Journal articles: 'Hepatic Stellate Cell IFN-γ'

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Shibata, Norikuni, Takamasa Watanabe, Teru Okitsu, Masakiyo Sakaguchi, Michihiko Takesue, Takemi Kunieda, Kenji Omoto, Shinichiro Yamamoto, Noriaki Tanaka, and Naoya Kobayashi. "Establishment of an Immortalized Human Hepatic Stellate Cell Line to Develop Antifibrotic Therapies." Cell Transplantation 12, no. 5 (July 2003): 499–507. http://dx.doi.org/10.3727/000000003108747064.

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Because human hepatic stellate cells (HSCs) perform a crucial role in the progress of hepatic fibrosis, it is of great value to establish an immortalized human cell line that exhibits HSC characteristics and grows well in tissue cultures for the development of antifibrotic therapies. Thus, we engineered an immortalized human hepatic stellate cell (HSC) line TWNT-4 by retrovirally inducing human telomerase reverse transcriptase (hTERT) into LI 90 cells established from a human liver mesenchymal tumor. Parental LI 90 entered replicative senescence, whereas TWNT-4 showed telomerase activity and proliferated for more than population doubling level (PDL) 200 without any crisis. TWNT-4 expressed platelet-derived growth factor-β receptor (PDGF-βR), α-smooth muscle actin (α-SMA), and type I collagen (α1) and was considered to be an activated form of HSCs. Treatment of TWNT-4 cells with either 100 U/ml of IFN-γ or 1 ng/ml of rapamycin (Rapa) for 14 days led to lower expression of type I collagen (α1) at RNA and protein levels. Exposure of TWNT-4 cells to both of IFN-γ (10 U/ml) and Rapa (0.1 ng/ml) for 14 days effectively decreased the expression of type I collagen (α1), PDGF-βR, and α-SMA expression and suppressed TGF-β1 secretion of TWNT-4 cells. We successfully induced apoptosis by transducing TNF-related apoptosis-inducing ligand (TRAIL) into TWNT-4 cells using adenovirus vectors Ad/GT-TRAIL and Ad/PGK-GV-17. These findings suggested that immortalized activated HSC line TWNT-4 would be a useful means to develop antifibrotic therapies.

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Luo, Xiao-Yu, Terumi Takahara, Kengo Kawai, Masayuki Fujino, Toshiro Sugiyama, Koichi Tsuneyama, Kazuhiro Tsukada, Susumu Nakae, Liang Zhong, and Xiao-Kang Li. "IFN-γ deficiency attenuates hepatic inflammation and fibrosis in a steatohepatitis model induced by a methionine- and choline-deficient high-fat diet." American Journal of Physiology-Gastrointestinal and Liver Physiology 305, no. 12 (December 15, 2013): G891—G899. http://dx.doi.org/10.1152/ajpgi.00193.2013.

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Cytokines play important roles in all stages of steatohepatitis, including hepatocyte injury, the inflammatory response, and the altered function of sinusoidal cells. This study examined the involvement of a major inflammatory cytokine, interferon-γ (IFN-γ), in the progression of steatohepatitis. In a steatohepatitis model by feeding a methionine- and choline-deficient high-fat (MCDHF) diet to both wild-type and IFN-γ-deficient mice, the liver histology, expression of genes encoding inflammatory cytokines, and fibrosis-related markers were examined. To analyze the effects of IFN-γ on Kupffer cells in vitro, we examined the tumor necrosis factor-α (TNF-α) production by a mouse macrophage cell line. Forty two days of MCDHF diet resulted in weight loss, elevated aminotransferases, liver steatosis, and inflammation in wild-type mice. However, the IFN-γ-deficient mice exhibited less extensive changes. RT-PCR revealed that the expression of tumor necrosis factor-α (TNF-α), transforming growth factor-β, inducible nitric oxide synthase, interleukin-4 and osteopontin were increased in wild-type mice, although they were suppressed in IFN-γ-deficient mice. Seventy days of MCDHF diet induced much more liver fibrosis in wild-type mice than in IFN-γ-deficient mice. The expression levels of fibrosis-related genes, α-smooth muscle actin, type I collagen, tissue inhibitor of matrix metalloproteinase-1, and matrix metalloproteinase-2, were dramatically increased in wild-type mice, whereas they were significantly suppressed in IFN-γ-deficient mice. Moreover, in vitro experiments showed that, when RAW 264.7 macrophages were treated with IFN-γ, they produced TNF-α in a dose-dependent manner. The present study showed that IFN-γ deficiency might inhibit the inflammatory response of macrophages cells and subsequently suppress stellate cell activation and liver fibrosis. These findings highlight the critical role of IFN-γ in the progression of steatohepatitis.

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Fimmel, C. J., K. E. Brown, R. O'Neill, and R. D. Kladney. "Complement C4 protein expression by rat hepatic stellate cells." Journal of Immunology 157, no. 6 (September 15, 1996): 2601–9. http://dx.doi.org/10.4049/jimmunol.157.6.2601.

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Abstract Stellate cells play an important role in the production and turnover of the normal extracellular matrix of the liver and are key effector cells in the hepatic fibrogenesis that occurs in response to liver injury. In the present study, we used a rat model of long term dietary iron supplementation to identify stellate cell genes that are expressed during chronic hepatic iron overload. Using a subtraction cloning strategy, we identified a rat isoform of the complement C4 protein gene whose expression was strongly induced in stellate cells after iron overload. Highly purified, cultured stellate cells synthesized the C4 precursor protein and released its subunits into the culture medium. The C4 protein secreted in vitro was biologically active in a C4-specific hemolytic assay. C4 mRNA expression was minimal in freshly isolated stellate cells and increased between days 3 and 7 of primary culture, coincident with the expression of smooth muscle alpha-actin (alpha-SMA), a marker of cellular activation. C4 expression was absent in strongly alpha-SMA-positive, passaged cells, but was induced by IFN-gamma, which simultaneously inhibited alpha-SMA expression. Our studies establish hepatic stellate cells as a previously unrecognized source of C4 and raise the possibility that complement protein expression by the cells plays a role in the hepatic injury response and in fibrogenesis. Our in vitro data point to the presence of two distinct stimulatory pathways for C4 expression in stellate cells that differ with regard to their sensitivity to IFN-gamma and their relationship to cellular activation.

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Tan, Yang, Xueqing Sun, Yizhu Xu, Bingjie Tang, Shuaiqi Xu, Dong Lu, Yan Ye, et al. "Small molecule targeting CELF1 RNA-binding activity to control HSC activation and liver fibrosis." Nucleic Acids Research 50, no. 5 (March 2, 2022): 2440–51. http://dx.doi.org/10.1093/nar/gkac139.

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Abstract CUGBP Elav-like family member 1 (CELF1), an RNA-binding protein (RBP), plays important roles in the pathogenesis of diseases such as myotonic dystrophy, liver fibrosis and cancers. However, targeting CELF1 is still a challenge, as RBPs are considered largely undruggable. Here, we discovered that compound 27 disrupted CELF1-RNA binding via structure-based virtual screening and biochemical assays. Compound 27 binds directly to CELF1 and competes with RNA for binding to CELF1. Compound 27 promotes IFN-γ secretion and suppresses TGF-β1-induced hepatic stellate cell (HSC) activation by inhibiting CELF1-mediated IFN-γ mRNA decay. In vivo, compound 27 attenuates CCl4-induced murine liver fibrosis. Furthermore, the structure-activity relationship analysis was performed and compound 841, a derivative of compound 27, was identified as a selective CELF1 inhibitor. In conclusion, targeting CELF1 RNA-binding activity with small molecules was achieved, which provides a novel strategy for treating liver fibrosis and other CELF1-mediated diseases.

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Gu, Xiaodong, Yan Wang, Jianbin Xiang, Zongyou Chen, Lianfu Wang, Lina Lu, and Shiguang Qian. "Interferon-γTriggers Hepatic Stellate Cell-Mediated Immune Regulation through MEK/ERK Signaling Pathway." Clinical and Developmental Immunology 2013 (2013): 1–6. http://dx.doi.org/10.1155/2013/389807.

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Hepatic stellate cells (HSCs) interact with immune cells to actively participate in regulating immune response in the liver which is mediated by the effector molecules, including B7-H1. We demonstrated here that expression of B7-H1 on HSCs was markedly enhanced by interferon-(IFN-)γstimulation. IFN-γstimulated HSCs inhibited T-cell proliferation via induction of T-cell apoptosis (22.1% ± 1.6%). This immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, or inhibitor of the MEK/ERK pathway inhibited IFN-γmediated expression of B7-H1. Thus, regulation of B7-H1 expression on HSCs by IFN-γrepresents an important mechanism that regulates immune responses in the liver favoring tolerogenicity rather than immunogenicity. Involvement of MEK/ERK pathway provides a novel target for therapeutic approaches.

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Ezhilarasan, Devaraj. "Endothelin-1 in portal hypertension: The intricate role of hepatic stellate cells." Experimental Biology and Medicine 245, no. 16 (August 13, 2020): 1504–12. http://dx.doi.org/10.1177/1535370220949148.

