• 제목/요약/키워드: Transforming growth factor-$\beta$1 (TGF-$\beta$1)

검색결과 296건 처리시간 0.028초

Inhibitors of DNA methylation support TGF-β1-induced IL11 expression in gingival fibroblasts

  • Sufaru, Irina-Georgeta;Beikircher, Gabriel;Weinhaeusel, Andreas;Gruber, Reinhard
    • Journal of Periodontal and Implant Science
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    • 제47권2호
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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.

사람 폐 섬유아세포의 전환성장인자-β1에 의한 fibronectin 분비와 α-smooth muscle actin 표현에 있어서 활성산소족의 역할 (Role of Reactive Oxygen Species in Transforming Growth Factor-β1-inuduced Fibronectin Secretion and α-Smooth Muscle Actin Expression in Human Lung Fibroblasts)

  • 하헌주;유미라;어수택;박춘식;이희발
    • Tuberculosis and Respiratory Diseases
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    • 제58권3호
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    • pp.267-276
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    • 2005
  • 연구배경 : 전환성장인자-${\beta}1$(transforming growth factor-${\beta}1$: $TGF-{\beta}1$)은 폐 섬유화를 매개하는 주된 인자이지만 $TGF-{\beta}1$에 의한 폐 섬유화의 발생과 진행기전의 이해는 아직 불완전하다. $TGF-{\beta}1$은 다양한 세포에서 활성산소족(reactive oxygen species: ROS)을 통하여 세포내 신호를 전달하고 ${\alpha}$-smooth muscle actin (${\alpha}$-SMA)의 신생합성을 통하여 상피세포와 폐 섬유아세포를 근 섬유아세포 표현형으로의 변화를 유도하는 주된 인자이다. ROS는 또 다양한 세포에서 세포외기질 (extracellular matrix: ECM) 축적을 유발하는 것이 알려져 있음으로 본 연구에서는 폐 섬유아세포인 MRC-5 세포에서 $TGF-{\beta}1$이 ROS를 매개하여 fibronectin 분비와 ${\alpha}-SMA$ 표현의 증가에 관여하는지를 검색하였다. 방 법 : 성장이 동일화된 MRC-5 세포를 $TGF-{\beta}1$ (0.2-10ng/ml)으로 96 시간까지 자극하였고, 필요에 따라 항산화제인 N-acetylcysteine (NAC)이나 NADPH oxidase 억제제인 diphenyleniodonium (DPI)을 $TGF-{\beta}1$ 투여 1 시간 전부터 전처리하였다. Dichlorofluorescein (DCF)에 민감한 세포내 ROS는 FACS로, 분비된 fibronectin과 세포의 ${\alpha}-SMA$ 표현은 Western blot 분석으로 측정하였다. 결 과 : $TGF-{\beta}1$은 용량의존적으로 fibronectin 분비와 ${\alpha}-SMA$ 표현을 상향조절하였다. NAC와 DPI는 $TGF-{\beta}1$에 의한 fibronectin 분비 증가와 ${\alpha}-SMA$ 상향조절을 유의하게 억제하였다. $TGF-{\beta}1$에 의한 세포내 ROS의 증가도 NAC나 DPI에 의하여 유의하게 억제되었다. 결 론 : 본 연구의 결과는 폐 섬유아세포에서 NADPH oxidase 에 의하여 생산된 ROS가 $TGF-{\beta}1$에 의한 fibronectin 분비와 ${\alpha}-SMA$ 표현을 상향조절함으로써 폐 섬유화의 발생과 진행에 관여할 수 있음을 증명하였다.

