scholarly journals Osteoprotegerin expression in liver is induced by IL-13 through TGF-β

2020 ◽  
Author(s):  
Adhyatmika Adhyatmika ◽  
Kurnia SS Putri ◽  
Emilia Gore ◽  
Keri Mangnus ◽  
Catharina Reker-Smit ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Liver Tissue ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Experimental Models ◽  
Wild Type ◽  
3T3 Fibroblasts ◽  
Liver Slices ◽  
Deficient Mice

Backgrounds: Osteoprotegerin (OPG) is a profibrotic mediator produced by myofibroblasts under influence of transforming growth factor β (TGFβ). Its expression in experimental models of liver fibrosis correlates well with disease severity and treatment responses. The regulation of OPG in liver tissue is largely unknown and we therefore set out to elucidate which growth factors/interleukins associated with fibrosis induce OPG and through which pathways. Methods: Precision-cut liver slices of wild type and STAT6-deficient mice and 3T3 fibroblasts were used to investigate the effects of TGFβ, interleukin (IL) 13 (IL13), IL1β, and platelet-derived growth factor BB (PDGF-BB) on expression of OPG. Results: In addition to TGFβ, only IL13 and not PDGF-BB or IL1β could induce OPG expression in 3T3 fibroblasts and liver slices. This IL13-dependent induction was not shown in liver slices of STAT6-deficient mice and when wild type slices were cotreated with TGFβ receptor 1 kinase inhibitor galunisertib, STAT6 inhibitor AS1517499, or AP1 inhibitor T5224. This suggests that the OPG-inducing effect of IL13 is mediated through IL13 receptor α1-activation and subsequent STAT6-dependent upregulation of IL13 receptor α2, which in turn activates AP1 and induces production of TGFβ and subsequent production of OPG. Conclusion: We have shown that IL13 induces OPG release by liver tissue through a TGFβ-dependent pathway involving both the α1 and the α2 receptor of IL13 and transcription factors STAT6 and AP1. OPG may therefore be a novel target for the treatment liver fibrosis as it is mechanistically linked to two important regulators of fibrosis in liver, namely IL13 and TGFβ1.

scholarly journals Syndecan-4 Deficiency Leads to High Mortality of Lipopolysaccharide-injected Mice

2001 ◽  
Vol 276 (50) ◽  
pp. 47483-47488 ◽  
Author(s):  
Kazuhiro Ishiguro ◽  
Kenji Kadomatsu ◽  
Tetsuhito Kojima ◽  
Hisako Muramatsu ◽  
Mitsunori Iwase ◽  
...  
Keyword(s):  
Growth Factor ◽  
High Mortality ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Endotoxin Shock ◽  
Left Ventricular ◽  
Wild Type ◽  
In The Wild ◽  
Deficient Mice ◽  
Fractional Shortening

Syndecan-4 is a transmembrane heparan sulfate proteoglycan belonging to the syndecan family. Following intraperitoneal injection of lipopolysaccharide (LPS), syndecan-4-deficient mice exhibited high mortality compared with wild-type controls. Severe endotoxin shock was observed in the deficient mice: systolic blood pressure and left ventricular fractional shortening were lower in the deficient mice than in the wild-type controls 9 h after LPS injection. Although histological examinations revealed no apparent differences between two groups, the plasma level of interleukin (IL)-1β was higher in the deficient mice than in the wild-type controls 9 h after LPS injection. Consistent with the regulatory roles of syndecan-4, its expression in monocytes and endothelial cells of microvasculature increased in the wild-type mice after LPS administration. Although IL-1β was produced to the same extent by macrophages from syndecan-4-deficient and wild-type mice after LPS stimulation, inhibition of its production by transforming growth factor-β1 was impaired in the syndecan-4-deficient macrophages. These results indicate that syndecan-4 could be involved in prevention of endotoxin shock, at least partly through the inhibitory action of transforming growth factor-β1 on IL-1β production.