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Portal hypertension is one of the most important cirrhosis-associated complications of chronic liver disease, leading to significant morbidity and mortality. After chronic liver injury, hepatic stellate cells reside in the perisinusoidal space activted and acquire a myofibroblast-like phenotype. The activated hepatic stellate cells act as both sources as well as the target for a potent vasoconstrictor endothelin-1. Activation of hepatic stellate cells plays a vital role in the onset of cirrhosis by way of increased extracellular matrix production and the enhanced contractile response to vasoactive mediators such as endothelin-1. In fibrotic/cirrhotic liver, activated hepatic stellate cells produce endothelin-1 leading to an imbalance between pro and antifibrotic factors responsible for enormous extracellular matrix synthesis. Thus, extracellular matrix deposition in the perisinusoidal space further augments liver stiffness and elevates the vascular tone and portal hypertension. Portal hypertension is a complex process modulated by several cell types like hepatic stellate cells, liver sinusoidal endothelial cells, Kupffer cells, injured hepatocytes, immune cells, and biliary epithelial cells. Therefore, targeting a single cell type may not be useful for regression of cirrhosis and portal hypertension. Nevertheless, numerous findings indicate that functionally liver sinusoidal endothelial cells and hepatic stellate cells closely regulate the sinusoidal blood flow via synthesis of several vasoactive molecules including endothelin-1, and hence targeting these cells with novel pharmacological agents may offer promising results. Impact statement Portal hypertension is pathologically defined as increase of portal venous pressure, mainly due to chronic liver diseases such as fibrosis and cirrhosis. In fibrotic liver, activated hepatic stellate cells increase their contraction in response to endothelin-1 (ET-1) via autocrine and paracrine stimulation from liver sinusoidal endothelial cells and injured hepatocytes. Clinical studies are limited with ET receptor antagonists in cirrhotic patients with portal hypertension. Hence, studies are needed to find molecules that block ET-1 synthesis. Accumulation of extracellular matrix proteins in the perisinusoidal space, tissue contraction, and alteration in blood flow are prominent during portal hypertension. Therefore, novel matrix modulators should be tested experimentally as well as in clinical studies. Specifically, tumor necrosis factor-α, transforming growth factor-β1, Wnt, Notch, rho-associated protein kinase 1 signaling antagonists, and peroxisome proliferator-activated receptor α and γ, interferon-γ and sirtuin 1 agonists should be tested elaborately against cirrhosis patients with portal hypertension.

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Giannelli, Gianluigi, Carlo Bergamini, Felice Marinosci, Emilia Fransvea, Nicola Napoli, Patrick Maurel, Pietro Dentico, and Salvatore Antonaci. "Antifibrogenic Effect of IFN-α2b on Hepatic Stellate Cell Activation by Human Hepatocytes." Journal of Interferon & Cytokine Research 26, no. 5 (May 2006): 301–8. http://dx.doi.org/10.1089/jir.2006.26.301.

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Xu, Jianye, Yumei Fu, and Anping Chen. "Activation of peroxisome proliferator-activated receptor-γ contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth." American Journal of Physiology-Gastrointestinal and Liver Physiology 285, no. 1 (July 2003): G20—G30. http://dx.doi.org/10.1152/ajpgi.00474.2002.

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Hepatic fibrogenesis occurs as a wound-healing process after many forms of chronic liver injury. Hepatic fibrosis ultimately leads to cirrhosis if not treated effectively. During liver injury, quiescent hepatic stellate cells (HSC), the most relevant cell type, become active and proliferative. Oxidative stress is a major and critical factor for HSC activation. Activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) inhibits the proliferation of nonadipocytes. The level of PPAR-γ is dramatically diminished along with activation of HSC. Curcumin, the yellow pigment in curry, is a potent antioxidant. The aims of this study were to evaluate the effect of curcumin on HSC proliferation and to begin elucidating underlying mechanisms. It was hypothesized that curcumin might inhibit the proliferation of activated HSC by inducing PPAR-γ gene expression and reviving PPAR-γ activation. Our results indicated that curcumin significantly inhibited the proliferation of activated HSC and induced apoptosis in vitro. We demonstrated, for the first time, that curcumin dramatically induced the gene expression of PPAR-γ and activated PPAR-γ in activated HSC. Blocking its trans-activating activity by a PPAR-γ antagonist markedly abrogated the effects of curcumin on inhibition of cell proliferation. Our results provide a novel insight into mechanisms underlying the inhibition of activated HSC growth by curcumin. The characteristics of curcumin, including antioxidant potential, reduction of activated HSC growth, and no adverse health effects, make it a potential antifibrotic candidate for prevention and treatment of hepatic fibrosis.

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Arriola Benitez, Paula Constanza, Ayelén Ivana Pesce Viglietti, María Mercedes Elizalde, Guillermo Hernán Giambartolomei, Jorge Fabián Quarleri, and María Victoria Delpino. "Hepatic Stellate Cells and Hepatocytes as Liver Antigen-Presenting Cells during B. abortus Infection." Pathogens 9, no. 7 (June 30, 2020): 527. http://dx.doi.org/10.3390/pathogens9070527.

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In Brucellosis, the role of hepatic stellate cells (HSCs) in the induction of liver fibrosis has been elucidated recently. Here, we study how the infection modulates the antigen-presenting capacity of LX-2 cells. Brucella abortus infection induces the upregulation of class II transactivator protein (CIITA) with concomitant MHC-I and -II expression in LX-2 cells in a manner that is independent from the expression of the type 4 secretion system (T4SS). In concordance, B. abortus infection increases the phagocytic ability of LX-2 cells and induces MHC-II-restricted antigen processing and presentation. In view of the ability of B. abortus-infected LX-2 cells to produce monocyte-attracting factors, we tested the capacity of culture supernatants from B. abortus-infected monocytes on MHC-I and –II expression in LX-2 cells. Culture supernatants from B. abortus-infected monocytes do not induce MHC-I and -II expression. However, these supernatants inhibit MHC-II expression induced by IFN-γ in an IL-10 dependent mechanism. Since hepatocytes constitute the most abundant epithelial cell in the liver, experiments were conducted to determine the contribution of these cells in antigen presentation in the context of B. abortus infection. Our results indicated that B. abortus-infected hepatocytes have an increased MHC-I expression, but MHC-II levels remain at basal levels. Overall, B. abortus infection induces MHC-I and -II expression in LX-2 cells, increasing the antigen presentation. Nevertheless, this response could be modulated by resident or infiltrating monocytes/macrophages.

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Rockey, D. C., and J. J. Chung. "Regulation of inducible nitric oxide synthase in hepatic sinusoidal endothelial cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 271, no. 2 (August 1, 1996): G260—G267. http://dx.doi.org/10.1152/ajpgi.1996.271.2.g260.

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Nitric oxide (NO) has many important physiological effects that depend in part on its cellular source(s). In liver, NO is produced by all major cell types, including hepatocytes, Kupffer, stellate, and sinusoidal endothelial cells (SECs). Although endothelial cells have been commonly associated with constitutive NO production, recent evidence suggests that NO is inducible in this cell type. Here, we investigated the regulation of inducible NO synthase (iNOS) in SECs. Interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) as individual compounds induced iNOS mRNA in SECs. Interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) had no effect when used alone but enhanced iNOS mRNA upregulation by IFN-gamma. iNOS transcription after LPS was present only for 4 h after exposure yet was more sustained after IFN-gamma/TNF-alpha, LPS was unique in that it transiently induced iNOS mRNA, whereas IFN-gamma/TNF-alpha resulted in prolonged increases in iNOS mRNA. Both LPS and IFN-gamma/TNF-alpha caused prolonged elevation of immunoreactive protein. However, when stimulated by LPS, iNOS remained enzymatically active for only 24-48 h. After IFN-gamma or IFN-gamma/TNF-alpha, iNOS activity declined only moderately. LPS added to IFN-gamma alone or IFN-gamma/TNF-alpha did not result in more rapid decay of iNOS enzymatic activity. These data indicate that induction of iNOS by sinusoidal endothelial cells is prominent and that it is regulated both transcriptionally and by its inactivation. Such complex regulation of iNOS has important implications for NO biology in liver disease.

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Maubach, Gunter, Michelle Chin Chia Lim, Saravana Kumar, and Lang Zhuo. "Expression and upregulation of cathepsin S and other early molecules required for antigen presentation in activated hepatic stellate cells upon IFN-γ treatment." Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1773, no. 2 (February 2007): 219–31. http://dx.doi.org/10.1016/j.bbamcr.2006.11.005.

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Khalil, Hany Ezzat, Hairul-Islam Mohamed Ibrahim, Kareem Ahmed El-Fass, Sabah H. Akrawi, and Mohamed A. Morsy. "Orientin Alleviates Liver Inflammation via Downregulation of ZEB-2/PTEN Markers—Hepatic Stellate Cells Approach." Applied Sciences 12, no. 5 (March 6, 2022): 2725. http://dx.doi.org/10.3390/app12052725.

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Liver inflammation is associated with an increased risk of liver fibrosis that substantially progresses to cirrhosis. Recently, usage of the herbal supplement has been increased because of its emerging role to dominate oxidative stress in hepatic injury. Orientin is one of the bioactive flavonoids that possesses a diversity of curative activities. Therefore, the present study was conducted to evaluate the anti-inflammatory role of orientin (1 mg/kg) in vitro in lipopolysaccharide (LPS)-induced inflammation in hepatic stellate cells (HSCs) and in vivo in carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Moreover, the current study was supported by in silico investigation. Orientin demonstrated protection against LPS-induced HSC inflammation as evidenced by a decrease in iNOS, NO, and TNF-α and inhibition of the fibrotic markers ZEB-2 and PTEN. In addition, orientin afforded protection against CCl4-induced liver fibrosis in mice as shown from decreased AST/ALT ratio, inhibition of the pro-inflammatory mediators TNF-α, IL-6, IL-8, and IFN-γ, reduction of fibrotic markers ZEB-2 and PTEN, and improvement of the histopathological changes. Furthermore, the docking study demonstrated virtual interactions of orientin with ZEB-2 and PTEN. Taken together, the current study suggested that the protective effects of orientin against LPS- and CCl4-induced liver inflammation are via inhibition of fibrotic markers and reduction of pro-inflammatory mediators.

