• KSBB Journal
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• 제19권5호
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• pp.335-340
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• 2004

Mesangial expansion caused by cell proliferation and glomerular extracellular matrix accumulation is one of the earliest renal abnormalties observed at the onset of hyperglycemia in diabetes mellitus. Transcription factor Sp1 is implicated in the transcriptional regulation of a wide range of genes participating in cell proliferation, and is assumed to play an essential role in mesangial expansion, transforming growth factor (TGF)-$\beta$1, plasminogen activator inhibitor (PAI)-1. We have generated a phosphorothioated double-stranded Sp1-decoy oligodeoxynucleotide that effectively blocks Sp1 binding to the promoter region for transcriptional regulation of TGF-$\beta$1 and PAI-1. The Sp1 decoy oligodeoxynucleotide suppressed transcription of these cytokines and proliferation of primary rat mesangial cells in response to serum stimulation. These results suggest that the Sp1 decoy oligodeoxynucleotide could bea powerful tool in preventing the pathogenesis of renal hypertrophy.

• Clinical and Experimental Pediatrics
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• 제51권8호
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• pp.879-885
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• 2008

목 적 : 폐섬유아세포는 예전에는 기도의 구조적 세포로만 알려져 왔으나, 최근에는 천식에서 기관지 운동의 톤을 조절할 뿐만 아니라 기도의 면역조절과 기도 개형에서 중요한 역할을 하는 것으로 밝혀지고 있다. VEGF는 혈관 내피세포에서 강력한 작용을 하는 다기능적 사이토카인으로서, 상피내 세포의 세포분열을 유도하고, 상피세포의 투과도를 증가시키며, 상피세포의 이동을 향상시키는 역할을 하는 것으로 알려져 있다. TARC는 Th2 세포의 선택적 이동을 유도하는 케모카인으로 알려져 있다. 본 연구에서는 PDGF와 TGF-${\beta}$로 자극시킨 인간 폐섬유아세포에서 VEGF와 TARC가 생성되는지와 dexamethasone이 폐섬유아세포에서 VEGF의 분비를 억제하는지를 알아보고자 하였다. 또한 폐섬유아세포와 기관지 평활근 세포와 함께 배양했을 때 VEGF 생성에 미치는 효과를 단독배양 시와 비교하였다. 방 법 : 폐섬유아세포와 인간 기관지 평활근세포를 각각 혹은 함께 배양한 뒤 48시간동안 무혈청 배지에서 성장을 정지시킨 후 TGF-${\beta}$ (10 ng/mL)와 PDGF (20 ng/mL)로 자극하였다. 자극 후의 세포 증식 반응과 배양액 상층액의 VEGF, TARC 농도를 측정하여 dexamethasone ($10^{-6}M$)으로 전처치 후 자극한 것과 비교하였다. 결 과 : PDGF와 TGF-${\beta}$로 자극하였을 경우 폐섬유아세포에서 VEGF 분비가 의미있게 증가하였고, 특히 PDGF와 TGF-${\beta}$로 함께 자극하였을 경우 더욱 의미있는 상승을 보였다. Dexamethasone은 폐섬유아세포의 VEGF 분비를 PDGF로 자극한 경우와 PDGF, TGF-${\beta}$ 같이 자극한 경우 모두에서 억제하였다. 인간 기관지 평활근 세포와 폐섬유아세포를 혼합 배양했을 때 VEGF 분비에는 상승적인 효과가 없었다. Dexamethasone은 폐섬유아세포 증식을 억제시키지 않았다. 폐섬유아세포를 PDGF와 TGF-${\beta}$로 자극했을 때 TARC는 분비되지 않았다. 결 론 : 폐섬유아세포는 VEGF 분비를 통해 기도 개형에 관여하며, 기관지 평활근 세포와 함께 배양해도 VEGF 분비에 상승 효과는 없다. Dexamethasone은 VEGF 분비를 억제하였으나 폐섬유아세포의 증식을 억제하지는 못하였다.