신생 백서의 저산소 허혈 뇌손상에서 Transforming Growth Factor-β1 투여에 따른 Nitric Oxide Synthase 이성체와 N-methyl-D-aspartate 수용체 아단위의 발현 (Expression of nitric oxide synthase isoforms and N-methyl-D-aspartate receptor subunits according to transforming growth factor-β1 administration after hypoxic-ischemic brain injury in neonatal rats)

  • 고혜영;서억수;김우택
    • Clinical and Experimental Pediatrics
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    • 제52권5호
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    • pp.594-602
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    • 2009
  • 목 적 : $TGF-{\beta}1$는 흥분독성을 억제시키고 질소 산화물 생성 억제를 통한 신경세포 보호 효과가 있다고 알려져 있지만 주산기저산소 허혈 뇌손상에서 그 기전은 아직도 확실히 밝혀져 있지 않고 있다. 따라서 이번 연구에서는 신생 백서의 저산소 허혈 뇌손상에서 산화질소로 인한 신경독성 및 글루탐산염에 의한 흥분독성과 $TGF-{\beta}1$의 관계를 보고자 하였다. 방 법 : 생체외 실험으로 재태 기간 19일된 태아 백서의 대뇌피질 세포를 배양하여 1% O2 배양기에서 저산소 상태로 뇌세포손상을 유도하여 저산소군(Hypoxia), 저산소 손상 30분 전 $TGF-{\beta}1$ (1, 5, 10 ng/mL) 투여군(H+$TGF-{\beta}1$)으로 나누어 정상 산소군 (Control)과 비교하였다. 생체 내 실험은 생후 7일된 백서의 좌측 총 경동맥을 결찰한 후 저산소 (7.5% O2) 상태로 2시간 노출시켜서, 저산소 허혈 뇌손상을 유발하였다. 아무런 처치도 하지 않은 정상 대조군(Control), 경동맥 노출 후 봉합 시술만 시행한 정상 Sham 수술군(Sham-OP), 손상 30분 전 생리식염수를 주입 후 경동맥 결찰과 저산소 노출을 시행한 저산소 허혈 대조군(HI+ Vehicle), 손상 30분 전 $TGF-{\beta}1$을 대뇌로 투여하고 경동맥 결찰과 저산소 노출을 시행한 저산소 허혈 $TGF-{\beta}1$ 투여군(HI+$TGF-{\beta}1$)으로 나누어 비교분석하였다. 흥분독성과의 관련을 알아보기 위하여 NMDA 수용체 아단위를 이용하였고, 질소산화물과의 관련을 알아보기 위해 iNOS, eNOS 및 nNOS를 이용하여 western blotting과 실시간 중합효소연쇄반응을 하였다. 결 과 : 생체 외 실험에서 iNOS의 발현은 정상 산소군과 저산소군 간에 차이가 없었으며, $TGF-{\beta}1$ 투여군에서는 발현이 증가하였으며 이는 농도와는 상관성이 없었다. eNOS, nNOS의 발현은 1 ng/mL의 $TGF-{\beta}1$ 투여군에서 저산소군보다 감소하였다. 생체 내 실험에서는 iNOS와 iNOS mRNA의 발현은 $TGF-{\beta}1$ 투여한 후 저산소 대조군보다 증가하였다. eNOS와 nNOS 발현은 정상 대조군 보다 저산소 대조군에서 감소하였고, eNOS의 발현은 $TGF-{\beta}1$ 투여군에서 증가하였지만 nNOS의 발현은 증가하지 않아 통계적 유의성이 없었다. eNOS mRNA와 nNOS mRNA의 발현은 iNOS와 반대로 $TGF-{\beta}1$ 투여군에서 저산소 대조군보다 감소하였다. NMDA 수용체 아단위 mRNA의 발현은 정상 대조군과 Sham 수술군에 비해 저산소 대조군에서 모두 감소하였으나 $TGF-{\beta}1$ 투여군에서 NR2C를 제외한 나머지 아단위의 발현은 저산소 대조군보다 증가하였다. 결 론 : 신생백서의 저산소 허혈 뇌손상에서 $TGF-{\beta}1$ 치료군에서 저산소로 인하여 감소된 NMDA 수용체 아단위의 발현을 증가시켜 흥분독성 기전과 관련성을 보이며, 증가된 iNOS 발현을 감소시키고 감소된 eNOS 발현을 증가시키는 질소 산화물 중재를 통한 뇌 보호 작용에 연관이 있을 것으로 생각된다.