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Cheng, Jason H., Hongyun She, Yuan-Ping Han, Jiaohong Wang, Shigang Xiong, Kinji Asahina, and Hidekazu Tsukamoto. "Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 1 (January 2008): G39—G49. http://dx.doi.org/10.1152/ajpgi.00263.2007.

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Activation of hepatic stellate cells (HSC), a key event in liver fibrosis, is caused by diminished adipogenic transcription. This study investigated whether Wnt signaling contributes to “antiadipogenic” activation of HSC and liver fibrogenesis. Culture-activated HSC from normal rats and HSC from cholestatic rat livers were examined for expression of Wnt, Frizzled (Fz) receptors, and coreceptors by quantitative PCR. Wnt signaling was assessed by nuclear β-catenin and T cell factor (TCF) promoter activity. Dickkopf-1 (Dkk-1), a Wnt coreceptor antagonist, was transduced by an adenoviral vector to assess the effects of Wnt antagonism on culture activation of HSC and cholestatic liver fibrosis in mice. Messenger RNA for canonical (Wnt3a and 10b) and noncanonical (Wnt4 and 5a) Wnt genes, Fz-1 and 2, and coreceptors [low-density lipoprotein-receptor-related protein (LRP)6 and Ryk] are increased ∼3–12-fold in culture-activated HSC compared with quiescent HSC. The nuclear β-catenin level and TCF DNA binding are markedly increased in activated HSC. TCF promoter activity is stimulated with Wnt1 but inhibited by Chibby, a protein that blocks β-catenin interaction with TCF, and by Dkk-1. Dkk-1 enhances peroxisome proliferator-activated receptor-γ (PPARγ)-driven PPAR response element (PPRE) promoter activity, a key adipogenic transcriptional parameter, abrogates agonist-stimulated contraction, and restores HSC quiescence in culture. High expression of Dkk-1 increases apoptosis of cultured HSC. Expression of Wnt and Fz genes is also induced in HSC isolated from experimental cholestatic liver fibrosis, and Dkk-1 expression ameliorates this form of liver fibrosis in mice. These results demonstrate antiadipogenic Wnt signaling in HSC activation and therapeutic potential of Wnt antagonism for liver fibrosis.

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Tang, Youcai, Shizhong Zheng, and Anping Chen. "Curcumin Eliminates Leptin’s Effects on Hepatic Stellate Cell Activation via Interrupting Leptin Signaling." Endocrinology 150, no. 7 (March 19, 2009): 3011–20. http://dx.doi.org/10.1210/en.2008-1601.

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Nonalcoholic steatohepatitis (NASH) is commonly found in patients with obesity and is often accompanied with abnormally elevated levels of plasma leptin, i.e. hyperleptinemia. A relatively high population of NASH patients develops hepatic fibrosis, even cirrhosis. Hepatic stellate cells (HSCs) are the major effector cells during liver fibrogenesis and could be activated by leptin. The antioxidant curcumin, a phytochemical from turmeric, has been shown to suppress HSC activation in vitro and in vivo. This project is to evaluate the effect of curcumin on leptin-induced HSC activation and to elucidate the underlying mechanisms. We hypothesize that curcumin abrogates the stimulatory effect of leptin on HSC activation by interrupting leptin signaling and attenuating leptin-induced oxidative stress. Curcumin eliminates the stimulatory effects of leptin on regulating expression of genes closely relevant to HSC activation. Curcumin interrupts leptin signaling by reducing phosphorylation levels of leptin receptor (Ob-R) and its downstream intermediators. In addition, curcumin suppresses gene expression of Ob-R in HSCs, which requires the activation of endogenous peroxisome proliferator-activated receptor-γ and de novo synthesis of glutathione. In conclusion, our results demonstrate that curcumin abrogates the stimulatory effect of leptin on HSC activation in vitro by reducing the phosphorylation level of Ob-R, stimulating peroxisome proliferator-activated receptor-γ activity, and attenuating oxidative stress, leading to the suppression of Ob-R gene expression and interruption of leptin signaling. These results provide novel insights into therapeutic mechanisms of curcumin in inhibiting HSC activation and intervening liver fibrogenesis associated with hyperleptinemia in NASH patients.

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Zhou, Da, Jing Wang, Ling-Nan He, Bing-Hang Li, Yong-Nian Ding, Yuan-Wen Chen, and Jian-Gao Fan. "Prolyl oligopeptidase attenuates hepatic stellate cell activation through induction of Smad7 and PPAR-γ." Experimental and Therapeutic Medicine 13, no. 2 (January 5, 2017): 780–86. http://dx.doi.org/10.3892/etm.2017.4033.

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Li, Tianxia, Zengdun Shi, and Don C. Rockey. "Preproendothelin-1 expression is negatively regulated by IFNγ during hepatic stellate cell activation." American Journal of Physiology-Gastrointestinal and Liver Physiology 302, no. 9 (May 1, 2012): G948—G957. http://dx.doi.org/10.1152/ajpgi.00359.2011.

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Endothelin-1 (ET-1), a powerful vasoconstrictor peptide, is produced by activated hepatic stellate cells (HSC) and promotes cell proliferation, fibrogenesis, and contraction, the latter of which has been thought to be mechanistically linked to portal hypertension in cirrhosis. Interferon-γ (IFNγ), a Th1 cytokine produced by T cells, inhibits stellate cell proliferation, fibrogenesis, and muscle-specific gene expression. Whether IFNγ-induced inhibitory effects are linked to regulation of ET-1 expression in activated stellate cells remains unknown. Here we examined IFNγ's effects on preproET-1 mRNA expression and the signaling pathways underlying this process. We demonstrated that preproET-1 mRNA expression in HSCs was prominently increased during cell culture-induced activation; IFNγ significantly inhibited both preproET-1 mRNA expression and ET-1 peptide production. Similar results were found in an in vivo model of liver injury and intraperitoneal administration of IFNγ. PreproET-1 promoter analysis revealed that IFNγ-induced inhibition of preproET-1 mRNA expression was closely linked to the AP-1 and Smad3 signaling pathways. Furthermore, IFNγ reduced JNK phosphorylation, which tightly was associated with decreased phosphorylation of downstream factors c-Jun and Smad3 and decreased binding activity of c-Jun and Smad3 in the preprpET-1 promoter. Importantly, IFNγ reduced both c-Jun mRNA and protein levels. Given the important role of ET-1 in wound healing, our results suggest a novel negative signaling network by which IFNγ inhibits preproET-1 expression, highlighting one potential molecular mechanism for IFNγ-induced host immunomodulation of liver fibrogenesis.

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Gong, Seong Chan, Yongdae Yoon, Pil Young Jung, Moon Young Kim, Soon Koo Baik, Hoon Ryu, and Young Woo Eom. "Antifibrotic TSG-6 Expression Is Synergistically Increased in Both Cells during Coculture of Mesenchymal Stem Cells and Macrophages via the JAK/STAT Signaling Pathway." International Journal of Molecular Sciences 23, no. 21 (October 28, 2022): 13122. http://dx.doi.org/10.3390/ijms232113122.

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The pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1β upregulate TNF-α-stimulated gene 6 (TSG-6); however, current knowledge about the optimal conditions for TSG-6 expression in mesenchymal stem cells (MSCs) is limited. Here, we investigated whether TSG-6 expression varies depending on the polarization state of macrophages co-cultured with adipose tissue-derived stem cells (ASCs) and analyzed the optimal conditions for TSG-6 expression in ASCs. TSG-6 expression increased in ASCs co-cultured with M0, M1, and M2 macrophages indirectly; among them, M1 macrophages resulted in the highest increase in TSG-6 expression in ASCs. TSG-6 expression in ASCs dramatically increased by combination (but not single) treatment of TNF-α, IL-1β, interferon-gamma (IFN-γ), and lipopolysaccharide (LPS). In addition, phosphorylation of signal transducer and activator of transcription (STAT) 1/3 was observed in response to IFN-γ and LPS treatment but not TNF-α and/or IL-1β. STAT1/3 activation synergistically increased TNF-α/IL-1β-dependent TSG-6 expression, and JAK inhibitors suppressed TSG-6 expression both in ASCs and macrophages. In LX-2 hepatic stellate cells, TSG-6 inhibited TGF-β-induced Smad3 phosphorylation, resulting in decreased α-smooth muscle actin (SMA) expression. Moreover, fibrotic activities of LX-2 cells induced by TGF-β were dramatically decreased after indirect co-culture with ASCs and M1 macrophages. These results suggest that a comprehensive inflammatory microenvironment may play an important role in determining the therapeutic properties of ASCs by increasing TSG-6 expression through STAT1/3 activation.

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Hasan, Hesham Farouk, Mohamed Khairy Abdel-Rafei, and Shereen Mohamed Galal. "Diosmin attenuates radiation-induced hepatic fibrosis by boosting PPAR-γ expression and hampering miR-17-5p-activated canonical Wnt–β-catenin signaling." Biochemistry and Cell Biology 95, no. 3 (June 2017): 400–414. http://dx.doi.org/10.1139/bcb-2016-0142.

