO-3 did not affect TGF-${\beta}1$-induced, Smad3/4-mediated $GL{\alpha}$ promoter activity, expression of endogenous $GL{\alpha}$ transcripts, surface IgA expression, and IgA production. Next, we tested the effect of the E3 ligase PIASy on TGF-${\beta}1$-induced, Smad3/4-mediated $GL{\alpha}$ promoter activity. We found that PIASy overexpression suppresses the $GL{\alpha}$ promoter activity in cooperation with histone deacetylase 1. Taken together, these results suggest that SUMO itself does not affect regulation of $GL{\alpha}$ transcription and IgA switching induced by TGF-${\beta}1$/Smad3/4, while PIASy acts as a repressor.

• Tuberculosis and Respiratory Diseases
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• v.58 no.3
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• pp.267-276
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• 2005

Background : The transforming growth $factor-{\beta}1$ ($TGF-{\beta}1$) plays a key role in lung fibrosis. However, the molecular mechanisms involved in $TGF-{\beta}1$-induced lung fibrosis are unclear. $TGF-{\beta}1$ is the key inducer of myofibroblast transdifferentiation via de novo synthesis of ${\alpha}-smooth$ muscle actin (${\alpha}-SMA$). Since $TGF-{\beta}1$ signals through reactive oxygen species (ROS) and ROS have been shown to induce accumulation of extracellular matrix (ECM) in various tissues, this study examined if ROS play a role in $TGF-{\beta}1$-induced fibronectin secretion and ${\alpha}-SMA$ expression in human lung fibroblasts, MRC-5 cells. Methods : Growth arrested and synchronized MRC-5 cells were stimulated with $TGF-{\beta}1$ (0.2-10 ng/ml) in the presence or absence of N-acetylcysteine (NAC) or diphenyleneiodonium (DPI) for up to 96 hours. Dichlorofluorescein (DCF)-sensitive cellular ROS were measured by FACScan and secreted fibronectin and cellular ${\alpha}-SMA$ by Western blot analysis. Results : $TGF-{\beta}1$ increased the level of fibronectin secretion and ${\alpha}-SMA$ expression in MRC-5 cells in a dosedependent manner. Both NAC (20 and 30 mM) and DPI (1 and $5{\mu}M$) significantly inhibited $TGF-{\beta}1$-induced fibronectin and ${\alpha}-SMA$ upregulation. The $TGF-{\beta}1$-induced cellular ROS level was also significantly reduced by NAC and DPI. Conclusions : The results suggest that NADPH oxidase-dependent ROS play an important role in $TGF-{\beta}1$-induced fibronectin secretion and ${\alpha}-SMA$ expression in MRC-5 cells, which leads to myofibroblast transdifferentiation and progressive lung fibrosis.

• 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.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.19 no.4
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• pp.414-434
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• 1997

Though many genetic and epigenetic alterations have been identified in hamster oral carcinogenesis model, there is no information about the possible role of transforming growth factor related with oral cancer. The purpose of this paper was to find the expression patterns of transforming growth factor alpha and beta during the stages of complete oral carcinogenesis model in hamster. 0.5% 9, 10-dimethyl-1, 2-benzanthracene(DMBA) in mineral oil was topically applied to the buccal pouch of 75 hamster three times a week during the experimental periods. The experimental animals were subdivided into two groups of control and experiment. Only the mineral oil was applied to the control group. 0.5% DMBA in mineral oil was applied to the experimental groups of 6, 8, 10, 12, 14, 16, 18 and 20 weeks. The expression of the $TGF-{\alpha}$ and $TGF-{\beta}$ protein were evaluated by the distribution and intensity of positive cells during the carcinogenesis using the immunohistochemical study. The following results were obtained ; 1. The buccal pouch epithelium of hamster was histologically changed to the dysplasia at 6, 8, 10 weeks, carcinoma in situ at 12 weeks, and squamous cell carcinoma at 14 weeks. 2. The expression of the $TGF-{\alpha}$ was restricted to the parabasal and basal layers of the normal and dysplastic mucosa, but those positive cells were extended to the spinous layers of the epithelium in the carcinoma. 3. The degree of $TGF-{\alpha}$ expression was markedly decreased in the carcinoma at 16, 18, 20. The strong positive staining in the center of cancer islands and weak positive staining in periphery of tumor were seen at the stage of squamous cell carcinoma. 4. The positive index of the $TGF-{\alpha}$ had a tendency to increase with DMBA- applied time. There was a statistically significant difference between 12, 18, 20 experimental group and control group (p<0.05). 5. The expression of the $TGF-{\beta}$ was shown at the cytoplasm of all control and experimental groups, and the parabasal and basal layers of the normal and dyslastic mucosa, but it was shown at the basal layers of the epithelium in the carcinoma. 6. $TGF-{\beta}$ was expressed diffusely at 16, 18, 20 experimental group. The strong positive staining in the center of cancer islands and positive staining in periphery of tumor were seen at the stage of squamous cell carcinoma. From the above findings, the expression of $TGF-{\alpha}$ and ${\beta}$ in oral carcinogenesis model seems to have two formal stages, the first being an overexpression step as reaction to uncontrolled growth and the second being one in which external protein accumulate in the surrounding stroma and intracytoplasm. Overexpression of $TGF-{\alpha}$ and ${\beta}$ may have important cooperative roles for the promotion of cancer and factor of prognosis.

• Maxillofacial Plastic and Reconstructive Surgery
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• v.20 no.4
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• pp.334-340
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• 1998

Stimulatory effects of epidermal growth factor (EGF) and transforming growth $factor-{\alpha}$($TGF-{\alpha}$) on the growth of squamous cancer cell lines established from human oral cancer tissue with moderate differentiation were studied in vitro. After culturing in serum-free media for 24 hours, growth factors-EGF only, $TGF-{\alpha}$ only and EGF, $TGF-{\alpha}$ together-were added to the media and numbers of cells were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and compared with the control at 96, 144 hours. Each of EGF and $TGF-{\alpha}$ showed statistically significant stimulatory effects on the growth of cells respectively. Dose-dependent relationship of the stimulatory effects were not clearly demonstrated. The effects of EGF were higher than those of $TGF-{\alpha}$ and combinative administration showed higher effects than those of single uses. In conclusion, EGF may play an important and major role in differentiation and growth of human oral squamous cancer cells. $TGF-{\alpha}$, produced from cells activated by EGF, also can stimulate the cell growth and could be an alternative ligand for EGF receptor.