세균 독소를 작용시킨 섬유아 세포에서 Transforming Growth Factor-${\beta}_1$의 생성 (PRODUCTION OF TRANSFORMING GROWTH FACTOR-${\beta}_1$ IN HUMAN FIBROBLASTS INDUCED WITH BACTERIAL TOXINS)

  • 이성근;김광혁
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • 제26권4호
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    • pp.345-354
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    • 2000
  • TGF-${\beta}_1$ is a potent chemotactic factor for inflammatory cells and fibroblasts. It also stimulates the celluar source and components of extracellular matrix and the production of proteinase inhibitors. Collectively, these biologic activities lead to the accumulation and stabilization of the nascent matrix, which is vital to wound healing. The objective of this study is to investigate production of TGF-${\beta}_1$ in vitro fibroblast culture in the presence of Staphylococcus enterotoxin B(SEB) and/or lipopolysaccharide(LPS) and to elucidate the role of TGF-${\beta}_1$ which may be responsible for wound healing. The fibroblasts were originated from facial dermis and hypertrophic scar in 26 year-old male patient. In the presence of LPS($0.01{\mu}g$, $0.1{\mu}g$, $1.0{\mu}g$), SEB($0.01{\mu}g$, $0.1{\mu}g$, $1.0{\mu}g$) respectively, cells($5{\times}10^3ml$) were cultivated in vitro. At 1, 3, and 5 days after incubation, cells were counted. Also, cells($2.5{\times}10^5ml$) were cultivated in EMEM with LPS(0.01, 0.1 and $1.0{\mu}g$), SEB(0.01, 0.1 and $1.0{\mu}g$) respectively and LPS($0.1{\mu}g$) and SEB($0.1{\mu}g$) in combination for 24, 48, and 72 hours respectively. Culture supernatants were harvested at 1, 2, and 3 days after incubation period and triplicate culture supernatants were pooled and TGF-${\beta}_1$ was assayed in duplicate. The results were as follows. 1. In facial dermal fibroblast induced with SEB and LPS respectively or in combination, the suppression of cell proliferation occurred very significantly at 1 day after incubation, compared with the control. In SEB exposure, the production of TGF-${\beta}_1$ was decreased very significantly at 1 day after incubation, compared with the control. However, in LPS, SEB and LPS exposure, the production of TGF-${\beta}_1$ was increased very significantly at 1 day after incubation, compared with the control. 2. In hypertrophic scar fibroblast induced with SEB and LPS respectively or in combination, the suppression of cell proliferation did not occur at 1 day after incubation, compared with the control. In SEB and LPS exposure in combination, the production of TGF-${\beta}_1$ was increased very significantly at 1 day after incubation, compared with the control. However, the production of TGF-${\beta}_1$ did not occur in SEB and LPS exposure respectively. In conclusion, the concentration of bacterial toxins and the incubation period correlated with cell proliferation and production of TGF-${\beta}_1$ very significantly and both fibroblasts have different phenotype each other in this regard. This data suggest that the significant production of TGF-${\beta}_1$ may develope abnormal wound healing associated with tissue fibroproliferative disorder, such as hypertrophic scar and keloid formation.

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Regulation of Tumor Immune Surveillance and Tumor Immune Subversion by TGF-$\beta$

  • Park, Hae-Young;Wakefield, Lalage M;Mamura, Mizuko
    • IMMUNE NETWORK
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    • 제9권4호
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    • pp.122-126
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    • 2009
  • Transforming growth factor-$\beta$ (TGF-$\beta$) is a highly pleiotropic cytokine playing pivotal roles in immune regulation. TGF-$\beta$ facilitates tumor cell survival and metastasis by targeting multiple cellular components. Focusing on its immunosuppressive functions, TGF-$\beta$ antagonists have been employed for cancer treatment to enhance tumor immunity. TGF-$\beta$ antagonists exert anti-tumor effects through #1 activating effector cells such as NK cells and cytotoxic $CD8^+$ Tcells (CTLs), #2 inhibiting regulatory/suppressor cell populations, #3 making tumor cells visible to immune cells, #4 inhibiting the production of tumor growth factors. This review focuses on the effect of TGF-$\beta$ on T cells, which are differentiated into effector T cells or newly identified tumor-supporting T cells.