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Background: Liver fibrosis is one of the major complications from upper right quadrant radiotherapy. MicroRNA-17-5p (miR-17-5p) is hypothesized to act as a regulator of hepatic stellate cell (HSCs) activation by activation of the canonical Wnt–β-catenin pathway. Diosmin (Dios), a citrus bioflavonoid, is known to possess potent antioxidant, anti-inflammatory, and anti-apoptotic properties. Purpose: To explore the molecular mechanisms that underlie radiation-induced liver fibrosis, and to evaluate the possible influence of Dios on the miR-17-5p–Wnt–β-catenin signaling axis during fibrogenesis provoked by irradiation (IRR) in rats. Also, the effect of Dios on hepatic peroxisome proliferator activated receptor-γ (PPAR-γ) expression as a regulator for HSC activation was considered. Methods: We administered 100 mg·(kg body mass)–1·day–1(per oral) of Dios were administered to IRR-exposed rats (overall dose of 12 Gy on 6 fractions of 2 Gy each) for 6 successive weeks. Results: Data analysis revealed that Dios treatment mitigated oxidative stress, enhanced antioxidant defenses, alleviated hepatic inflammatory responses, abrogated pro-fibrogenic cytokines, and stimulated PPAR-γ expression. Dios treatment repressed the miR-17-5p activated Wnt–β-catenin signaling induced by IRR. Moreover, Dios treatment restored the normal hepatic architecture and reversed pathological alterations induced by IRR. Conclusion: We hypothesize that the stimulation of PPAR-γ expression and interference with miR-17-5p activated Wnt–β-catenin signaling mediates the antifibrotic properties of Dios.

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Qiao, Haowen, Yu Zhou, Xingping Qin, Jing Cheng, Yun He, and Yugang Jiang. "NADPH Oxidase Signaling Pathway Mediates Mesenchymal Stem Cell-Induced Inhibition of Hepatic Stellate Cell Activation." Stem Cells International 2018 (2018): 1–13. http://dx.doi.org/10.1155/2018/1239143.

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Background. Bone marrow-derived mesenchymal stem cells (BMSCs) have blossomed into an effective approach with great potential for the treatment of liver fibrosis. The aim of this study was to investigate the underlying antifibrosis mechanisms by which the BMSC inhibit activated hepatic stellate cells (HSCs) in vivo and in vitro. Methods. To study the effect of human bone marrow-derived mesenchymal stem cells (hBM-MSCs) on activated HSCs, we used HSCs and the coculture systems to evaluate the inhibition of activated HSCs from the aspects of the apoptosis of activated HSCs. In addition, activation of NADPH oxidase pathway and the changes in liver histopathology were tested by using the carbon tetrachloride- (CCl4-) induced liver fibrosis in mice. Results. Introduction of hBM-MSCs significantly inhibited the proliferation of activated HSCs by inducing the apoptosis process of activated HSCs. The effect of hBM-MSCs reduced the signaling pathway of NADPH oxidase in activated HSCs. Besides, the signaling pathway of NADPH oxidase mediated hBM-MSC upregulation of the expression of the peroxisome proliferator-activated receptor γ and downregulation of the expression of α1(I) collagen and alpha-smooth muscle actin (α-SMA) in activated HSCs. Moreover, the hBM-MSC-induced decrease in the signaling pathway of NADPH oxidase was accompanied by the decrease of the activated HSC number and liver fibrosis in a mouse model of CCl4-induced liver fibrosis. Conclusion. The hBM-MSCs act as a promising drug source against liver fibrosis development with respect to hepatopathy as a therapeutic target.

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Locatelli, Irene, Salvatore Sutti, Marco Vacchiano, Cristina Bozzola, and Emanuele Albano. "NF-κB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses." Clinical Science 124, no. 4 (November 5, 2012): 279–87. http://dx.doi.org/10.1042/cs20120289.

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Growing evidence indicates that NF-κB (nuclear factor κB) activation contributes to the pathogenesis of NASH (non-alcoholic steatohepatisis). Among the NF-κB subunits, p50/NF-κB1 has regulatory activities down-modulating NF-κB-mediated responses. In the present study, we investigated the effects of NF-κB1 deficiency on the progression of NASH induced by feeding mice on an MCD (methionine/choline-deficient) diet. Following 4 weeks on the MCD diet, steatosis, ALT (alanine aminotransferase) release, hepatocyte apoptosis, lobular inflammation and TNFα (tumour necrosis factor α) production were higher in NF-κB1−/− (NF-κB1-knockout) mice than in WT (wild-type) mice. NF-κB1−/− mice also showed appreciable centrilobular collagen deposition, an increased number of activated hepatic stellate cells and higher type-I procollagen-α and TIMP-1 (tissue inhibitor of metalloproteases-1) mRNA expression. Although NF-κB p50 homodimers regulate macrophage activation, the number of hepatic macrophages and liver mRNAs for iNOS (inducible NO synthase), IL (interleukin)-12p40, CCL2 (CC chemokine ligand 2) and CXCL10 (CXC chemokine ligand 10) were comparable in the two strains. NASH was associated with an increase in liver infiltrating T-cells that was more evident in MCD-fed NF-κB1−/− than in similarly treated WT mice. Flow cytorimetry showed that T-cell recruitment involved effector CD8+ T-cells without changes in the helper CD4+ T-cell fraction. Furthermore, although NASH lowered hepatic NKT cells [NK (natural killer) T-cells] in WT mice, the NKT cell pool was selectively increased in the livers of MCD-fed NF-κB1−/− mice. Such NKT cell recruitment was associated with an early overexpression of IL-15, a cytokine controlling NKT cell survival and maturation. In the livers of MCD-fed NF-κB1−/− mice, but not in those of WT littermates, we also observed an up-regulation in the production of NKT-related cytokines IFN (interferon)-γ and osteopontin. Taken together, these results indicate that NF-κB1 down-modulation enhanced NASH progression to fibrosis by favouring NKT cell recruitment, stressing the contribution of NKT cells in the pathogenesis of NASH.

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Zhu, Nian-Ling, Jiaohong Wang, and Hidekazu Tsukamoto. "The Necdin-Wnt Pathway Causes Epigenetic Peroxisome Proliferator-activated Receptor γ Repression in Hepatic Stellate Cells." Journal of Biological Chemistry 285, no. 40 (July 27, 2010): 30463–71. http://dx.doi.org/10.1074/jbc.m110.156703.

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Hazra, Saswati, Shigang Xiong, Jiaohong Wang, Richard A. Rippe, V. Krishna, K. Chatterjee, and Hidekazu Tsukamoto. "Peroxisome Proliferator-activated Receptor γ Induces a Phenotypic Switch from Activated to Quiescent Hepatic Stellate Cells." Journal of Biological Chemistry 279, no. 12 (December 31, 2003): 11392–401. http://dx.doi.org/10.1074/jbc.m310284200.

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Wang, Siqi, Jing Li, Shengdi Wu, Lisha Cheng, Yue Shen, Wei Ma, Weimin She, Changqing Yang, Jiyao Wang, and Wei Jiang. "Type 3 innate lymphoid cell: a new player in liver fibrosis progression." Clinical Science 132, no. 24 (December 13, 2018): 2565–82. http://dx.doi.org/10.1042/cs20180482.

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Type 3 innate lymphoid cell (ILC3) has recently emerged as a crucial effector in inflammatory and fibrotic diseases. The present study was designed to determine the roles of ILC3 in liver fibrosis. By flow cytometry, we documented increased frequencies of peripheral ILC3 (Lin−CD127+CD117+CD294− lymphocytes) in patients, especially at the advanced stage of hepatitis B virus (HBV)-related chronic liver diseases, and demonstrated their correlations with disease progression. The in vitro fibrogenic effects by ILC3 were determined by co-culture experiments with LX-2 (a human hepatic stellate cell (HSC) line). The data indicate that pathogenic ILC3 can directly promote LX-2 fibrogenesis in non-contact manners by producing interleukin (IL)-17A and IL-22. Additionally, they had indirect fibrogenic effects by producing IL-22 to suppress interferon (IFN)-γ (a well-known anti-fibrotic cytokine) production by other immune cells. In carbon tetrachloride (CCl4)-induced wild-type mouse liver fibrosis models, we also documented significantly increased frequencies of both non-natural killer (NK) ILC (Lin−CD127+ lymphocytes) and ILC3 (Lin−CD127+RORγt+ lymphocytes) in liver and spleen specimens. Furthermore, the ILC3 from fibrotic mice contained more IL-17A+ILC3 and IL-22+ILC3 subsets than those from normal and less-fibrotic mice. The in vivo effects of ILC3 in liver fibrogenesis were further determined using RAG-1−/− mice with ILC depletion and further adoptive transfer of ILC3 from wild-type mice. The immunohistochemical staining of liver specimens showed the beneficial effects by ILC depletion and the detrimental effects by ILC3 transfer in CCl4-induced mouse liver fibrosis models. Collectively, ILC3 plays a pro-fibrotic role in liver fibrosis progression.

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Zhang, Bimi, Dehong Tan, Bing Bai, Yin He, and Shujuan Ji. "γ-Glutamyl-S-allyl-cysteine inhibits hepatic stellate cell proliferation and collagen secretion via a proapoptotic mechanism." European Food Research and Technology 240, no. 6 (April 2, 2015): 1271–80. http://dx.doi.org/10.1007/s00217-015-2453-7.

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Zhu, Dandan, Jianxin Wang, Xiaolei Sun, Jinling Chen, Yinong Duan, Jing Pan, Tianhua Xu, Yongwei Qin, Xingxin He, and Caiqun Huang. "Septin4_i1 Regulates Apoptosis in Hepatic Stellate Cells through Peroxisome Proliferator-Activated Receptor-γ/Akt/B-Cell Lymphoma 2 Pathway." Journal of Histochemistry & Cytochemistry 63, no. 3 (December 19, 2014): 163–69. http://dx.doi.org/10.1369/0022155414567230.

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Zheng, Shizhong, and Anping Chen. "Disruption of transforming growth factor-β signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-γ in rat hepatic stellate cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 292, no. 1 (January 2007): G113—G123. http://dx.doi.org/10.1152/ajpgi.00200.2006.

