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1.
Liver fibrosis occurs in most types of chronic liver diseases and is characterized by excessive accumulation of extracellular
matrix proteins, leading to disruption of tissue function and eventually organ failure. Transforming growth factor (TGF)-β
represents an important pro-fibrogenic factor and aberrant TGF-β action has been implicated in many disease processes of the
liver. Endoglin is a TGF-β co-receptor expressed mainly in endothelial cells that has been shown to differentially regulates
TGF-β signal transduction by inhibiting ALK5-Smad2/3 signalling and augmenting ALK1-Smad1/5 signalling. Recent reports demonstrating
upregulation of endoglin expression in pro-fibrogenic cell types such as scleroderma fibroblasts and hepatic stellate cells
have led to studies exploring the potential involvement of this TGF-β co-receptor in organ fibrosis. A recent article by Meurer
and colleagues now shows that endoglin expression is increased in transdifferentiating hepatic stellate cells in vitro and
in two different models (carbon tetrachloride intoxication and bile duct ligation) of liver fibrosis in vivo. Moreover, they
show that endoglin overexpression in hepatic stellate cells is associated with enhanced TGF-β-driven Smad1/5 phosphorylation
and α-smooth muscle actin production without altering Smad2/3 signaling. These findings suggest that endoglin may play an
important role in hepatic fibrosis by altering the balance of TGF-β signaling via the ALK1-Smad1/5 and ALK-Smad2/3 pathways
and raise the possibility that targeting endoglin expression in transdifferentiating hepatic stellate cells may represent
a novel therapeutic strategy for the treatment of liver fibrosis. 相似文献
2.
Thy-1, a glycophosphatidylinositol-linked glycoprotein of the outer membrane leaflet, has been described in myofibroblasts
of several organs. Previous studies have shown that, in fetal liver, Thy-1 is expressed in a subpopulation of ductular/progenitor cells. The aim of this study has been to investigate whether the liver
myofibroblasts belong to the Thy-1-positive subpopulation of the adult liver. The expression of Thy-1 has been studied in normal rat liver, in the rat liver regeneration model following 2-acetylaminofluorene treatment and partial
hepatectomy (AAF/PH), and in isolated rat liver cells, at the mRNA and protein levels. In normal rat liver, Thy-1 is detected
in sparse cells of the periportal area, whereas 7 days after PH in the AAF/PH model, a marked increase of the number of Thy-1-positive
cells is detectable by immunohistochemistry. Comparative immunohistochemical analysis has revealed the co-localization of
Thy-1 and smooth muscle actin, but not of Thy-1 and cytokeratin-19, both in normal rat liver and in the AAF/PH model. Investigation
of isolated rat liver cell populations has confirmed that liver myofibroblasts are Thy-1-positive cells, whereas hepatocytes,
hepatic stellate cells, and liver macrophages are not. Thy-1 is the first cell surface marker for identifying liver myofibroblasts
in vivo and in vitro.
Jozsef Dudas and Tümen Mansuroglu contributed equally to this study.
This work was supported by grants from the Deutsche Forschungsgemeinschaft (SFB 402, projects C6, D3, D4). 相似文献
3.
Matsuzaki K 《Cell and tissue research》2012,347(1):225-243
Hepatocellular carcinoma (HCC) usually arises from hepatic fibrosis caused by chronic inflammation. In chronic liver damage,
hepatic stellate cells undergo progressive activation to myofibroblasts (MFB), which are important extracellular-matrix-producing
mesenchymal cells. Concomitantly, perturbation of transforming growth factor (TGF)-β signaling by pro-inflammatory cytokines
in the epithelial cells of the liver (hepatocytes) promotes both fibrogenesis and carcinogenesis (fibro-carcinogenesis). Insights
into fibro-carcinogenic effects on chronically damaged hepatocytes have come from recent detailed analyses of the TGF-β signaling
process. Smad proteins, which convey signals from TGF-β receptors to the nucleus, have intermediate linker regions between
conserved Mad homology (MH) 1 and MH2 domains. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially
phosphorylate Smad2 and Smad3 to create phosphoisoforms phosphorylated at the COOH-terminal, linker, or both (L/C) regions.
