Cell Type-Specific Intervention of Transforming Growth Factor β/Smad Signaling Suppresses Collagen Gene Expression and Hepatic Fibrosis in Mice

Inagaki, Yutaka; Kushida, Miwa; Higashi, Kiyoshi; Itoh, Johbu; Higashiyama, Reiichi; Hong, Yun Yu; Kawada, Norifumi; Namikawa, Kazuhiko; Kiyama, Hiroshi; Bou‐Gharios, George; Watanabe, Tetsu; Okazaki, Isao; Ikeda, Kazuo

doi:10.1053/j.gastro.2005.03.088

Cited by 80 publications

(58 citation statements)

References 39 publications

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“…In addition, Dooley et al (13) observed that YB-1 is a potent inducer of Smad7 expression in activated hepatic stellate cells and that it could be used to antagonize TGF-␤ in liver, kidney, and other tissues during chronic stages of fibroproliferative diseases. Adenovirus-mediated overexpression of YB-1 driven by a collagen enhancer suppressed the progression of hepatic fibrosis and enhanced the antifibrotic effects of IFN-␥ (14). Furthermore, we have demonstrated that a novel small compound HSc025 stimulates nuclear translocation of YB-1 and improves skin and pulmonary fibrosis (15).…”

mentioning

confidence: 81%

“…Moreover, adenovirus-mediated YB-1 expression under the control of the collagen enhancer/promoter significantly suppressed the progression of hepatic fibrosis (14). Random screening of a chemical library and modification of hit compounds using the YB-1-dependent collagen promoter assay system revealed that cinnamoyl derivatives activate the nuclear translocation of YB-1.…”

Section: Hsc025 Suppresses Collagen Gene Expression In Activatedmentioning

confidence: 99%

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A Novel Small Compound That Promotes Nuclear Translocation of YB-1 Ameliorates Experimental Hepatic Fibrosis in Mice

Higashi

Tomigahara

Shiraki

et al. 2011

Journal of Biological Chemistry

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confidence: 81%

Section: Hsc025 Suppresses Collagen Gene Expression In Activatedmentioning

confidence: 99%

A Novel Small Compound That Promotes Nuclear Translocation of YB-1 Ameliorates Experimental Hepatic Fibrosis in Mice

Higashi

Tomigahara

Shiraki

et al. 2011

Journal of Biological Chemistry

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“…The presented data and recent findings by Higashi et al (10) indicate that the beneficial effects of IFN-␥ on fibroproliferative disorders are mediated by YB-1, which among other effects counteracts TGF-␤ signaling. Finally, Inagaki and co-workers (56) reported that adenoviral overexpression of YB-1 under the control of the col1A2 promoter blunted liver fibrosis in mice treated with CCl 4 .…”