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Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-β (TGF-β) and a dramatic reduction in the peroxisome proliferator-activated receptor-γ (PPAR-γ). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-γ in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-γ activation suppressed gene expression of TGF-β receptors in activated HSC, leading to the interruption of TGF-β signaling. This observation supported our assumption of an antagonistic relationship between PPAR-γ activation and TGF-β signaling in HSC. In this study, we further hypothesize that TGF-β signaling might negatively regulate gene expression of PPAR-γ in activated HSC. The present report demonstrates that exogenous TGF-β1 inhibits gene expression of PPAR-γ in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-β signaling. Transfection assays further indicate that blocking TGF-β signaling by dominant negative type II TGF-β receptor increases the promoter activity of PPAR-γ gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-γ gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-γ gene promoter and TGF-β signaling. Taken together, these results demonstrate that the interruption of TGF-β signaling by curcumin induces gene expression of PPAR-γ in activated HSC in vitro. Our studies provide novel insights into the molecular mechanisms of curcumin in the induction of PPAR-γ gene expression and in the inhibition of HSC activation.

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Shapiro, Haim, and Rafael Bruck. "Therapeutic potential of curcumin in non-alcoholic steatohepatitis." Nutrition Research Reviews 18, no. 2 (December 2005): 212–21. http://dx.doi.org/10.1079/nrr2005106.

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Non-alcoholic steatohepatitis (NASH) may be associated with a number of clinical conditions, but it occurs most commonly in patients with insulin resistance. There is as yet no established disease-modifying treatment, and a safe and broadly available agent that targets hepatic steatosis, insulin resistance, inflammation and fibrosis is necessary. The polyphenolic compound curcumin exhibits antioxidant and anti-inflammatory properties, inhibits NF-κB and activates PPAR-γ. In rodents, curcumin prevents dietary-induced hepatic steatosis, hepatic stellate cell activation and production of fibrotic proteins, and ameliorates steatohepatitis induced by the intake of alcohol or a methionine–choline-deficient diet. Indirect evidence suggests that curcumin may improve insulin sensitivity in diabetes and inflammatory states. The present paper reviews the numerous cellular and animal studies indicating that curcumin attenuates many of the pathophysiological processes involved in the development and progression of NASH. It is suggested that basic and clinical studies on curcumin in the development and progression of NASH are indicated.

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Bhatt, Sumantha, Kathleen Brown, Feng Lin, Michael P. Meyer, Margaret V. Ragni, and Lina Lu. "Hepatic Stellate Cell Conditioned Myeloid Cells Provide a Novel Therapy for Prevention of Factor VIII Antibody Formation in the Hemophilia A Mouse Model." Blood 120, no. 21 (November 16, 2012): 4117. http://dx.doi.org/10.1182/blood.v120.21.4117.4117.

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Abstract Abstract 4117 Background: Hemophilia is an X-linked bleeding disorder resulting from a mutation in coagulation factor VIII (F.VIII). A major drawback of current plasma-derived or recombinant F.VIII therapy is the formation of F.VIII antibodies (inhibitors). Inhibitor formation is a T cell-dependent, B cell-mediated immune response to foreign infused F.VIII. Myeloid derived suppressor cells (MDSCs) are potent suppressors of T cell and B cell responses and are currently under study for therapeutic applications in transplantation and autoimmune diseases. However, the mechanisms of MDSC development and function remain unknown, and in vitro propagation of MDSCs has been a challenge. We hypothesized that MDSCs might be effective in inhibiting F.VIII inhibitor formation in the hemophilia A model. Methods: We developed a novel method for generating MDSCs in vitro by culturing bone marrow cells from hemophilia A mice with hepatic stellate cells (HSCs), hereafter referred to as HSC-conditioned myeloid cells (H-MCs). DCs were propagated from the bone marrow with GM-CSF and IL-4, whereas H-MCs were propagated from the bone marrow with GM-CSF and HSCs. Granulocyte contaminants were removed on day 2 and the remaining monocytic populations were harvested on day 5. Expression of cell surface antigens was analyzed by flow cytometry. Arginase1 and iNOS levels were compared by qPCR, with or without LPS stimulation. The in vitro suppressive capacity of the H-MCs was determined by a mixed leukocyte reaction culture. Splenic T cells from hemophilia A mice were stimulated by irradiated DCs (at a 1–20 ratio, APC to T cell) and recombinant F.VIII. Additional irradiated DCs or H-MCs were added in graded numbers as regulators. The proliferative response was determined by 3H-thymidine incorporation. The phenotype of cultured CD4+ T cells was characterized by intracellular staining for Foxp3 and IFN-gamma and analyzed by flow cytometry. Inhibition of B cells by H-MCs was determined by a CFSE dilution assay. Purified splenic B cells were labeled with CFSE and stimulated by Ig-M and IL-4. APCs (spleen cells) or H-MCs were added at a ratio of 1:10 (APC to B cell). The proportion of proliferating B cells was determined by CFSE dilution of B220 stained cells. In the COX-2 suppression assay, CFSE labeled B cells were treated with varying concentrations of the selective inhibitor of COX-2, NS398. The suppressive effect of H-MCs on B cells in vivo was determined by simultaneously administering H-MCs (I.V) and F.VIII (I.V.) to hemophila A mice on day 0 and rechallenging with recombinant F.VIII on days 2 and 4. WT B6 mice and hemophilia A mice without H-MC transfer served as controls. Plasma anti-F.VIII antibody titers were measured on day 12 by a modified ELISA assay. Results: H-MCs expressed low levels of costimulatory molecules but high levels of the inhibitory molecule B7-H1 and immunoregulatory enzyme arginase-1. In contrast, DCs expressed high levels of costimulatory molecules and MHC class II. In vitro studies demonstrated that the H-MCs markedly inhibited antigen specific T cell proliferation induced by dendritic cells in response to recombinant F.VIII (Fig. 1). H-MCs altered the T cell response in hemophilia A mice by promoting the expansion of regulatory T cells and inhibiting IFN-γ producing CD4+ T cells. When the H-MCs were cocultured with B cells isolated from hemophilia A mice, in the presence of Ig-M and IL-4, the H-MCs abrogated B cell activation and proliferation directly (Fig. 2). H-MCs may be modulating the B cell response through the Cox-2 pathway, as inhibition of Cox-2 through NS398 led to the restoration of B cell proliferation. More importantly, adoptive transfer of H-MCs into hemophilia Amice, at the time of F.VIII infusion, markedly suppressed anti-F.VIII antibody formation (Fig. 3). Conclusion: These results suggest that HSC conditioned myeloid cells may represent a potential therapeutic approach to induction of immune tolerance in patients with hemophilia A andother immune disorders. Disclosures: No relevant conflicts of interest to declare.

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Bae, Minkyung, Mi-Bo Kim, and Ji-Young Lee. "Fucoxanthin Attenuates the Reprogramming of Energy Metabolism during the Activation of Hepatic Stellate Cells." Nutrients 14, no. 9 (May 1, 2022): 1902. http://dx.doi.org/10.3390/nu14091902.

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Hepatic stellate cells (HSC) play a major role in developing liver fibrosis. Upon activation during liver injury, activated HSC (aHSC) increase cell proliferation, fibrogenesis, contractility, chemotaxis, and cytokine release. We previously showed that aHSC have increased mitochondrial respiration but decreased glycolysis compared to quiescent HSC (qHSC). We also demonstrated that fucoxanthin (FCX), a xanthophyll carotenoid, has an anti-fibrogenic effect in HSC. The objective of this study was to investigate whether FCX attenuates metabolic reprogramming occurring during HSC activation. Mouse primary HSC were activated in the presence or absence of FCX for seven days. aHSC displayed significantly decreased glycolysis and increased mitochondrial respiration compared to qHSC, which was ameliorated by FCX present during activation. In addition, FCX partially attenuated the changes in the expression of genes involved in glycolysis and mitochondrial respiration, including hexokinase 1 (Hk1), Hk2, peroxisome proliferator-activated receptor γ coactivator 1β, and pyruvate dehydrogenase kinase 3. Our data suggest that FCX may prevent HSC activation by modulating the expression of genes crucial for metabolic reprogramming in HSC.

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Oh, Ji Eun, Kwang Yong Shim, Jong In Lee, Soo In Choi, Soon Koo Baik, and Young Woo Eom. "1-Methyl-L-tryptophan promotes the apoptosis of hepatic stellate cells arrested by interferon-γ by increasing the expression of IFN-γRβ, IRF-1 and FAS." International Journal of Molecular Medicine 40, no. 2 (June 26, 2017): 576–82. http://dx.doi.org/10.3892/ijmm.2017.3043.

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Zheng, Shizhong, and Anping Chen. "Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 5 (May 2006): G883—G893. http://dx.doi.org/10.1152/ajpgi.00450.2005.