After acute liver injury, TGF-β-mediated pSmad3C signaling terminates hepatocytic proliferation induced by the pro-inflammatory
cytokine-mediated mitogenic pSmad3L pathway; TGF-β and pro-inflammatory cytokines synergistically enhance collagen synthesis
by activated hepatic stellate cells via pSmad2L/C and pSmad3L/C pathways. During chronic liver disease progression, pre-neoplastic
hepatocytes persistently affected by TGF-β together with pro-inflammatory cytokines come to exhibit the same carcinogenic
(mitogenic) pSmad3L and fibrogenic pSmad2L/C signaling as do MFB, thereby accelerating liver fibrosis while increasing risk
of HCC. This review of Smad phosphoisoform-mediated signals examines similarities and differences between epithelial and mesenchymal
cells in acute and chronic liver injuries and considers Smad linker phosphorylation as a potential target for the chemoprevention
of fibro-carcinogenesis. 相似文献
4.
Gu K Zhao JD Ren ZG Ma NY Lai ST Wang J Liu J Jiang GL 《Molecular biology reports》2011,38(3):1687-1696
Characteristics of thioacetamide (TAA)-induced liver cirrhosis in rat was observed for 120 days after TAA withdrawal as part
of the radiobiological study of partial liver irradiation on TAA-induced cirrhotic rats. The natural process focused on cirrhosis
and regeneration was recorded as a baseline condition for the interpretation of the outcome of the partial liver irradiation
study. Cirrhosis in rats was successfully induced by drinking 0.03% TAA water orally for 29 weeks with a modeling rate of
96%. After establishment of the cirrhosis model, the rats were observed for 120 days upon TAA withdrawal to investigate the
dynamic changes of cirrhosis and regeneration. The following characteristics were observed: (1) Histological changes; (2)
Liver functions; (3) Cirrhosis: trichrome stain, quantification of hydroxyproline in hydrolysed liver tissue and TGF-β1; (4)
Liver regeneration: liver index, hepatocyte mitotic index (MI), hepatocyte proliferation index (PI) by flow cytometry, PCNA
labeling index (LI) by IHC and expression of PCNA mRNA; and (5) Growth factors: serum HGF, VEGF, TGF-α, and IL-6. After TAA
withdrawal, gradual improvement in liver functions was noted with decreases of ALT, AST, and ALP, and increase of PA. The
resolution of cirrhosis was evident by histological improvement with attenuation of collagen fiber and decrease of TGF-β1
IHC index, and also decrease of trichrome stain and hydroxyproline content. However, cirrhosis was still existed on 120 days
after TAA withdrawal. Significant deceleration of liver regeneration was demonstrated with TAA withdrawal, evidenced by decrease
of MI and PI, reduced expression of PCNA mRNA and PCNA LI. In conclusion, upon TAA withdrawal hepatic cirrhosis was continuously
resolved, but persisted up to 120 days, and liver regeneration was significantly decelerated. 相似文献
5.
Transforming growth factor-β (TGF-β) is a central regulator in chronic liver disease contributing to all stages of disease
progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver-damage-induced
levels of active TGF-β enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting
in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Being recognised as a
major profibrogenic cytokine, the targeting of the TGF-β signalling pathway has been explored with respect to the inhibition
of liver disease progression. Whereas interference with TGF-β signalling in various short-term animal models has provided
promising results, liver disease progression in humans is a process of decades with different phases in which TGF-β or its
targeting might have both beneficial and adverse outcomes. Based on recent literature, we summarise the cell-type-directed
double-edged role of TGF-β in various liver disease stages. We emphasise that, in order to achieve therapeutic effects, we
need to target TGF-β signalling in the right cell type at the right time. 相似文献
6.
Hisanaga T Terai S Iwamoto T Takami T Yamamoto N Murata T Matsuyama T Nishina H Sakaida I 《Cell and tissue research》2011,346(1):79-88
The importance of TNF-α signals mediated by tumor necrosis factor receptor type 1 (TNFR1) in inflammation and fibrosis induced
by carbon tetrachloride (CCl4), and in post-injury liver regeneration including a GFP/CCl4 model developed as a liver repair model by bone marrow cell (BMC) infusion, was investigated. In mice in which TNFR1 was
suppressed by antagonist administration or by knockout, liver fibrosis induced by CCl4 was significantly decreased. In these mice, intrahepatic macrophage infiltration and TGF-β1 expression were reduced and stellate
cell activity was decreased; however, expression of MMP-9 was also decreased. With GFP-positive BMC (TNFR1 wild-type, WT)
infusion in these mice, fibrosis proliferation, including host endogenous intrahepatic macrophage infiltration, TGF-β1 expression
and stellate cell activity, increased significantly. There was no significant increase of MMP-9 expression. In this study,
TNFR1 in hosts had a promoting effect on CCl4-induced hepatotoxicity and fibrosis, whereas BMC infusion in TNFR1 knockout mice enhanced host-derived intrahepatic inflammation
and fibrosis proliferation. These findings differed from those in WT recipient mice, in which improvement in inflammation
and fibrosis with BMC infusion had previously been reported. TNFR1-mediated signaling might be important to induce the improvement
of liver fibrosis by bone marrow cell infusion. 相似文献
7.
