JAK-STAT signaling in hepatic fibrosis

Mair, Markus; Blaas, Leander; Österreicher, Christoph H.; Casanova, Emilio; Eferl, Robert

doi:10.2741/3886

Cited by 57 publications

(49 citation statements)

References 168 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activated STATs translocate into nucleus and serve as transcription factors for multiple downstream target genes. In normal cells, liganddependent activation of STATs is transient, but in liver cancer, STAT proteins are often constitutively activated in primary tumors (Calvisi et al 2006;Kusaba et al 2007;Mair et al 2011). This constitutive activation is because of the inactivation of specific STAT inhibitors, SOCSs (suppressors of cytokine signaling) which are inactivated by DNA hypermethylation in liver and other cancers (Yoshikawa et al 2001;Niwa et al 2005).…”

Section: Jak/stat Pathwaymentioning

confidence: 99%

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

Qiu

Xie

et al. 2014

Cytotechnology

View full text Add to dashboard Cite

As cellular models for in vitro liver cancer and toxicity studies, HepG2 and Hep3B are the two most frequently used liver cancer cell lines. Because of their similarities they are often treated as the same in experimental studies. However, there are many differences that have been largely over-sighted or ignored between them. In this review, we summarize the differences between HepG2 and Hep3B cell lines that can be found in the literature based on PubMed search. We particularly focus on the differential gene expression, differential drug responses (chemosensitivity, cell cycle and growth inhibition, and gene induction), signaling pathways associated with these differences, as well as the factors in governing these differences between HepG2 and Hep3B cell lines. Based on our analyses of the available data, we suggest that neither HBx nor p53 may be the crucial factor to determine the differences between HepG2 and Hep3B cell lines although HBx regulates the expression of the majority of genes that are differentially expressed between HepG2 and Hep3B. Instead, the different maturation stages in cancer development of the original specimen between HepG2 and Hep3B may be responsible for the differences between them. This review provides insight into the molecular mechanisms underlying the differences between HepG2 and Hep3B and help investigators especially the beginners in the areas of liver cancer research and drug metabolism to fully understand, and thus better use and interpret the data from these two cell lines in their studies.

show abstract

Section: Jak/stat Pathwaymentioning

confidence: 99%

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

Qiu

Xie

et al. 2014

Cytotechnology

View full text Add to dashboard Cite

show abstract

“…28,29 It has been also proposed that IL-10 is able to inhibit HSC activation and to promote their apoptosis during liver fibrogenesis. 28,29 Beside its well-known interference with the pro-inflammatory cytokine signaling pathways, 30,31 SOCS3 has been found to negatively regulate fibrogenesis in the liver 32,33 and to suppress the signaling molecule STAT3, which activates TGF-b transcription. 32 Our data demonstrate that the hepatic expression of all these molecules are deeply affected in cirrhosis leading to a pro-fibrogenic environment, which is fully counteracted by CB1 receptor antagonism.…”

Section: Endocannabinoids and Liver Cirrhosismentioning

confidence: 99%

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

Giannone

Baldassarre

Domenicali

et al. 2012

Laboratory Investigation

View full text Add to dashboard Cite

The endocannabinoid system is involved in the pathogenesis of liver fibrosis. Although many substances have been proved to reduce fibrosis in experimental models of chronic liver injury, most of them appear to be effective only if given as a prophylactic or early treatment. This study aimed to explore the effect of pharmacological antagonism of the endocannabinoid cannabinoid type 1 (CB1) receptor started after the stage of full-blown cirrhosis had been reached. Wistar-Han rats with carbon tetrachloride (CCl 4 )-induced cirrhosis were randomized to receive the CB1 receptor antagonist Rimonabant (10 mg/kg/day) or the vehicle for 2 weeks. Age-matched healthy rats served as controls. Liver fibrosis was assessed using Sirius red staining, hydroxyproline concentration and a-smooth muscle actin expression. Hepatic gene expression of mediators of fibrogenesis and inflammation were evaluated by real-time PCR. We also assessed the hepatic expression of CB1 and CB2 receptors and that of the enzymes implicated in the endocannabinoid metabolism. Fibrosis was significantly reduced in rats treated with Rimonabant compared with rats receiving the vehicle. CB1 receptor antagonism limited the gene upregulation of fibrogenic and inflammatory mediators occurring in untreated cirrhotic rats. CB1 and CB2 receptor expression was increased in cirrhotic animals. Interestingly, pharmacological CB1 receptor antagonism was associated with a further induction of the CB2 receptor expression. Regression of fibrosis can be achieved by pharmacological blockade of the CB1 receptor even when started in an advanced stage of the disease. This effect is associated with the suppression of pro-fibrogenic and inflammatory mediators and may have been indirectly favoured by the induction of CB2 receptor expression.