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Upon liver injury, quiescent hepatic stellate cells (HSCs), the most relevant cell type for hepatic fibrogenesis, become active and overproduce extracellular matrix (ECM). Connective tissue growth factor (CTGF) promotes ECM production. Overexpression of CTGF during hepatic fibrogenesis is induced by transforming growth factor (TGF)-β. We recently demonstrated that curcumin reduced cell growth and inhibited ECM gene expression in activated HSCs. Curcumin induced gene expression of peroxisome proliferator-activated receptor (PPAR)-γ and stimulated its activity in activated HSCs, which was required for curcumin to suppress ECM gene expression, including αI(I)-collagen. The underlying mechanisms remain largely unknown. The aim of this study was to elucidate the mechanisms by which curcumin suppresses αI(I)-collagen gene expression in activated HSCs. We hypothesize that inhibition of αI(I)-collagen gene expression in HSCs by curcumin is mediated by suppressing CTGF gene expression through attenuating oxidative stress and interrupting TGF-β signaling. The present report demonstrated that curcumin significantly reduced the abundance of CTGF in passaged HSCs and suppressed its gene expression. Exogenous CTGF dose dependently abrogated the inhibitory effect of curcumin. Activation of PPAR-γ by curcumin resulted in the interruption of TGF-β signaling by suppressing gene expression of TGF-β receptors, leading to inhibition of CTGF gene expression. The phytochemical showed its potent antioxidant property by significantly increasing the level of total glutathione (GSH) and the ratio of GSH to GSSG in activated HSCs. De novo synthesis of cellular GSH was a prerequisite for curcumin to interrupt TGF-β signaling and inhibited gene expression of CTGF and αI(I)-collagen in activated HSCs. Taken together, our results demonstrate that inhibition of αI(I)-collagen gene expression by curcumin in activated HSCs results from suppression of CTGF gene expression through increasing cellular GSH contents and interruption of TGF-β signaling. These results provide novel insights into the mechanisms underlying inhibition of HSC activation by curcumin.

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Tao, Le, Liu Wu, Wei Zhang, Wen-ting Ma, Guang-yue Yang, Jie Zhang, Dong-ying Xue, Bei Chen, and Cheng Liu. "Peroxisome proliferator-activated receptor γ inhibits hepatic stellate cell activation regulated by miR-942 in chronic hepatitis B liver fibrosis." Life Sciences 253 (July 2020): 117572. http://dx.doi.org/10.1016/j.lfs.2020.117572.

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Lee, Jung Il, Yong-Han Paik, Kwan Sik Lee, Jin Woo Lee, Yong Soo Kim, Seok Jeong, Kye Sook Kwon, et al. "A peroxisome-proliferator activated receptor-γ ligand could regulate the expression of leptin receptor on human hepatic stellate cells." Histochemistry and Cell Biology 127, no. 5 (March 29, 2007): 495–502. http://dx.doi.org/10.1007/s00418-007-0282-x.

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Gao, Wenxi, Wenxia Peng, Xingpei Ji, Dandan Zhu, Jinling Chen, Jinrong Feng, Yang Yu, Lian Duan, and Yinong Duan. "Expression of recombinant Schistosoma japonicum protein rSjE16 and its effects on LX-2 cells in vitro." Journal of International Medical Research 48, no. 12 (December 2020): 030006052097222. http://dx.doi.org/10.1177/0300060520972228.

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Objective The activation of hepatic stellate cells (HSCs) is a key event in schistosome-induced liver fibrosis. Previous studies have shown that soluble egg antigens and the recombinant P40 protein from Schistosoma japonicum eggs inhibit HSC activation. In the present study, we observed the direct effect of the S. japonicum recombinant (r)SjE16 protein on HSCs. Methods The sequence of SjE16 was analyzed by bioinformatics. Then western blotting, quantitative PCR, and MTT assays were performed to observe the effects of rSjE16 on HSCs. Results The SjE16 protein has no signal peptide or transmembrane region. rSjE16 significantly inhibited expression levels of α-smooth muscle actin and collagen I protein in LX-2 cells. rSjE16 also significantly increased the expression levels of interleukin (IL)-6 and IL-8, and enhanced the expression of matrix metalloproteinase (MMP)-2, MMP-9, and peroxisome proliferator-activated receptor-γ in LX-2 cells. LX-2 cell viability was not inhibited by rSjE16. Conclusion rSjE16 may be involved in the progression of HSC activation via a complex molecular mechanism, which requires further study to fully understand.

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Yang, Hui, Li Zhang, Jie Chen, Xiaoqian Zhang, Zhongfu Zhao, and Longfeng Zhao. "Heme Oxygenase-1 Inhibits the Proliferation of Hepatic Stellate Cells by Activating PPARγ and Suppressing NF-κB." Computational and Mathematical Methods in Medicine 2022 (January 10, 2022): 1–10. http://dx.doi.org/10.1155/2022/8920861.

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Background. Hepatic stellate cells (HSCs) are reported to play significant roles in the development of liver fibrosis. Heme oxygenase-1 (HO-1) is a key rate-limiting enzyme, which could decrease collagen synthesis and liver damage. Nevertheless, it was yet elusive towards the function and mechanism of HO-1. Methods. An HO-1 inducer Hemin or an HO-1 inhibitor ZnPP-IX was used to treat the activated HSC-T6, respectively. MTT assay was adopted to detect cell proliferation. Immunocytochemical staining was employed to test the levels of alpha-smooth muscle actin (α-SMA), peroxisome proliferator-activated receptor-γ (PPARγ), and nuclear factor-kappa B (NF-kappa B) levels in HSC-T6. HO-1, PPARγ, and NF-κB expression levels were measured by qRT-PCR and Western blotting. ELISA was then used to detect the levels of transforming growth factor- (TGF-) beta 1 (TGF-β1), interleukin-6 (IL-6), serum hyaluronic acid (HA), and serum type III procollagen aminopeptide (PIIIP). Results. HSC-T6 proliferation was inhibited in Hemin-treated HSCs. The levels of α-SMA, HA, and PIIIP and the production of ECM were lower in Hemin-treated HSCs, whereas those could be rescued by ZnPP-IX. NF-κB activation was decreased, but PPARγ expression was increased after HO-1 upregulation. Furthermore, the levels of TGF-β1 and IL-6, which were downstream of activated NF-κB in HSC-T6, were reduced. The PPAR-specific inhibitor GW9662 could block those mentioned effects. Conclusions. Our data demonstrated that HO-1 induction could inhibit HSC proliferation and activation by regulating PPARγ expression and NF-κB activation directly or indirectly, which makes it a promising therapeutic target for liver fibrosis.

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Choi, Jae Ho, Seul Mi Kim, Gi Ho Lee, Sun Woo Jin, Hyun Sun Lee, Young Chul Chung, and Hye Gwang Jeong. "Platyconic Acid A, Platycodi Radix-Derived Saponin, Suppresses TGF-β1-Induced Activation of Hepatic Stellate Cells via Blocking SMAD and Activating the PPARγ Signaling Pathway." Cells 8, no. 12 (November 29, 2019): 1544. http://dx.doi.org/10.3390/cells8121544.

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Platycodi radix is a widely sold health food worldwide, which contains numerous phytochemicals that are beneficial to health. Previously, we reported that saponin from the roots of Platycodi radix-derived saponin inhibited toxicant-induced liver diseases. Nevertheless, the inhibitory effect of platyconic acid A (PA), the active component of Platycodi radix-derived saponin, on the anti-fibrotic activity involving the SMAD pathway remains unclear. We investigated the inhibitory effects of PA on TGF-β1-induced activation of hepatic stellate cells (HSCs). PA inhibited TGF-β1-enhanced cell proliferation, as well as expression of α-SMA and collagen Iα1 in HSC-T6 cells. PA suppressed TGF-β1-induced smad2/3 phosphorylation and smad binding elements 4 (SBE4) luciferase activity. Reversely, PA restored TGF-β1-reduced expression of smad7 and peroxisome proliferator-activated receptor (PPAR)γ. PA also repressed TGF-β1-induced phosphorylation of Akt and MAPKs. In summary, the results suggest that the inhibitory effect of PA on HSCs occurs through the blocking of SMAD-dependent and SMAD-independent pathways, leading to the suppression of α-SMA and collagen Iα1 expression.

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ZHENG, Shizhong, and Anping CHEN. "Activation of PPARγ is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro." Biochemical Journal 384, no. 1 (November 9, 2004): 149–57. http://dx.doi.org/10.1042/bj20040928.

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During liver fibrogenesis, quiescent HSC (hepatic stellate cells) become active, a transformation that is associated with enhanced cell proliferation and overproduction of ECM (extracellular matrix). Inhibition of cell proliferation and induction of apoptosis are potential strategies to block the activation of HSC for the prevention and treatment of liver fibrosis. Levels of PPARγ (peroxisome proliferator-activated receptor γ) are dramatically diminished in parallel with HSC activation. Stimulation of PPARγ by its agonists inhibits HSC activation in vitro and in vivo. We demonstrated recently that curcumin, the yellow pigment in curry, inhibited HSC activation in vitro, reducing cell proliferation, inducing apoptosis and inhibiting ECM gene expression. Further studies indicated that curcumin induced the gene expression of PPARγ and stimulated its activity in activated HSC in vitro, which was required for curcumin to inhibit HSC proliferation. The aims of the present study were to evaluate the roles of PPARγ activation in the induction of apoptosis and suppression of ECM gene expression by curcumin in activated HSC, and to elucidate the underlying mechanisms. Our results demonstrated that blocking PPARγ activation abrogated the effects of curcumin on the induction of apoptosis and inhibition of the expression of ECM genes in activated HSC in vitro. Further experiments demonstrated that curcumin suppressed the gene expression of TGF-β (transforming growth factor-β) receptors and interrupted the TGF-β signalling pathway in activated HSC, which was mediated by PPARγ activation. Taken together, our results demonstrate that curcumin stimulated PPARγ activity in activated HSC in vitro, which was required for curcumin to reduce cell proliferation, induce apoptosis and suppress ECM gene expression. These results provide novel insight into the mechanisms responsible for the inhibition of HSC activation by curcumin. The characteristics of curcumin, which has no adverse health effects, make it a potential candidate for prevention and treatment of hepatic fibrosis.