Xirong Li Ping Feng Jianfeng Ou Zhijuan Luo Ping Dai Dapeng Wei Chongjie Zhang 《Biochemistry. Biokhimii?a》2009,74(9):979-985
Dermatopontin (DPT) was recently found as a downstream target of vitamin D receptor, which is a key molecule in the 1,25-dihydroxy-vitamin
D3 anti-hepatoma proliferation pathway. MCTx-1 from Millepora, a homolog of DPT, is identified as a cytotoxin towards leukemia cells. The aim of this study was to analyze DPT expression
in hepatocellular carcinoma (HCC) based on the analysis for DPT gene in normal tissues in order to estimate its function in
the progression of HCC. DPT mRNA expression was analyzed in normal tissues and HCC cell lines by RT-PCR, and in HCC tissue
by RT-PCR and real-time PCR. Its protein was examined in HCC tissues by Western blot and immunohistochemistry assays. Meanwhile,
transforming growth factor-β1 (TGF-β1) that is closely associated with HCC and DPT was observed by immunohistochemistry in
HCC tissues. The results showed that DPT mRNA was strongly expressed in human fetal and adult liver, kidney, and spleen, weakly
in ovary and heart, and absent in other tissues and HCC cell lines examined. Its mRNA was significantly downregulated in HCC
tissues, while its protein was weakly expressed in tumor compared with non-tumor. DPT is located mainly in the cytoplasm of
several cell types in the liver; it has been identified also in the extra-cellular matrix of the skin. TGF-β1 was observed
in extensive tumor tissue of HCC. This fact suggests that DPT can play various roles in different tissues and might be a molecule
related to carcinogenesis and the progression of HCC via possible interaction with TGF-β1 and other potential mechanisms. 相似文献
8.
El-Bassiouni NE Nosseir MM Madkour ME Zoheiry MM Bekheit IW Ibrahim RA Ibrahim IM El Bassiouny AE 《Molecular biology reports》2012,39(6):6843-6850
Detection and follow up of fibrogenesis in chronic hepatitis C (CHC) is mandatory for early treatment and risk stratification.
The current study included 120 patients with CHC, of whom 30 had liver cirrhosis (LC) and 30 had hepatocellular carcinoma
(HCC). 15 wedge liver biopsies, taken during laparoscopic cholecystectomy, were included as normal controls. Cases were subjected
to laboratory investigations, serologic markers for viral hepatitis and assessment of circulating levels of hyaluronic acid
(HA) and platelet-derived growth factor (PDGF). Immunohistochemical expression of connective tissue growth factor (CTGF),
PDGF and transforming growth factor-β1 (TGF-β1) was also carried out. A significant increase (p < 0.01) in serum HA was noticed in CHC, LC and HCC compared to controls. Although, a significant decrease in serum PDGF was
detected in CHC and LC compared to controls, HCC values were comparable. A significant up-regulation of CTGF was detected
in CHC, LC and HCC (p < 0.01) in contrast to its limited mild expression in normal livers. Intense PDGF positive staining was noticed in CHC, LC
and HCC compared to scattered faint expression in controls. The significant expression and marked intensity of PDGF staining
matched the progress to tumorigenesis. A positive TGF-β1 immunostaining was also noticed in CHC, LC and HCC. An intense and
extensive cytoplasmic expression of TGF-β1 was encountered in patients with LC revealing that CTGF, PDGF and TGF-β1 act synergistically
in LC. Data revealed that HA and CTGF may be implicated as important diagnostic parameters for assessment of hepatic fibrosis
and PDGF for monitoring malignant transformation in CHC. 相似文献
9.