Section: Ifn-␥ and Tgf-␤ Have Opposing Effects On Ecm Deposition-mentioning

confidence: 96%

Y-box Protein-1 Is the Crucial Mediator of Antifibrotic Interferon-γ Effects

Dooley

Said

Gressner

et al. 2006

Journal of Biological Chemistry

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Y-box protein-1 (YB-1) is a known negative regulator of collagen (Col) expression by two different mechanisms, acting directly through binding to an interferon-␥ response element within the col1A2 promoter and/or by physically interacting with p300/ Smad3, thereby abrogating the stimulatory effect of transforming growth factor-␤ (TGF-␤). Here, we report that YB-1 activation via the Jak1 signaling pathway is required and sufficient to confer interferon-␥-dependent activation of the smad7 gene. By binding to a bona fide recognition site within the smad7 promoter, YB-1 up-regulates smad7 transcription, which was additively enhanced by autoinhibitory TGF-␤ signaling. Importantly, the anti-TGF-␤ effect was not only supplied by induced Smad7 expression but was recapitulated in the context of the col1A2 promoter, where YB-1 overexpression abolished the trans-stimulatory TGF-␤ effect in a dominant fashion. In conclusion, YB-1 is the main target of interferon-␥ signaling via Jak1 that exerts antifibrotic action by both interference with TGF-␤ signaling and direct down-regulation of collagen expression.Y-box proteins belong to a family of DNA-and RNA-binding factors, also named cold shock proteins, that are highly conserved during evolution and have been shown to function as regulators of gene transcription and translation (1, 2). A wide range of nucleic acid structures are reported to be specifically bound by Y-box proteins, most of which harbor an inverted CCAAT-box (ATTGG) as the core binding site. YB-1 3 was originally identified by an expression cloning strategy using the Y-box of the major histocompatibility complex class II and epidermal growth factor receptor promoters as probes (3,4). It is a ubiquitously expressed early response gene that is induced among others following interleukin-2 stimulation of cloned T helper lymphocytes (5) and after partial hepatectomy (6). YB-1 has been implicated in the regulation of proliferation-associated genes (e.g. thymidine kinase, proliferating cellular nuclear antigen, and epidermal growth factor receptor (7)), and most recently a direct effect on p53 protein expression and interaction with p53 has been described (8). In regard to ECM synthesis and deposition, YB-1 was identified as a negative regulator in glomerular mesangial cells, where it trans-activates transcription of the matrix metalloproteinase-2 gene via combinatorial interactions with p53 and AP-2, which may be antagonized by nonmetastasizing protein 23 (Nm23) (9). In human embryonic kidney cells and dermal fibroblasts, a repressive function of YB-1 on the col1A2 gene promoter was reported, which is mediated by IFN-␥ (10). Screening of a human fibroblast cDNA expression library with a radiolabeled col1A2 IFN-␥ response element (IgRE) probe exclusively yielded clones with a sequence identical to YB-1 (10). Studies with a mutated IgRE and expression vectors containing partially deleted YB-1 cDNAs that were GFP-tagged for detection by immunofluorescence microscopy indicated that IFN-␥ facilitates nuclear translocation ...

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“…Furthermore, continuous hepatic stellate cells activation leads to myofibroblast transition via the release of pro-fibrogenic cytokines including transforming growth factor (TGF-) (Bisselle et al, 1995;Desmouliere et al, 1993;Dooley et al, 2012), platelet-derived growth factor, and connective tissue growth factor (Tsukada et al, 2006). Therefore, it is one important reason that hepatic stellate cells and expressed cytokines e.g., TGF- (Inagaki et al, 2005;Tiggelman et al, 1995 ) is investigated as a therapeutic target for treating liver fibrosis and cirrhosis.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of methanolic extract of Phragmites karka on carbon tetrachloride-induced liver fibrosis in rat

Rehman

Liaqat

Asghar

et al. 2017

Bangladesh J Pharmacol

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Phragmites karka has been reported for its anti-inflammatory and analgesic activities. Here, extracts of leaf and rhizome of the plant were individually investigated in CCl4-induced hepatofibrosis in male Wistar rats by administering CCl4 intraperitoneally biweekly for 6 weeks. Afterwards the animals were investigated for liver fibrosis at biochemical, molecular and histological levels, and it showed a profound increase (p<0.001) in elevation of serum levels of transaminases, γ-glutamyl transpeptidase, mRNA expression of α smooth muscle actin, collagen and transforming growth factor beta (TGFβ), and extracellular matrix deposition and perilobular necrosis. Both extracts markedly (p<0.001) decreased the elevated levels of these markers. Histopathological investigations also substantiated the above results by exhibiting a decreased in extracellular matrix deposition in post-treatment animals. In conclusion, both extracts had substantially modified the biochemical and molecular markers of liver fibrosis, in addition to histological improvement in architecture of liver.

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Cell Type-Specific Intervention of Transforming Growth Factor β/Smad Signaling Suppresses Collagen Gene Expression and Hepatic Fibrosis in Mice

Cited by 80 publications

References 39 publications

A Novel Small Compound That Promotes Nuclear Translocation of YB-1 Ameliorates Experimental Hepatic Fibrosis in Mice

A Novel Small Compound That Promotes Nuclear Translocation of YB-1 Ameliorates Experimental Hepatic Fibrosis in Mice

Y-box Protein-1 Is the Crucial Mediator of Antifibrotic Interferon-γ Effects

Evaluation of methanolic extract of Phragmites karka on carbon tetrachloride-induced liver fibrosis in rat

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