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Wang, Xueqing, Guangcun Huang, Shuang Mei, Jin Qian, Juling Ji, and Jinsheng Zhang. "Over-expression of C/EBP-α induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-γ." Biochemical and Biophysical Research Communications 380, no. 2 (March 2009): 286–91. http://dx.doi.org/10.1016/j.bbrc.2009.01.060.

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Saile, Bernhard, Christoph Eisenbach, Jozsef Dudas, Hammoudeh El-Armouche, and Giuliano Ramadori. "Interferon-γ acts proapoptotic on hepatic stellate cells (HSC) and abrogates the antiapoptotic effect of interferon-α by an HSP70-dependant pathway." European Journal of Cell Biology 83, no. 9 (2004): 469–76. http://dx.doi.org/10.1078/0171-9335-00409.

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Yavrom, Sharon, Li Chen, Shigang Xiong, Jiaohong Wang, Richard A. Rippe, and Hidekazu Tsukamoto. "Peroxisome Proliferator-activated Receptor γ Suppresses Proximal α1(I) Collagen Promoter via Inhibition of p300-facilitated NF-I Binding to DNA in Hepatic Stellate Cells." Journal of Biological Chemistry 280, no. 49 (October 10, 2005): 40650–59. http://dx.doi.org/10.1074/jbc.m510094200.

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Beltagy, Doha M., Khloud Gamal Abdelsalam, Tarek M. Mohamed, and Mai M. El-Keey. "Role of Harmaline as Adiponectin Modulator in Defeating Liver Cirrhosis Induced By Thioacetamide in Mice." Biomedical and Pharmacology Journal 14, no. 1 (March 28, 2021): 123–31. http://dx.doi.org/10.13005/bpj/2106.

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Liver cirrhosis is currently the 11th most common cause of death which includes inflammatory, oxidative damage, and immune response. Harmaline has antioxidant and anti-inflammatory mechanisms which can defeat against hepatic cirrhosis pathways. The present work aimed to evaluate the ameliorating effect of harmaline against liver cirrhosis induced by thioacetamide in mice. The study was carried out on sixty male mice divided into three main groups. Control and harmaline groups (GIa and GIb), thioacetamide-group (GII) and harmaline co-treated and treated groups (GIIIa and GIIIb). By the end of the experiment, adiponectin concentrations were measured in serum and liver tissue. Gene expression of adiponectin, transforming growth factor beta-1 (TGF-β1), tissue inhibitor metalloprotease-1(TIMP-1) and peroxisome proliferator activated receptor-gamma (PPAR-γ) were assessed. Some oxidative stress biomarkers as malondialdehyde, reduced glutathione, catalase, superoxide dismutase and nitric oxide were determined. The results indicated that harmaline administration cause significant suppression of oxidative stress and inflammatory response.Inhibition of hepatic stellate cell activation and extracellular matrix deposition were also noticed with a significant decrease in the expression of the profibrotic markers(TGF-β1 and TIMP-1) which have direct effects on adiponectin activation. These results were confirmed by the histological studies in liver tissue. In Conclusion,Harmaline has excellent protective role against liver cirrhosis induced by thioacetamide in mice via its antioxidant and anti-inflammatory properties.It can be therapeutically used as a safe liver support by a dose of 10 mg/kg after furtherin vivo studies.

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Saile, Bernhard, Christoph Eisenbach, Hammoudeh El-Armouche, Katrin Neubauer, and Giuliano Ramadori. "Antiapoptotic effect of interferon-α on hepatic stellate cells (HSC): A novel pathway of IFN-α signal transduction via Janus kinase 2 (JAK2) and caspase-8." European Journal of Cell Biology 82, no. 1 (January 2003): 31–41. http://dx.doi.org/10.1078/0171-9335-00285.

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Correia, Ana Luisa. "Abstract SY31-02: Revisiting NK cell immunity to prevent metastasis." Cancer Research 82, no. 12_Supplement (June 15, 2022): SY31–02—SY31–02. http://dx.doi.org/10.1158/1538-7445.am2022-sy31-02.

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Abstract Metastases arising in distant tissues continue to cause the majority of all cancer-related deaths. The uncertainty of whether and when metastases will occur poses a major challenge to treatment effectiveness. In many cancer patients, persistent disseminated tumor cells (DTCs) enter a state of dormancy upon arrival at the distant tissue, only to awaken years or even decades afterwards and initiate deadly metastases. How are DTCs kept dormant, what prompts them to awaken, and how can dormant DTCs be targeted are pressing questions in cancer research. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Recently, we developed a tool to follow dormant DTCs, and surveyed the anatomical distribution of dormant reservoirs in models of breast cancer metastasis. We discovered that DTCs laid preferentially dormant in the liver, and spatially distinct liver sub-microenvironments allow coexistence of dormant DTCs and rare growing metastases even within the same tissue. To explore whether the distinct fates of DTCs stemmed from intra-organ microenvironmental differences, we performed global transcriptomic profiling on hepatic milieus corresponding to dormancy and metastasis. We found that stromal cells clustered on the basis of disease stage, and genes that were upregulated in dormancy samples were associated with host defense processes and natural killer (NK) cell-mediated response. A thorough examination of viable populations of immune cells in each hepatic milieu revealed that NK cells were the only type of immune cell that increased in dormancy milieus. Gain- and loss-of-function experiments in vivo further indicated that the pool of NK cells encountered by DTCs is decisive on their awakening. Remarkably, adjuvant interleukin-15-based immunotherapy ensured an abundant pool of NK cells that sustained dormancy, thereby preventing hepatic metastases and prolonging survival. In addition, we demonstrated in vivo and in liver-like co-cultures that NK cells control dormant DTCs through IFN-γ-induced quiescence. Thus, we uncovered an alternative cytostatic IFNγ-mediated mechanism of NK cell immunity that is essential to the control of breast cancer dormancy. This finding reroutes the importance of IFNγ to much earlier stages of disease, and encourages its therapeutic use for establishing the non-permissive cytokine milieu that is necessary to limit the emergence of DTCs from dormancy. Another key finding of our work is that liver injury limits NK cell expansion, thus triggering the switch from dormancy to liver metastasis. Using a model of chemically-induced liver injury, we found that activated hepatic stellate cells (aHSCs, which activate from quiescent HSCs to proliferative myofibroblasts) orchestrate a stromal response that hampers NK cell-mediated immunity and precipitates metastasis. Mechanistically, we show that aHSCs secrete the chemokine CXCL12, inducing NK cell quiescence via its cognate receptor CXCR4. This NK cell-inhibitory function of CXCL12 adds to its canonical effect as an inducer of DTC proliferation, and contributes to metastatic outgrowth. Our findings revive clinical interest on the use of CXCR4 inhibitors in the treatment of patients with cancer, but suggest that they should be repurposed to earlier stages to prevent progression of dormant disease. Because the size of the NK cell pool can itself determine metastatic outgrowth, a decrease of NK cells in patients with cancer who are apparently disease-free might identify individuals who are at risk of recurrence and who would benefit from CXCR4 inhibition therapy - a question that we will address in a clinical trial that we are currently setting up at the University Hospital Basel. All this work, which I am the first and corresponding author of, was recently published in Nature (Correia et al. Nature, 2021). In summary, our study shows that DTC dormancy is achieved by preserving normal tissue physiology—particularly tissue innate immunity—and that disruptions of the latter present DTCs with an opportunity for reactivation. In patients, this is reflected in the invariable decline in host defense capabilities that occurs during ageing, but also in the increased risk that recurrent infections and lifestyle-related injury triggers (such as alcohol, obesity and smoking) bring to the sprouting of site-specific metastases. We envision adjuvant NK cell immunotherapy as a means to preserve tissue physiology and prevent metastatic disease. Citation Format: Ana Luisa Correia. Revisiting NK cell immunity to prevent metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY31-02.

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Tsai, Cheng-Chieh, Wei-Ching Huang, Chia-Ling Chen, Chia-Yuan Hsieh, Yee-Shin Lin, Shun-Hua Chen, Kao-Chi Yang, and Chiou-Feng Lin. "Glycogen synthase kinase-3 facilitates Con A-induced IFN-γ-mediated immune hepatic injury (54.24)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 54.24. http://dx.doi.org/10.4049/jimmunol.188.supp.54.24.

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Abstract IFN-γ-mediated inflammation followed by hepatic cell death determines Con A-induced immune hepatic injury. Glycogen synthase kinase (GSK)-3, which acts proapoptotically and is proinflammatory, is also important for facilitating IFN-γ signaling. We hypothesized a pathogenic role for GSK-3 in Con A hepatic injury. Con A stimulation caused GSK-3 activation in the livers of C57BL/6 mice. Inhibiting GSK-3 reduced Con A hepatic injury, including hepatic necrosis and apoptosis, inflammation, infiltration of T cells and granulocytes, and deregulated expression of adhesion molecule CD54. Con A induced hepatic injury in an IFN-γ receptor 1-dependent manner. Con A/IFN-γ induced activation and expression of STAT1 in a GSK-3-dependent manner. GSK-3 facilitated IFN-γ-induced inducible NO synthase, but had limited effects on CD95 upregulation and CD95-mediated hepatocyte apoptosis in vitro. Notably, inhibiting GSK-3 decreased Con A-induced IFN-γ production in both wild-type and IFN-γ receptor 1-deficient C57BL/6 mice. In Con A-activated NKT cells, GSK-3 was also activated and was required for nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ, but it was not required for CD95 ligand expression or activation-induced cell death. These results demonstrate the dual and indispensable role of GSK-3 in Con A hepatic injury by facilitating IFN-γ-induced hepatopathy.