• IMMUNE NETWORK
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• 제1권3호
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• pp.244-249
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• 2001

The transforming growth $factor-{\beta}$ ($TGF-{\beta}$) is a multifunctional cytokine modulating the onset and course of autoimmune disease as shown in experimental models. In synovial inflammation, there is a potential role for $TGF-{\beta}$ in repairment, the inhibition of cartilage and bone destruction, and the down-regulation of immune response. The biologic effects of $TGF-{\beta}$ depend on the cell type, the isoform and the availability of active $TGF-{\beta}$. We investigated $TGF-{\beta}$ expression in patients with rheumatoid arthritis (RA) and compared to those of osteoarthritis (OA). And we determined a correlation between $TGF-{\beta}1$ and $TGF-{\beta}2$, and also the relationships between each $TGF-{\beta}$ isoform and the parameters for disease activity of RA. Methods: The study population consisted of 20 patients with RA and 20 patients with OA. The commercial ELISA kit was used to study $TGF-{\beta}1$ and $TGF-{\beta}2$ levels in peripheral blood (PB) and synovial fluids (SF). Results: 1) While PB $TGF-{\beta}1$ level was of no difference between RA and OA patient groups, SF $TGF-{\beta}1$ level was higher in RA group than OA group. Similarly, PB $TGF-{\beta}2$ levels of RA and OA groups was not different, but SF $TGF-{\beta}2$ levels was higher in RA group than OA group. 2) In patients with RA, the $TGF-{\beta}1$ levels were higher than $TGF-{\beta}2$ in both the PB and SF, while in patients with OA, there showed higher readings for $TGF-{\beta}1$ than $TGF-{\beta}2$ in SF but no difference between $TGF-{\beta}1$ and $TGF-{\beta}2$ levels in PB. 3) In patients with RA, there were no correlations between PB $TGF-{\beta}1$ and PB $TGF-{\beta}2$ levels, nor between SF $TGF-{\beta}1$ and SF $TGF-{\beta}2$ levels. At the same way, there was no correlation between PB $TGF-{\beta}1$ and SF $TGF-{\beta}1$ levels, nor between each levels of $TGF-{\beta}2$ in patients with RA. 4) There was also no correlation between each $TGF-{\beta}$ isoform and the parameters for disease activity such as ESR, CRP, tender joint count, swollen joint count, rheumatoid factor, and the duration of morning stiffness except between in PB $TGF-{\beta}1$ and disease duration of RA (r=0.637, p<0.01). Conclusion: Each $TGF-{\beta}$ isoforms were higher in synovial fluid of patients with RA than that of patients with OA. The data from the RA patients demonstrated different patterns of expressions of the isoforms depending on which compartment (PB or SF) was investigated. The quantification of different $TGF-{\beta}$ isoform is thought to be important when $TGF-{\beta}$ is measured under disease conditions of RA.

• 생명과학회지
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• 제11권2호
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• pp.181-189
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• 2001