Thy-1 is expressed in myofibroblasts but not found in hepatic stellate cells following liver injury 总被引:1,自引:1,他引:0
Thy-1 (CD90) is an adhesion molecule induced in fibroblast populations associated with wound healing and fibrosis. In this
study the question whether Thy-1-gene-expression can be induced in hepatic stellate cells (HSC) in vivo, under conditions
of liver injury or liver regeneration was addressed. Acute and chronic rat liver injury was induced by the administration
of CCl4. For comparison, cirrhotic human liver, and rat 67% partial hepatectomy (PH) was studied as well. Thy-1-gene-expression was
examined also in isolated human liver myofibroblasts. Thy-1-mRNA expression was significantly upregulated in chronic liver
injury. Thy-1+ cells were detected in the periportal area of rat liver specimens in normal-, injured- and regenerative-conditions. In chronic
human and rat liver injury, Thy-1+ cells were located predominantly in scar tissue. In the pericentral necrotic zone after CCl4-treatment, no induction of Thy-1 was found. Gremlin and Thy-1 showed comparable localization in the periportal areas. Thy-1
was not detected in either normal or capillarized sinusoids, in isolated rat HSC, and was neither inducible by inflammatory
cytokines in isolated HSC, nor upregulated in treated myofibroblasts. Based upon these data Thy-1 is not a marker of “activated”
sinusoidal HSC, but it is a marker of “activated” (myo)fibroblasts found in portal areas and in scar tissue.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
10.
11.
Antagonism of Transforming Growth Factor-Β Signaling Inhibits
Fibrosis-Related Genes 总被引:4,自引:0,他引:4
In the fibrotic process, the transforming growth factor-β1 (TGF-β1)/Smad3 (Sma- and Mad-related protein␣3) signaling plays
a central role. To screen for antagonists of TGF-β1/Smad3 signaling and to investigate their effects on the genes related
to fibrosis, we construct a molecular model with a luciferase reporter gene. Results showed that both SB-431542 [4-(5-benzo[1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide] and small interference RNA (siRNA) against Smad3 could dose-dependently suppress the reporter gene.
More importantly, they both significantly inhibited the expression of plasminogen activator inhibitor-type 1 (PAI-1) and type
I collagenα1 (Col Iα1) genes in rat hepatic stellate cells. Thus, SB-431542 and Smad3/siRNA may be potential therapeutics
for fibrosis. 相似文献
12.
Kuang PP Goldstein RH Liu Y Rishikof DC Jean JC Joyce-Brady M 《American journal of physiology. Lung cellular and molecular physiology》2003,285(5):L1147-L1152
Fibulin-5, previously known as DANCE and EVEC, is a secreted extracellular matrix protein that functions as a scaffold for elastin fiber assembly and as a ligand for integrins alphavbeta3, alphavbeta5, and alpha9beta1. Fibulin-5 is developmentally regulated in the lung, and lung air space enlargement develops in mice deficient in fibulin-5. Fibulin-5 is also induced in adult lung following lung injury by hyperoxia. To further examine the role of fibulin-5 during repair of lung injury, we assessed fibulin-5 expression during elastase-induced emphysema in C57/b mice. Mice were treated with either saline or elastase via the trachea, and the lung was examined 20 days after treatment. Fibulin-5 mRNA was induced almost fourfold, whereas elastin mRNA was minimally elevated. Immunohistochemistry studies showed that fibulin-5 was induced in cells within the alveolar wall following elastase treatment. Western analysis demonstrates that fibulin-5 was strongly expressed in isolated primary lung interstitial fibroblasts. Fibulin-5 protein was localized to the fibroblast cell layer in culture, and brief elastase treatment degraded the protein. Intact fibulin-5 did not accumulate in the culture media. Treatment of fibroblasts with the proinflammatory cytokine interleukin-1beta abolished fibulin-5 mRNA expression. Our results indicate that fibulin-5 is coordinately expressed and regulated with elastin in lung fibroblasts and may serve a key role during lung injury and repair. 相似文献
13.