TGF-$\alpha$, -$\beta$$_1$, and bFGF mRNA Expression of Lens Epithelial Cells in Senile and Diabetic Cataract

  • Hwang, Bum-Noon;Her, Jun
    • 대한의생명과학회지
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    • 제8권3호
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    • pp.127-135
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    • 2002
  • Anterior subcapsular cataract was developed by opacification with transdifferentiation and abnormal proliferation of lens epithelial cells (LECs) and pathological accumulation of extracellular matrix (ECM). After-cataract also be caused by a similar transdifferentiation of LECs remaining after surgery and the accompanying increase of ECM deposits. It is blown that prostaglandin E2 and cytokine, such as TGF-$\beta$, bFGF, and IL-1, were associated with abnormal proliferation and transdifferentiation of LECs. The aim of this study was to detect the expression of transforming growth factor-$\alpha$ (TGF-$\alpha$), transforming growth factor-$\beta_1$(TGF-$\beta_1$) and basic fibroblast growth factor (bFGF) in LECs of senile and diabetic cataract. The expressions of these growth factors in lens epithelial cells were determined. The sample for growth factor determination were collected in senile cataract patients without metabolic disorder, especially diabetes mellitus and diabetic cataract patients. The mRNA expression of growth factors was detected by semi-quantitative reverse transcription - polymerase chain reaction (RT-PCR) followed by Southern blot analysis. Statistics were analysed using Wilcoxon rank sum test. Semi-quantitative RT-PCR/southern analysis of RNA obtained from thirty surgical specimens demonstrated that the level of mRNA expression of TGF-$\alpha$, -$\beta_1$ and bFGF was increased in diabetic cataract lens tissues compared with senile cataract specimens but non-significant, bFGF and TGF-$\beta_1$ mRNA expression were detected in most patients, expression level of TGF-$\beta_1$ was most high on the basis of normal ocular concentration. Detection rate of TGF-$\alpha$ in diabetic cataract was 1.5 fold higher than in senile cataract (P=0.098). TGF-$\alpha$, TGF-$\beta_1$, and bFGF mRNA expression of LECs were detected in senile and diabetic cataract. In both patient groups, expression level of TGF-$\beta_1$, mRNA was high, so We suggest TGF-$\beta_1$ strong influence in development of senile cataract and of diabetic cataract also. TGF-$\alpha$ expression level was similar but more frequently detected in diabetic cataract than in senile cataract. In conclusion, TGF-$\alpha$ may be associated with early development of diabetic cataract.

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Effects of TGF-${\beta}1$ Ribbon Antisense on $CCl_4$-induced Liver Fibrosis

  • Doh, Kyung-Oh
    • The Korean Journal of Physiology and Pharmacology
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    • 제12권1호
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    • pp.1-6
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    • 2008
  • Ribbon-type antisense oligonucleotide to TGF-${\beta}1$ (TGF-${\beta}1$ RiAS) was designed and tested to prevent or resolve the fibrotic changes induced by $CCl_4$ injection. When Hepa1c1c7 cells were transfected with TGF-${\beta}1$ RiAS, the level of TGF-${\beta}1$ mRNA was effectively reduced. TGF-${\beta}1$ RiAS, mismatched RiAS, and normal saline were each injected to mice via tail veins. When examined for the biochemical effects on the liver, TGF-${\beta}1$ mRNA levels were significantly reduced only in the TGF-${\beta}1$ RiAS-treated group. The results of immunohistochemical studies showed that TGF-${\beta}1$ RiAS prevented the accumulation of collagen and ${\alpha}$-smooth muscle actin, but could not resolve established fibrosis. These results indicate that ribbon antisense to TGF-${\beta}1$ with efficient uptake can effectively prevent fibrosis of the liver.