Cytokines are hormone-like proteins which mediate and regulast inflammatory and immune responses. Transforming growth factor -$\beta$1(TGF-$\beta$) plays an important role in the control of the immune response and wound healing, and in the development o various tissues and organs, Nitric oxide(NO) is major messenger molecule regulating immune function and blood vessel dilation and serving as a neurotransmitter in the brain and peripheral nervous system. Also, NO is to be a potent mutagen that cause mutation in the p53 tumor suppressor gene in early phases of human gastric carcinogenesis. The purpose of this study was to investigate the effect of Helicobacter phlori lystes, lipopolysaccharide (LPS), and Staphylococcus enterotoxin B(SEB) on production of TGF-$\beta$1 and NO by human fibroblasts. Primary cultured human fibroblasts were incubated with H. pylori lysates(Hp), LPs, SEB, Hp+LPS, Hp+SEB, Hp+LPS+SEB. Cultured supernatants that were collected at 24, 48 and 72 hr were assessed for TGF-$\beta$1 by enzyme-linked immunosorbent assay and NO production by quantification of nitrite ion. TGF-$\beta$1 production in fibroblasts exposed with Hp, LPS or SEB for 48 hrs was enhanced, but for 72 hrs inhibited. Its production by doble exposure such as Hp+LPS, Hp+SEB, Hp+LPS+SEB was lowered in comparison with single exposure of Hp in cases of 24 and 48 hrs incubation, but for 72 hrs decreased in Hp vaculoating toxin(+), increased in Hp vacuolating toxin(-). No production in fibroblasts increaed at all doses of LPS. But its production by exposure of SEB increased or decreased according to dose and incubation time. Also, NO production by Hp vacuolating toxin(+) increased at all doses, but its production by Hp vacuolating toxin(-) decreased. Its production by doble exposure such as Hp+LPS, Hp+SEB, Hp+LPS+SEB decreased in comparison with single exposure Hp Therefore, quantities pf TGB-$\beta$1 and NO released by human fibroblasts shows differences according to kinds of stimulants. Also, in care stimulated with same kinds of stimulants, its productions exhibit quantitative differences according to exposure times. These results suggest that the decreased of TGF-$\beta$1 in fibroblasts by mixed exposure with Hp producing vacuolating toxin and bacterial toxins such as LPS and SEB may effect negatively in healing of host tissue and increased of NO by infection oh H. pylori may related to the increased susceptibility for human gastric carcinogenesis.

• 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.

• Archives of Pharmacal Research
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• 제25권6호
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• pp.917-922
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• 2002

We investigated the long term effects of Sopungsungi-won (SP), a Korean traditional formula used for senile constipation and diabetes mellitus, on the development of diabetic nephropathy (DN) in Zucker diabetic fatty (ZDF) rats. ZDF rats were fed regular laboratory chow mixed with SP or rosiglitazone (RSG) for an 8-week period. Kidney hypertrophy was developed with increasing plasma glucose level, and glomerular hypertrophy was improved by 22% and 45% in SP- and RSG-treated rats, respectively. Urinary glucose and albumin excretions were also significantly lower in SP-treated rats than in ZDF control rats. Activation of the mitogen-activated protein kinase (MAPK)-transforming growth factor ${\beta}1$ (TGF ${\beta}1$)-fibronectin pathway in kidney, responsible for glomerular dysfunction, was markedly blunted by SP treatment in a dose dependent manner. Our findings, for the first time, provide strong evidence that long-term administration of SP formula prevents the development and progression of DN in ZDF rats. Human trials are needed to confirm these experimental results.

• 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.

• Macromolecular Research
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• 제13권4호
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• pp.285-292
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• 2005

We developed alginate beads loaded with transforming growth $factor-{\beta}_{1}(TGF-{\beta}_{1})$ to examine the possible application of the scaffold and cytokine carrier in tissue engineering. In this study, bone marrow stromal cells (BMSCs) and $TGF{\beta}_{1}$ were uniformly encapsulated in the alginate beads and then cultured in vitro. The cell morphology and shape of the alginate beads were observed using inverted microscope, scanning electron microscope (SEM), histological staining and RT-PCR to confirm chondrogenic differentiation. The amount of the $TGF{\beta}_{1}$ released from the $TGF-{\beta}_{1}$ loaded alginate beads was analyzed for 28 days in vitro in a phosphate buffered saline (pH 7.4) at $37^{\circ}C$. We observed the release profile of $TGF-{\beta}_{1}$ from $TGF-{\beta}_{1}$ loaded alginate beads with a sustained release pattern for 35 days. Microscopic observation showed the open cell pore structure and abundant cells with a round morphology in the alginate beads. In addition, histology and RT-PCR results revealed the evidence of chondrogenic differentiation in the beads. In conclusion, these results confirmed that $TGF-{\beta}_{1}$ loaded alginate beads provide excellent conditions for chondrogenic differentiation.