Yoshida M Nishikawa Y Omori Y Yoshioka T Tokairin T McCourt P Enomoto K 《Cell and tissue research》2007,329(2):273-282
Embryonic development of the liver is closely associated with vascular organization. However, little is known about the mechanisms
of vascular differentiation during liver development. Our previous study showed that the maturation of sinusoidal endothelial
cells (SECs) occurred during embryonic day 13.0 (E13.0) to E15.0. To improve our understanding of SEC differentiation, we
examined here the expression of maturation markers, SE-1 and stabilin-2, in fetal livers and also attempted to establish an
in vitro SEC differentiation system by culturing E13.5 fetal liver cells. Immunohistochemical examination of SE-1 and stabilin-2
expression during fetal rat liver development revealed that these differentiation markers were co-expressed in SECs in the
late stage of liver development, although stabilin-2 was expressed in almost all vascular endothelial cells in the early stage.
Liver cells from the E13.5 rat fetus were cultured in EBM-2 medium containing vascular endothelial growth factor (VEGF), transforming
growth factor β1 (TGF-β1) and VEGF plus SB-431542 (an inhibitor of the TGF-β1 receptor, activin receptor-like kinase 5 [ALK-5]).
In vitro SEC differentiation, as indicated by the appearance of cells co-expressing SE-1 and stabilin-2 and of cells with
cytoplasmic fenestrae in endothelial sheets, was induced by the addition of both VEGF and SB-431542, an inhibitor of the phosphorylation
of Smad2/3 but not that of Smad1/5/8 in the cultured cells. These results indicate for the first time that both VEGF signaling
and the blocking of the ALK-5-Smad2/3 signal pathway are important for the fetal differentiation of SECs. 相似文献
14.
Amanzada A Malik IA Nischwitz M Sultan S Naz N Ramadori G 《Histochemistry and cell biology》2011,135(3):305-315
Myeloperoxidase (MPO) is involved in acute and chronic inflammatory diseases. The source of MPO in acute liver diseases is
still a matter of debate. Therefore, we analysed MPO-gene expression on sections from normal and acutely damaged [carbon tetrachloride-(CCl4) or whole liver γ-Irradiation] rat liver by immunohistochemistry, real time PCR and Western blot analysis of total RNA and protein. Also total
RNA and protein from isolated Kupffer cells, hepatic stellate cells, Hepatocytes, endothelial cells and neutrophil granulocytes
(NG) was analysed by real time PCR and Western blot, respectively. Sections of acutely injured human liver were prepared for
MPO and CD68 immunofluorescence double staining. In normal rat liver MPO was detected immunohistochemically and by immunofluorescence
double staining only in single NG. No MPO was detected in isolated parenchymal and non-parenchymal cell populations of the
normal rat liver. In acutely damaged rat liver mRNA of MPO increased 2.8-fold at 24 h after administration of CCl4 and 3.3-fold at 3 h after γ-Irradiation and MPO was detected by immunofluorescence double staining only in elastase (NE) positive NGs but not in macrophages
(ED1 or CD68 positive cells). Our results demonstrate that, increased expression of MPO in damaged rat and human liver is
due to recruited elastase positive NGs. 相似文献
15.
Dirk Pohlers Andreas Beyer Dirk Koczan Thomas Wilhelm Hans-Jürgen Thiesen Raimund W Kinne 《Arthritis research & therapy》2007,9(3):R59
Genome-wide gene expression was comparatively investigated in early-passage rheumatoid arthritis (RA) and osteoarthritis (OA)
synovial fibroblasts (SFBs; n = 6 each) using oligonucleotide microarrays; mRNA/protein data were validated by quantitative PCR (qPCR) and western blotting
and immunohistochemistry, respectively. Gene set enrichment analysis (GSEA) of the microarray data suggested constitutive
upregulation of components of the transforming growth factor (TGF)-β pathway in RA SFBs, with 2 hits in the top 30 regulated
pathways. The growth factor TGF-β1, its receptor TGFBR1, the TGF-β binding proteins LTBP1/2, the TGF-β-releasing thrombospondin
1 (THBS1), the negative effector SkiL, and the smad-associated molecule SARA were upregulated in RA SFBs compared to OA SFBs,
whereas TGF-β2 was downregulated. Upregulation of TGF-β1 and THBS1 mRNA (both positively correlated with clinical markers
of disease activity/severity) and downregulation of TGF-β2 mRNA in RA SFBs were confirmed by qPCR. TGFBR1 mRNA (only numerically
upregulated in RA SFBs) and SkiL mRNA were not differentially expressed. At the protein level, TGF-β1 showed a slightly higher
expression, and the signal-transducing TGFBR1 and the TGF-β-activating THBS1 a significantly higher expression in RA SFBs
than in OA SFBs. Consistent with the upregulated TGF-β pathway in RA SFBs, stimulation with TGF-β1 resulted in a significantly
enhanced expression of matrix-metalloproteinase (MMP)-11 mRNA and protein in RA SFBs, but not in OA SFBs. In conclusion, RA
SFBs show broad, constitutive alterations of the TGF-β pathway. The abundance of TGF-β, in conjunction with an augmented mRNA
and/or protein expression of TGF-β-releasing THBS1 and TGFBR1, suggests a pathogenetic role of TGF-β-induced effects on SFBs
in RA, for example, the augmentation of MMP-mediated matrix degradation/remodeling. 相似文献
16.