Imatinib mesylate (STI-571) attenuates liver fibrosis development in rats

2005 ◽  
Vol 288 (5) ◽  
pp. G907-G913 ◽  
Author(s):  
Hitoshi Yoshiji ◽  
Ryuichi Noguchi ◽  
Shigeki Kuriyama ◽  
Yasuhide Ikenaka ◽  
Junichi Yoshii ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Imatinib Mesylate ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
Smooth Muscle Actin ◽  
In Vitro Study ◽  
Dependent Manner ◽  
Sti 571

It is widely recognized that activated hepatic stellate cells (HSC) play a pivotal role in development of liver fibrosis. A platelet-derived growth factor (PDGF) is the most potent mitogen for HSC. The aim of this study was to examine the effect of imatinib mesylate (STI-571, Gleevec), a clinically used PDGF receptor (PDGFR) tyrosine kinase inhibitor, on development of experimental liver fibrosis. The rat model of pig serum-induced hepatic fibrosis was used to assess the effect of daily oral administration of STI-571 on the indexes of fibrosis. STI-571 markedly attenuated development of liver fibrosis and hepatic hydroxyproline and serum fibrosis markers. The number of α-smooth muscle actin-positive cells and mRNA expression of α2-(I)-procollagen, tissue inhibitor of metalloproteinases-1, and transforming growth factor-β were also significantly suppressed by STI-571. Our in vitro study showed that STI-571 markedly attenuated PDGF-BB-induced proliferation and migration and α-SMA and α2-(I)-procollagen mRNA of activated HSC in a dose-dependent manner. STI-571 also significantly attenuated PDGF-BB-induced phosphorylation of PDGFR-β, MEK1/2, and Akt in activated HSC. Because STI-571 is widely used in clinical practice, it may provide an effective new strategy for antifibrosis therapy.

scholarly journals The Effect of Curcumin on Regression of Liver Fibrosis through Decreased Expression of Transforming Growth Factor-β1 (TGF-β1)

2019 ◽  
Vol 11 (1) ◽  
pp. 52-8 ◽  
Author(s):  
Supriono Supriono ◽  
Asri Nugraheni ◽  
Handono Kalim ◽  
Mudjiwijono Handaru Eko
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Liver Tissue ◽  
Transforming Growth Factor ◽  
Positive Control ◽  
Negative Control ◽  
Control Groups ◽  
Treatment Groups ◽  
Tgf Β1

BACKGROUND: Transforming growth factor (TGF)-β1 has a pivotal role in liver fibrogenesis. Curcumin effectively prevent the progression of liver fibrosis through inhibition of TGF-β1/Sma and drosophila MAD (Smad) signaling pathway. However, the role of curcumin in the regression of liver fibrosis is still unknown. This study investigated the role of curcumin and TGF-β1 in liver fibrosis regression.METHODS: An experimental Wistar rat model included 6 treatment groups as well as positive and negative control groups. The treatment and positive control groups were injected with carbon tetrachlorid (CCl4) for 9 weeks to induce liver fibrosis. After cessation of injection, 3 of the treatment groups were given curcumin and 3 were given carboxymethylcellulose (CMC) for 2, 5 and 9 weeks, while the positive control was untreated. The negative control was injected with normal saline. TGF-β1 liver tissue levels were analyzed by ELISA, while the TGF-β1 expression in liver cells was analyzed by immunohistochemical assay. The metavir score was used to assess the degree of liver fibrosis. Values of p<0.05 were regarded as statistically significant.RESULTS: Nine weeks of CCl4 injection induced liver fibrosis (metavir F3); and significantly increased TGF-β1 levels and expression in tissues (p=0.00, p=0.021, respectively). Curcumin administration decreased levels and expression of TGF-β1 in the liver and accelerated regression of liver fibrosis. There was a significant correlation between duration of administration of curcumin with an expression of TGF-β1 in the liver tissue (r=0.87; p<0.00).CONCLUSION: Curcumin accelerates regression of liver fibrosis, likely through decreasing of TGF-β1 expression in the liver.KEYWORDS: curcumin, TGF-β1, liver fibrosis regression, CCl4, animal model

Transforming Growth Factor-β Activation is Diminished in Fibrosis-Resistant Neutrophil Elastase-Deficient Mice

2003 ◽  
Vol 104 (s49) ◽  
pp. 58P-59P
Author(s):  
Felix Chua ◽  
Sarah E. Dunsmore ◽  
Peter Clingen ◽  
Anthony W. Segal ◽  
Jurgen Roes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Neutrophil Elastase ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Deficient Mice

