The Dependence of Transforming Growth Factor-β-Induced Collagen Production on Autocrine Factor Activin A in Hepatic Stellate Cells

Wada, Wataru; Kuwano, Hiroyuki; Hasegawa, Yoshihisa; Kojima, Itaru

doi:10.1210/en.2003-1663

Cited by 76 publications

(71 citation statements)

References 25 publications

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“…For example, recombinant follistatin attenuated liver fibrosis in a rat model of CCl 4 -induced liver injury (Patella et al, 2006) and lung fibrosis in a rat model of bleomycin-induced lung injury (Aoki et al, 2005). Interestingly, follistatin not only blocked the action of activin itself, but also inhibited TGF-b-induced collagen production, indicating that this function of TGF-b is at least in part mediated through the activation of an autocrine loop that involves activin (Wada et al, 2004). Taken together, these results identify activin as a potent pro-fibrotic factor in different tissues and organs, whereas follistatin is found to counteract this effect.…”

Section: Introductionmentioning

confidence: 99%

The bright and the dark sides of activin in wound healing and cancer

Antsiferova

Werner

2012

Journal of Cell Science

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SummaryActivin was initially described as a protein that stimulates release of follicle stimulating hormone from the pituitary, and it is well known for its important roles in different reproductive functions. In recent years, this multifunctional factor has attracted the attention of researchers in other fields, as new functions of activin in angiogenesis, inflammation, immunity, fibrosis and cancer have been discovered. Studies from our laboratory have identified activin as a crucial regulator of wound healing and skin carcinogenesis. On the one hand, it strongly accelerates the healing process of skin wounds but, on the other hand, it enhances scar formation and the susceptibility to skin tumorigenesis. Finally, results from several laboratories have revealed that activin enhances tumour formation and/ or progression in some other organs, in particular through its effect on the tumour microenvironment, and that it also promotes cancerinduced bone disruption and muscle wasting. These findings provide the basis for the use of activin or its downstream targets for the improvement of impaired wound healing, and of activin antagonists for the prevention and treatment of fibrosis and of malignant tumours that overexpress activin. Here, we summarize the previously described roles of activin in wound healing and scar formation and discuss functional studies that revealed different functions of activin in the pathogenesis of cancer. The relevance of these findings for clinical applications will be highlighted.

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Section: Introductionmentioning

confidence: 99%

The bright and the dark sides of activin in wound healing and cancer

Antsiferova

Werner

2012

Journal of Cell Science

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“…The latest studies have reported that as an important regulator, activin also has effects on inducing liver fibrosis, suppressing hepatocyte growth and so on [21][22][23][24][25][26] . It has been demonstrated that activin was produced by hepatocyte and hepatic stellate cell (HSC) and could promote HSC activation and stimulate excess production of ECM components, for example, collagen and fibronectin [3,16,25] . It has been reported that activin A could be expressed positively in fibrotic hepatocytes, and it also could take actions by autocrine [3,26] .…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that activin was produced by hepatocyte and hepatic stellate cell (HSC) and could promote HSC activation and stimulate excess production of ECM components, for example, collagen and fibronectin [3,16,25] . It has been reported that activin A could be expressed positively in fibrotic hepatocytes, and it also could take actions by autocrine [3,26] . In this study, we found that activin A could stimulate the expression of type Ⅳ collagen mRNA, whereas, the ARIP2 overexpression could remarkably suppress the mRNA expression of type Ⅳ collagen in Hepal-6 cells induced by activin A (Figure 4) and decrease the protein expression levels of type Ⅳ collagen.…”

Section: Discussionmentioning

confidence: 99%

“…The previous studies showed that activin A could induce liver fibrosis and stimulate excess secretion of ECM components, for example, collagen and fibronectin [3,16] . As an inhibitor of activin signal transduction, ARIP2 maybe influence the collagen production in hepatocytes induced by activin A.…”

Section: Arip2 Overexpression Suppressed Type ⅳ Collagen Expression Imentioning

confidence: 99%

“…As an important regulator, activin is involved in the acute phase response of inflammatory diseases and tissue repair, and also play an important role in inducing liver fibrosis [3][4][5] . The actions of activin on target cells are tissue-specific, which associate with the difference of activin receptor signal transduction.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagen type IV

Zhou

Tai²,

Zhou³

et al. 2007

WJG

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AIM:To investigate the regulation of activin receptorinteracting protein 2 (ARIP2) expression and its possible relationships with collagen type Ⅳ (collagen Ⅳ) in mouse hepatoma cell line Hepal-6 cells. METHODS:The ARIP2 mRNA expression kinetics in Hepal-6 cells was detected by RT-PCR, and its regulation fa c t o r s w e re a n a l y ze d by t re a t m e n t w i t h s i g n a l transduction activators such as phorbol 12-myristate 13-acetate (PMA), forskolin and A23187. After pcDNA3-ARIP2 was transfected into Hepal-6 cells, the effects of ARIP2 overexpression on activin type Ⅱ receptor (ActRII) and collagen Ⅳ expression were evaluated. RESULTS:The expression levels of ARIP2 mRNA in Hapel-6 cells were elevated in time-dependent manner 12 h after treatment with activin A and endotoxin LPS, but not changed evidently in the early stage of stimulation (2 or 4 h). The ARIP2 mRNA expression was increased after stimulated with signal transduction activators such as PMA and forskolin in Hepal-6 cells, whereas decreased after treatment with A23187 (25.3% ± 5.7% vs 48.1% ± 3.6%, P < 0.01). ARIP2 overexpression could remarkably suppress the expression of ActRIIA mRNA in dose-dependent manner, but has no effect on ActRIIB in Hepal-6 cells induced by activin A. Furthermore, we have found that overexpression of ARIP2 could inhibit collagen Ⅳ mRNA and protein expressions induced by activin A in Hapel-6 cells. CONCLUSION:

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Activin B promotes the initiation and progression of liver fibrosis

et al. 2022

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The role of activin B, a transforming growth factor β (TGFβ) superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl 4 )-induced liver fibrosis. Hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. Injured hepatocytes produced excessive activin B. Neutralizing activin B largely prevented, as well as improved, CCl 4 -induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B mediated the activation of c-Jun-N-terminal kinase (JNK), the induction of inducible nitric oxide synthase (iNOS) expression, and the maintenance of poly (ADP-ribose) polymerase 1 (PARP1) expression in injured livers.Moreover, activin B directly induced a profibrotic expression profile in hepatic stellate cells (HSCs) and stimulated these cells to form a septa structure. Conclusions:We demonstrate that activin B, cooperating with activin A, mediates the activation or expression of JNK, iNOS, and PARP1 and the activation of HSCs, driving the initiation and progression of liver fibrosis.

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The Dependence of Transforming Growth Factor-β-Induced Collagen Production on Autocrine Factor Activin A in Hepatic Stellate Cells

Cited by 76 publications

References 25 publications

The bright and the dark sides of activin in wound healing and cancer

The bright and the dark sides of activin in wound healing and cancer

Regulation of activin receptor-interacting protein 2 expression in mouse hepatoma Hepa1-6 cells and its relationship with collagen type IV

Activin B promotes the initiation and progression of liver fibrosis

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