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He, Xing, Yue Sun, Nanhang Lei, Xiaobin Fan, Cheng Zhang, Yange Wang, Kuiyang Zheng, Dongmei Zhang, and Weiqing Pan. "MicroRNA-351 promotes schistosomiasis-induced hepatic fibrosis by targeting the vitamin D receptor." Proceedings of the National Academy of Sciences 115, no. 1 (December 18, 2017): 180–85. http://dx.doi.org/10.1073/pnas.1715965115.

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Aberrant expression of microRNAs (miRNAs) underlies a spectrum of human diseases including organ fibrosis, and hepatic stellate cells (HSCs) are the main effectors of hepatic fibrosis. Here, we showed that the expression of host miR-351 in HSCs was markedly reduced during the early stage of Schistosoma infection. However, this expression was significantly increased during the later stage of infection (after 52 d of infection). The elevated levels of miR-351 promoted hepatic fibrosis by targeting the vitamin D receptor (VDR), which is an antagonist of SMAD signaling. Importantly, efficient and sustained inhibition of miR-351 in liver tissues using the highly hepatotropic recombinant adeno-associated virus serotype 8 (rAAV8), alleviated the hepatic fibrosis, partially protecting the host from lethal schistosomiasis. In addition, we found that miR-351 is negatively regulated by IFN-γ in HSCs during infection. At the early stage of infection, the elevated levels of IFN-γ inhibited the expression of miR-351 in HSCs through activation of signal transducer and activator of transcription 1 and induction of IFN regulatory factor 2, which binds the promotor of pre–miR-351. Our study provides insights into the mechanisms by which miR-351 regulates schistosomiasis hepatic fibrosis and highlights the potential of rAAV8-mediated miR-351 inhibition as a therapeutic intervention for fibrotic diseases.

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Bokhari, Sirosh M., Kee-Jun Kim, David M. Pinson, Joyce Slusser, Hung-Wen Yeh, and Michael J. Parmely. "NK Cells and Gamma Interferon Coordinate the Formation and Function of Hepatic Granulomas in Mice Infected with the Francisella tularensis Live Vaccine Strain." Infection and Immunity 76, no. 4 (January 28, 2008): 1379–89. http://dx.doi.org/10.1128/iai.00745-07.

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ABSTRACT Host innate immune responses to many intracellular pathogens include the formation of inflammatory granulomas that are thought to provide a physical barrier between the microbe and host. Because two common features of infections with the live vaccine strain (LVS) of Francisella tularensis within the mouse liver are the formation of granulomas and the production of gamma interferon (IFN-γ), we have asked what role IFN-γ plays in hepatic granuloma formation and function. Francisella antigens were predominantly localized within granulomas of the livers of mice infected with F. tularensis LVS 4 days postinfection. Hepatic granulomas also contained large numbers of dying cells, some of which coexpressed the F4/80 macrophage antigen and activated caspase-3. IFN-γ-deficient mice did not form normal numbers of hepatic granulomas and showed widely disseminated Francisella antigens within the liver. The incidence of cell death within hepatic granulomas also decreased significantly in the absence of IFN-γ. Inducible NO synthase (iNOS) expression was restricted to the granulomas of wild-type mice but was not seen for IFN-γ-deficient mice. Cell death within granulomas was also significantly decreased for iNOS-deficient mice. The predominant IFN-γ-expressing cells in the liver were NK cells. Depleting NK cells resulted in the expression of bacterial antigens and iNOS outside the granulomas and the appearance of extensive hepatic focal necrosis. These findings indicate that IFN-γ and hepatic NK cells that are activated during F. tularensis LVS infections regulate hepatic granuloma formation, the spatial containment of infection, the expression of iNOS, and the induction of cell death within the liver.

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Werner, Melanie, Stefan Schefczyk, Martin Trippler, Juergen W. Treckmann, Hideo A. Baba, Guido Gerken, Joerg F. Schlaak, and Ruth Broering. "Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3." Viruses 14, no. 2 (January 24, 2022): 218. http://dx.doi.org/10.3390/v14020218.

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The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.

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Shields, Philip L., Clare M. Morland, Michael Salmon, Shixin Qin, Stefan G. Hubscher, and David H. Adams. "Chemokine and Chemokine Receptor Interactions Provide a Mechanism for Selective T Cell Recruitment to Specific Liver Compartments Within Hepatitis C-Infected Liver." Journal of Immunology 163, no. 11 (December 1, 1999): 6236–43. http://dx.doi.org/10.4049/jimmunol.163.11.6236.

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Abstract The role played by chemokines in regulating the selective recruitment of lymphocytes to different tissue compartments in disease is poorly characterized. In hepatitis C infection, inflammation confined to portal areas is associated with a less aggressive course, whereas T cell infiltration of the liver parenchyma is associated with progressive liver injury and cirrhosis. We propose a mechanism to explain how lymphocytes are recruited to hepatic lobules during bursts of necroinflammatory activity in chronic hepatitis C infection. We report here that lymphocytes infiltrating hepatitis C-infected liver express high levels of the chemokine receptors CCR5 and CXCR3. However, whereas the CCR5 ligands macrophage inflammatory protein-1α and -1β were largely confined to vessels within portal tracts, the CXCR3 ligands IFN-inducible protein-10 and monokine-induced by IFN-γ were selectively up-regulated on sinusoidal endothelium. In vitro, human hepatic sinusoidal endothelial cells secreted IFN-inducible protein-10 and monokine-induced by IFN-γ in response to stimulation with IFN-γ in combination with either IL-1 or TNF-α. This suggests that intrahepatic Th1 cytokines drive the increased expression of IFN-inducible protein-10 and monokine-induced by IFN-γ and thereby promote the continuing recruitment of CXCR3-expressing T cells into the hepatic lobule in chronic hepatitis C infection.

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Jaruga, Barbara, Feng Hong, Won-Ho Kim, and Bin Gao. "IFN-γ/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: a critical role of IRF-1." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 5 (November 2004): G1044—G1052. http://dx.doi.org/10.1152/ajpgi.00184.2004.

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We have previously shown that IFN-γ/STAT1 plays an essential role in concanavalin A (ConA)-induced T cell hepatitis via activation of apoptotic signaling pathways. Here we demonstrate that IFN-γ/STAT1 also plays a crucial role in leukocyte infiltration into the liver in T cell hepatitis. After injection of ConA, leukocytes were significantly infiltrated into the liver, which was suppressed in IFN-γ−/− and STAT1−/− mice. Disruption of the IFN regulatory factor-1 (IRF-1) gene, a downstream target of IFN-γ/STAT1, abolished ConA-induced liver injury and suppressed leukocyte infiltration into the liver. Additionally, ConA injection induced expression of a wide variety of chemokines and adhesion molecules in the liver. Among them, expression of ICAM-1, VCAM-1, monokine induced by IFN-γ (Mig), CC chemokine ligand-20, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IFN-inducible T cell-α chemoattractant (I-TAC), and IFN-inducible protein-10 (IP-10) was markedly attenuated in IFN-γ−/−, STAT1−/−, and IRF-1−/− mice. In primary mouse hepatocytes, Kupffer cells, and endothelial cells, in vitro treatment with IFN-γ activated STAT1, STAT3, and IRF-1, and induced expression of VCAM-1, ICAM-1, Mig, ENA-78, I-TAC, and IP-10 mRNA. Induction of these chemokines and adhesion molecules was markedly diminished in STAT1−/− and IRF-1−/− hepatic cells compared with wild-type hepatic cells. These findings suggest that in addition to induction of apoptosis, previously well documented, IFN-γ also stimulated hepatocytes, sinusoidal endothelial cells, and Kupffer cells partly via an STAT1/IRF-1-dependent mechanism to produce multiple chemokines and adhesive molecules responsible for promoting infiltration of leukocytes and, ultimately, resulting in hepatitis.

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RADAEVA, Svetlana, Barbara JARUGA, Won-Ho KIM, Theo HELLER, T. Jake LIANG, and Bin GAO. "Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C." Biochemical Journal 379, no. 1 (April 1, 2004): 199–208. http://dx.doi.org/10.1042/bj20031495.

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IFN-γ (interferon-γ) modulates IFN-α therapy in chronic hepatitis C infection; however, the underlying mechanism remains unclear. Here we demonstrate that long-term (3–6 days) but not short-term (up to 1 day) IFN-γ treatment of human hepatoma Hep3B cells attenuates IFN-α activation of STAT1 (signal transducers and activators of transcription factor 1), STAT2 and STAT3, but enhances IFN-γ and interleukin 6 activation of STATs. Prolonged exposure to IFN-γ also significantly induces STAT1 protein expression without affecting STAT2, STAT3 and ERK (extracellular-signal-regulated kinase) 1/2 protein expression. To determine the role of STAT1 protein overexpression in regulation of IFN-α signalling, Hep3B cells were stably transfected with wild-type STAT1. Overexpression of STAT1 via stable transfection enhances IFN-γ activation of STAT1, but surprisingly attenuates IFN-α activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation. This STAT1-mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant-negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-α activation of STAT1, STAT2 and STAT3. Moreover, overexpression of STAT1 blocks IFN-α-activated STAT2 translocation from IFN-α receptor 2 to IFN-α receptor 1, a critical step in IFN-α signalling activation. Finally, significantly higher levels of STAT1 protein expression, which is probably induced by IFN-γ, are detected in the majority of hepatitis C virus-infected livers compared with healthy controls. In conclusion, long-term IFN-γ treatment inhibits IFN-α-activated signals most probably, at least in part, through the induction of STAT1 protein expression, which could partly contribute to IFN-α treatment failure in hepatitis C patients.

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Journal articles on the topic 'Hepatic Stellate Cell IFN-γ'

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