show abstract

“…The STAT signaling pathway has been shown to be an integral part of the responses of the myocardium to various cardiac insults, including myocardial infarction, oxidative damage, myocarditis, hypertrophy and remodeling, in addition to having a prominent role in cardioprotective therapies such as ischemic preconditioning [9]. The STAT pathway also has been documented to take a part in the pathogenesis of liver fibrosis, pulmonary fibrosis and renal fibrosis [10,11,12], as an especially important mechanism for renal fibrosis by which hyperglycemia contributes to renal damage [13]. These results predict that STAT may have a role in the process of myocardial fibrosis induced by HG.…”

Section: Introductionmentioning

confidence: 99%

STAT1/3 and ERK1/2 Synergistically Regulate Cardiac Fibrosis Induced by High Glucose

Dai

Cui

Zhu

et al. 2013

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Hyperglycaemia promotes the proliferation of cardiac fibroblasts (CFs) and collagen synthesis in CFs. However, the molecular mechanism underlying the effects of HG on proliferation and collagen synthesis of CF, is not completely understood. Objectives: The objectives of the present study were to determine whether the STAT proteins has a functional role in high glucose-induced proliferation of CFs and collagen synthesis in vitro and whether the STAT signaling pathway and MAPK signaling pathway have synergetical effects on high glucose-mediated cardiac fibroblasts proliferation and collagen synthesis. Methods: Rat CFs were cultured in Dulbecco's modified Eagle's medium, supplemented with 5.5 or 25 mmol/L D-glucose, in the presence of absence of STAT1 inhibitor Fludarabine, STAT3 inhibitor S31-201 and ERK1/2 inhibitor PD98059. Proliferation were measured by the 3-(4,5-dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, the production of Type I and III collagen was evaluated using real-time quantitative RT-PCR and ELISA, and the phosphorylation expression of STAT1 and STAT3 were analyzed by Western blot. Results: High glucose treatment promoted the proliferation of cardiac fibroblasts and collagen types I and III synthesis. High glucose treatment induced STAT1 and STAT3 phosphorylation in cardiac fibroblasts, the mode and level of STAT1 and STAT3 phosphorylation were significantly different. Fludarabine and S31-201 could both inhibited high glucose stimulated proliferation of cardiac fibroblasts and collagen types I and III synthesis with different effects. Combination of Fludarabine and PD98059 or combination of S31-201 and PD98059 both exhibited stronger inhibitions on proliferation of cardiac fibroblasts and collagen types I synthesis, but the effects and functional modes are different. Conclusion: Both STAT1 and STAT3 mediate the proliferation of cardiac fibroblasts and collagen synthesis induced by high glucose. STAT1 and STAT3 both have synergetic effects with ERK1/2 on regulating proliferation of cardiac fibroblasts and collagen types I synthesis.

show abstract

JAK-STAT signaling in hepatic fibrosis

Cited by 57 publications

References 168 publications

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

Distinctive pharmacological differences between liver cancer cell lines HepG2 and Hep3B

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl4-induced advanced cirrhosis

STAT1/3 and ERK1/2 Synergistically Regulate Cardiac Fibrosis Induced by High Glucose

Contact Info

Product

Resources

About