• Molecules and Cells
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• 제40권3호
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• pp.211-221
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• 2017

Transforming growth factor ${\beta}1$ $(TGF{\beta}1)/Smad4$ signaling plays a pivotal role in maintenance of the dynamic balance between bone formation and resorption. The microRNA miR-155 has been reported to exert a significant role in the differentiation of macrophage and dendritic cells. The goal of this study was to determine whether miR-155 regulates osteoclast differentiation through $TGF{\beta}1/Smad4$ signaling. Here, we present that $TGF{\beta}1$ elevated miR-155 levels during osteoclast differentiation through the stimulation of M-CSF and RANKL. Additionally, we found that silencing Smad4 attenuated the upregulation of miR-155 induced by $TGF{\beta}1$. The results of luciferase reporter experiments and ChIP assays demonstrated that $TGF{\beta}1$ promoted the binding of Smad4 to the miR-155 promoter at a site located in 454 bp from the transcription start site in vivo, further verifying that miR-155 is a transcriptional target of the $TGF{\beta}1/Smad4$ pathway. Subsequently, TRAP staining and qRT-PCR analysis revealed that silencing Smad4 impaired the $TGF{\beta}1$-mediated inhibition on osteoclast differentiation. Finally, we found that miR-155 may target SOCS1 and MITF to suppress osteoclast differentiation. Taken together, we provide the first evidence that $TGF{\beta}1/Smad4$ signaling affects osteoclast differentiation by regulation of miR-155 expression and the use of miR-155 as a potential therapeutic target for osteoclast-related diseases shows great promise.

• Tuberculosis and Respiratory Diseases
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• 제43권2호
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• pp.164-172
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• 1996

연구배경 : TGF-$\beta$는 25kD의 단백으로써, 폐섬유증의 병인에 있어 TGF-$\beta$의 발현과 밀접한 관계가 있다고 보고되고 있다. TGF-$\beta$는 세포외 분자들의 합성 및 생산을 촉진할 뿐만아니라 세포간질의 붕괴를 감소시킨다. 특발성 폐섬유증을 포함한 다른원인에 의한 간질성 폐질환의 폐섬유증에 있어 TGF-$\beta$의 발현양상은 상향조절된다고 알려져 있다. 연구방법 : 본연구는 특발성 폐섬유증과, bleomycin, 유육종증, 및 폐의 호산구성 육아종에 의한 간질성 폐질환에 있어서 TGF-$\beta$의 발현 양상를 연구하고자 개흉 폐생검으로 채취된 특발성 간질성 폐섬유증 3예의 6절편과 폐절제시 채취한 5예의 정상조직을 연구재료로 하였고 bleomycin, 유육종증 및 폐의 호산구성 육아종에 의한 간질성 폐질환환자 각각 3예로부터 얻은 6절편에서 TGF-$\beta$의 단세포군항체를 이용하여 면역조직화학적 검색을 실시하였다 결과 : TGF-$\beta$은 5예의 정상조직의 기관지 상피세포나 폐포세포에서는 약하거나 중등도로 발현되었다. 3예의 특발성 폐섬유증 6절편 중 5절편에서 폐포벽의 간질성 섬유모세포들에서 발현되었고, 1절편에서는 증식된 폐포내 폐포세포에서 발현되었으며 그 정도는 비균질적인 양상을 보였다. 3예의 6절편 중 5절편에서 강한발현을 1절편에서는 중등도의 발현을 나타냈으며 bleomycin이 원인이 되는 간질성 폐질환 6절편중 2절편에서는 중등도의 발현을 4절편에서는 강한발현을 보였고, 유육종증이 원인이 되는 간질성 폐질환 6절편 중 3절편에서 중등도의 발현을, 3절편에서 강한 발현을 보였다. 폐의 호산구성 육이종이 원인이 되는 간질성 폐질환 6절편중 2절편에서 중등도의 발현을, 4절편에서 강한 발현을 보였다. 결론 : TGF-$\beta$의 발현 증가는 특발성 폐섬유증, bleomycin, 유육종증 및 폐의 호산구성 육아종에 의한 간질성 폐질환에 있어서 폐섬유증의 병인과 상당한 관련이 있음을 암시해 주는 것으로 생각된다.