Systematic studies on hepatic stellate cells and myofibroblasts have so far mainly focused on cells located in the perisinusoidal space of Disse, the so-called littoral compartment. Here, these cells play a key role for intralobular fibrogenesis and sinusoidal capillarization. However, advanced hepatic fibrosis and cirrhosis are characterized by portal tract fibrosis and septal fibrosis, thus involving cells outside the perisinusoidal space. To study the question as to whether hepatic stellate cells occur and are expanded in an extralittoral (extrasinusoidal) compartment in cirrhogenesis, we systematically analyzed the distribution and density of desminreactive stellate cells in a rat model of hepatic fibrosis. Fibrosis and remodeling of the liver were induced by bile duct ligation, and stellate cells were identified by single and double immunohistochemistry. We can show that desmin-reactive cells are reproducibly detectable in extralittoral compartments of the normal and fibrotic rat liver. Periductular extralittoral stellate cells are significantly more frequent in cirrhosis, indicating that extralittoral stellate cells expand in concert with proliferating ductules. The findings suggest that ductular proliferation thought to represent a pacemaker of hepatic remodeling is accompanied by a population of cells exhibiting the same phenotype as perisinusoidal stellate cells. 相似文献
17.
Matrix and TGF-β-related gene expression during human dental pulp stem cell (DPSC) mineralization 总被引:2,自引:0,他引:2
Liu J Jin T Chang S Ritchie HH Smith AJ Clarkson BH 《In vitro cellular & developmental biology. Animal》2007,43(3-4):120-128
We have recently reported the induction of dental pulp stem cells (DPSCs) into dentin-secreting odontoblast-like cells after
stimulation by isolated dentin matrix components, thus mimicking the nature of tissue regeneration seen after tooth disease
and injury. After confluency, the cells were further cultured for 21 d in the 10% fetal bovine serum (FBS) Dulbecco’s modified
Eagle’s medium (DMEM) (control), and in this medium, with the addition of dentin extract (DE) and the mineralization supplement
(MS) of ascorbic acid and β-glycerophosphate (treatment). To identify genes associated with this process, specimens were analyzed
with a HG-U133A human gene chip and Arrayassist software. A total of 425 genes, among them 21 matrix and eight TGF-β-related
genes, were either up- or downregulated in the experimental group in which the cells showed odontoblast-like differentiation
and mineralization. Expression of selected genes was further confirmed by real-time polymerase chain reaction (PCR) analysis.
Of the extracellular matrix (ECM)-related genes, two types of collagen genes were upregulated and seven others downregulated.
Other ECM-related genes, for example fibulin-1, tenascin C, and particularly thrombospondin 1, were upregulated, and fibulin-2
was downregulated. Most noticeably, the matrix metalloproteinase 1 was induced by the treatment. In the TGF-β superfamily,
upregulation of the type II receptor, endoglin, and growth/differentiation factor 5 was coordinated with the downregulation
of activin A, TGF-β2, and TGF-β1 itself. This study identifies the matrix and TGF-β-related gene profiles during the DPSC
cell mineralization in which several genes are reported for the first time to be associated with this process, thus greatly
expanding our molecular knowledge of the induced disease repair process. 相似文献
18.