Piceatannol increases the expression of hepatocyte growth factor and IL-10 thereby protecting hepatocytes in thioacetamide-induced liver fibrosis

2016 ◽  
Vol 94 (7) ◽  
pp. 779-787 ◽  
Author(s):  
Hazem Abd-Elgawad ◽  
Nashwa Abu-Elsaad ◽  
Amr El-Karef ◽  
Tarek Ibrahim
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Liver Function ◽  
Hepatocyte Growth Factor ◽  
Transforming Growth Factor ◽  
Histopathological Examination ◽  
Smooth Muscle Actin ◽  
Interleukin 10 ◽  
Hepatocyte Growth ◽  
Inflammatory Effect

Piceatannol is a polyphenolic analog of resveratrol that selectively inhibits the non-receptor tyrosine kinase-Syk. This study investigates the potential ability of piceatannol to attenuate liver fibrosis and protect hepatocytes from injury. Thioacetamide was injected in adult male mice (100 mg/kg, i.p., 3 times/week) for 8 weeks. Piceatannol (1 or 5 mg/kg per day) was administered by oral gavage during the last 4 weeks. Liver function biomarkers, tissue malondialdehyde (MDA), cytokeratin-18 (CK18), hepatocyte growth factor (HGF), and interleukin-10 (IL-10) were measured. Necroinflammation, fibrosis, expression of transforming growth factor (TGF)-β1, and α-smooth muscle actin (SMA) were scored by histopathological examination and immunohistochemistry. Obtained results showed ability of piceatannol (1 mg/kg) to restore liver function and reduce inflammation. It significantly (p < 0.001) reduced MDA, CK18, TGF-β1, and α-SMA expression, and increased HGF and IL-10. It can be concluded that piceatannol at low dose can inhibit TGF-β1 induced hepatocytes apoptosis and exerts an anti-inflammatory effect attenuating fibrosis progression.

Elevated transforming growth factor β2 enhances apoptosis and contributes to abnormal outflow tract and aortic sac development in retinoic X receptor α knockout embryos

Development ◽  
2002 ◽  
Vol 129 (3) ◽  
pp. 733-746
Author(s):  
Steven W. Kubalak ◽  
D. Reneé Hutson ◽  
Karen K. Scott ◽  
Rebecca A. Shannon
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Qualitative Difference ◽  
Outflow Tract ◽  
Brdu Incorporation ◽  
Wild Type ◽  
Endocardial Cushions ◽  
Precise Integration ◽  
Partial Restoration ◽  
Transforming Growth Factor Β2

Septation of the single tubular embryonic outflow tract into two outlet segments in the heart requires the precise integration of proliferation, differentiation and apoptosis during remodeling. Lack of proper coordination between these processes would result in a variety of congenital cardiac defects such as those seen in the retinoid X receptor α knockout (Rxra–/–) mouse. Rxra–/– embryos exhibit lethality between embryonic day (E) 13.5 and 15.5 and harbor a variety of conotruncal and aortic sac defects making it an excellent system to investigate the molecular and morphogenic causes of these cardiac malformations. At E12.5, before the embryonic lethality, we found no qualitative difference between wild type and Rxra–/– proliferation (BrdU incorporation) in outflow tract cushion tissue but a significant increase in apoptosis as assessed by both TUNEL labeling in paraffin sections and caspase activity in trypsin-dispersed hearts. Additionally, E12.5 embryos demonstrated elevated levels of transforming growth factor β2 (TGFβ2) protein in multiple cell lineages in the heart. Using a whole-mouse-embryo culture system, wild-type E11.5 embryos treated with TGFβ2 protein for 24 hours displayed enhanced apoptosis in both the sinistroventralconal cushion and dextrodorsalconal cushion in a manner analogous to that observed in the Rxra–/–. TGFβ2 protein treatment also led to malformations in both the outflow tract and aortic sac. Importantly, Rxra–/– embryos that were heterozygous for a null mutation in the Tgfb2 allele exhibited a partial restoration of the elevated apoptosis and of the malformations. This was evident at both E12.5 and E13.5. The data suggests that elevated levels of TGFβ2 can (1) contribute to abnormal outflow tract morphogenesis by enhancing apoptosis in the endocardial cushions and (2) promote aortic sac malformations by interfering with the normal development of the aorticopulmonary septum.

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