Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.
ABSTRACT Aberrant expression of transforming growth factor beta 1 (TGF-beta 1) has been implicated in a number of disease processes, particularly those involving fibrotic and inflammatory lesions. To determine the in vivo effects of overexpression of TGF-beta 1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-beta 1) consisting of modified porcine TGF-beta 1 cDNA under the control of the regulatory elements of the mouse albumin gene. Five transgenic lines were developed, all of which expressed the Alb/TGF-beta 1 transgene selectively in hepatocytes. The transgenic line 25 expressing the highest level of the transgene in the liver also had high (> 10-fold over control) plasma levels of TGF-beta 1. Hepatic fibrosis and apoptotic death of hepatocytes developed in all the transgenic lines but was more pronounced in line 25. The fibrotic process was characterized by deposition of collagen around individual hepatocytes and within the space of Disse in a radiating linear pattern. Several extrahepatic lesions developed in line 25, including glomerulonephritis and renal failure, arteritis and myocarditis, as well as atrophic changes in pancreas and testis. The results from this transgenic model strongly support the proposed etiological role for TGF-beta 1 in a variety of fibrotic and inflammatory disorders. The transgenic model may also provide an appropriate paradigm for testing therapeutic interventions aimed at neutralizing the detrimental effects of this important cytokine.
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ABSTRACT: Nuclear factor κB (NF-κB) is an antiapoptotic factor involved in development, regeneration, and neoplastic progression of the liver. Previously, we have shown that stabilization of inhibitor κB (IκB)-α protein following treatment of hepatocytes with transforming growth factor (TGF)-β1 promoted NF-κB repression, which then permitted induction of AP-1/SMAD-mediated liver cell death. Because basal IκB-α protein turnover is regulated by protein kinase CK2, here we have elucidated the regulation of CK2 kinase activity and its role in control of NF-κB levels following treatment with TGF-β1. We show that both messenger RNA (mRNA) and protein levels of the CK2α catalytic subunit are down-regulated following TGF-β1 stimulation in murine hepatocyte cells. The ensuing inhibition of CK2 kinase activity promotes stabilization of IκB protein, which is followed by the shutoff of constitutive NF-κB activity and induction of apoptosis. Ectopic expression of CK2α inhibits TGF-β1-induced apoptosis through sustained activation of NF-κB. Conversely, expression of a kinase-dead mutant of CK2α potentiates TGF-β1 cell killing. Importantly, we show that hepatocellular carcinomas (HCCs) derived from TGF-β1 transgenic mice and human HCC cell lines display enhanced CK2 IκB kinase activity that contributes in part to an elevated NF-κB activity in vivo. In conclusion, inhibition of CK2 expression levels by TGF-β1 is crucial for the induction of apoptosis of hepatocytes. Circumvention of this process by up-regulation of CK2 activity in transformed cells may contribute to the promotion of TGF-β1-induced liver carcinogenesis. (Hepatology 2003;38:1540-1551.)Hepatology 12/2003; 38(6):1540-1551. DOI:10.1053/jhep.2003.09019 · 11.19 Impact Factor
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ABSTRACT: TGF-β (transforming growth factor-β) is well identified as a central mediator in renal fibrosis. TGF-β initiates canonical and non-canonical pathways to exert multiple biological effects. Among them, Smad signaling is recognized as a major pathway of TGF-β signaling in progressive renal fibrosis. During fibrogenesis, Smad3 is highly activated, which is associated with the down-regulation of an inhibitory Smad7 via an ubiquitin E3-ligases-dependent degradation mechanism. The equilibrium shift between Smad3 and Smad7 leads to accumulation and activation of myofibroblasts, overproduction of ECM (extracellular matrix), and reduction in ECM degradation in the diseased kidney. Therefore, overexpression of Smad7 has been shown to be a therapeutic agent for renal fibrosis in various models of kidney diseases. In contrast, another downstream effecter of TGF-β/Smad signaling pathway, Smad2, exerts its renal protective role by counter-regulating the Smad3. Furthermore, recent studies demonstrated that Smad3 mediates renal fibrosis by down-regulating miR-29 and miR-200 but up-regulating miR-21 and miR-192. Thus, overexpression of miR-29 and miR-200 or down-regulation of miR-21 and miR-192 is capable of attenuating Smad3-mediated renal fibrosis in various mouse models of chronic kidney diseases (CKD). Taken together, TGF-β/Smad signaling plays an important role in renal fibrosis. Targeting TGF-β/Smad3 signaling may represent a specific and effective therapy for CKD associated with renal fibrosis.Frontiers in Physiology 03/2015; 6:82. DOI:10.3389/fphys.2015.00082
Frontiers in Bioscience 01/2011; 16(1):2794. DOI:10.2741/3886 · 4.25 Impact Factor