Hye-Young Hong Woo-Kwang Jeon Eun-Jin Bae Shin-Tae Kim Ho-Jae Lee Seong-Jin Kim Byung-Chul Kim 《Molecules and cells》2010,29(3):305-309
The expression of 14-3-3 proteins is dysregulated in various types of cancer. This study was undertaken to investigate the
effects of 14-3-3 ζ and 14-3-3 σ on cell growth inhibition mediated by transforming growth factor-beta 1 (TGF-β1). Mouse mammary
epithelial cells (Eph4) that are transformed with oncogenic c-H-Ras (EpRas) and no longer sensitive to TGF-β1-mediated growth
inhibition displayed increased expression of 14-3-3 ζ and decreased expression of 14-3-3 σ compared with parental Eph4 cells.
Using small interfering RNA-mediated knockdown and overexpression of 14-3-3 σ or 14-3-3 ζ, we showed that 14-3-3 σ is required
for TGF-β1-mediated growth inhibition whereas 14-3-3 ζ negatively modulates this growth inhibitory response. Notably, overexpression
of 14-3-3 ζ increased the level of Smad3 protein that is phosphorylated at linker regions and cannot mediate the TGF-β1 growth
inhibitory response. Consistent with this finding, mutation of the 14-3-3 ζ phosphorylation sites in Smad3 markedly reduced
the 14-3-3 ζ-mediated inhibition of TGF-β1-induced p15 promoter-reporter activity and cell cycle arrest, suggesting that these
residues are critical targets of 14-3-3 ζ in the suppression of TGF-β1-mediated growth. Taken together, our findings indicate
that dysregulation of 14-3-3 σ or 14-3-3 ζ contributes to TGF-β1 resistance in cancer cells. 相似文献
19.
Transforming growth factor-β (TGF-β) is a pleiotropic cytokine that plays a critical role in modulating immune response and
inflammation. We have investigated the effects of TGF-β1 on the expression of type IV collagenases, matrix metalloproteinase
(MMP)-2 and MMP-9, in mouse peritoneal macrophages. TGF-β1 alone enhanced the secretion of MMP-9, while it blocked lipopolysaccharide
(LPS)-stimulated MMP-9 production. We have shown that this biphasic effect of TGF-β1 is exerted at the mRNA level of the MMP-9
gene. Although TGF-β1 increased both basal and LPS-induced MMP-2 production at the protein and mRNA levels, the extent of
the increase was smaller in LPS-activated macrophages than in control macrophages. The expression of type I and type II receptors
for TGF-β was significantly decreased upon activation, suggesting that the lesser effect of TGF-β1 in activated macrophages
may result from the decreased expression of TGF-β receptors. In addition, the expression of endogenous TGF-β1 mRNA was decreased
significantly in activated macrophages. These findings suggest that activated macrophages not only produce less TGF-β1, but
also respond less well to TGF-β to provide for inflammatory response. 相似文献
20.
A milk growth factor extract reduces chemotherapeutic drug toxicity in epithelial cells in vitro 总被引:1,自引:0,他引:1
Summary Transforming growth factor-β (TGF-β) and insulin-like growth factor (IGF-I) can attenuate drug-induced cell death in epithelial
cells. Since milk whey contains a mixture of these and other growth factors, we evaluated mitogenic bovine whey extract (MBWE)
for protective activity against chemotherapy drug damage in cultured epithelial cells (mink lung, Mu1.Lu). Etoposide and vinblastine
reduced cell survival by up to 90%. This was attenuated by the addition of MBWE before and during drug exposure, but not following
drug removal. MBWE was compared with individual growth factors known to be present in the mixture. IGF-I and platelet-derived
growth factor were ineffective, whereas TGF-β2 induced growth inhibition and cell survival, with a maximum response at 3 ng/ml.
TGF-β2 bioactivity was also demonstrated by showing that acidification of MBWE (A-MBWE), to activate TGF-β2, enhanced its
growth inhibitory and chemoprotective activities 60- and 12-fold, respectively. However, MBWE contained additional protective
factors. When TGF-β2 and the MBWE preparations were compared, on the basis of growth inhibition equivalents, MBWE protected
cells against drug toxicity at concentrations an order of magnitude lower than with TGF-β2 or A-MBWE. Immunoneutralization
of the TGF-β present in MBWE and A-MBWE eliminated all growth inhibitory activity but not all cell survival activity. We conclude
that the MBWE preparations are cytoprotective against two chemotherapy drugs when added before and during drug exposure. TGF-β
contributes to this activity, but the extracts contain other factors that promote the survival of epithelial cells after chemotherapy
drug exposure. 相似文献