CONTROL OF SCARRING IN ADULT WOUNDS USING ANTISENSE TRANSFORMING GROWTH FACTOR-$\beta$ OLIGODEOXYNUCLEOTIDES

  • Park, Byung-Min;Kim, Su-Ung;Lee, Seong-Yong;Chung, Hun-Taeg
    • 한국응용약물학회:학술대회논문집
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    • 한국응용약물학회 1995년도 춘계학술대회
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    • pp.79-79
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    • 1995
  • Although synthetic antisense oligodeoxynucleotides (ODNs) have been used to dissect gene function in vitro, technical difficulties of targeted delivery prevented the use of this approach for investigating the effect of gene products in vivo. Here we report the use of local delivery of antisense transforming growth factor-${\beta}$l (TGF-${\beta}$1) oligonucleotides to decrease the fibrosis in the skin wound. Adult wounds heal with scar-tissue formation, whereas fetal wounds heal without scarring and with a lesser inflammatory and cytokine response. We reasoned that strategy emptying antisense TGF-${\beta}$1 ODNs complementary to TGF-${\beta}$1 mRNA might decrease the scarring in dermal wound of mouse. To evaluate this concept, we tested the effects of antisense ODNs targeted to TGF-${\beta}$1 mRNA by topical application of the chemical on the skin wound. Phosphorothioate antisense ODNs was employed to retard their degradation. When antisense TGF-${\beta}$1 ODNs were applied into the wound site, there was a maked reduction of scar compared with control wound site, These effects of antisense TGF-${\beta}$1 ODNs on the scar formation were associated with decreased expression of TGF-${\beta}$1 gene. However sense TGF-${\beta}$l ODNs had no effect on expression of TGF-${\beta}$1 gene. Also, control wounds healed with excessive fibrosis, whereas the antisense treated wounds healed with less fibrosis. In conclusion, our results indicate that antisense TGF-${\beta}$1 ODNs could be used for amelioating scar formation during wound healing.

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Significant fibrosis after radiation therapy in a patient with Marfan syndrome

  • Suarez, Eva M.;Knackstedt, Rebecca J.;Jenrette, Joseph M.
    • Radiation Oncology Journal
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    • 제32권3호
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    • pp.208-212
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    • 2014
  • Marfan syndrome is one of the collagen vascular diseases that theoretically predisposes patients to excessive radiation-induced fibrosis yet there is minimal published literature regarding this clinical scenario. We present a patient with a history of Marfan syndrome requiring radiation for a diagnosis of a right brachial plexus malignant nerve sheath tumor. It has been suggested that plasma transforming growth factor beta 1 (TGF-${\beta}1$) can be monitored as a predictor of subsequent fibrosis in this population of high risk patients. We therefore monitored the patient's TGF-${\beta}1$ level during and after treatment. Despite maintaining stable levels of plasma TGF-${\beta}1$, our patient still developed extensive fibrosis resulting in impaired range of motion. Our case reports presents a review of the literature of patients with Marfan syndrome requiring radiation therapy and the limitations of serum markers on predicting long-term toxicity.

A Single Nucleotide Polymorphism in Transforming Growth Factor-$\beta$ type II Receptor of the Rat

  • Ryu, Doug-Young
    • Toxicological Research
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    • 제16권1호
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    • pp.59-61
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    • 2000
  • A single nucleotide polymorphism in the transforming growth factor-$\beta$ type II receptor (TGE$\beta$RII) gene of the rat was studied. TGF$\beta$RII is a tumor suppressor that is frequently inactivated by mutation in human colon cancers. A novel nucleotide polymorphism of G to A(or A to G), which causes a silent mutation at codon 129, was found in G:C rich sequence in the TGF$\beta$RII gene of Sprague-Dawley rats. The results suggest that genetic polymorphism occures without a strain of the laboratory animal.

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