Ito Cell Proliferation Research Articles

Extrahepatic bile duct ligation in broiler chickens: ultrastructural study of Ito cell

The Ito cell (fat-storing cell) is a cell lying in perisinusoidal space of liver. The function of Ito cell is expanding from a site of fat-storing site to a center of extracellular matrix metabolism and mediator production in the liver. This study was performed in order to evaluate the Ito cells in cholestatic condition. The artificial cholestatic was conducted by ligation of extrahepatic bile ducts (bile duct ligation = BDL) in broilers. The results showed that BDL induced bile congestion, fibrosis, proliferation of Ito cells and intrahepatic bile ductules. Immunohistochemistry demonstrated that Ito cells were scattered throughout the fibrotic areas, and larger in size with more extensive immunoreactivity than those in normal livers. Ultrastructural study demonstrated that Ito cells were closely associated with the production of extracellular collagen fibers. Ito cells actively react against hepatocytic injuries, especially in fibrogenesis of cholestatic livers. Key words: Bile duct, ito cell, broiler

STEREOLOGICAL ESTIMATION OF ITO CELLS FROM RAT LIVER USING THE OPTICAL FRACTIONATOR - A PRELIMINARY REPORT

In the last two decades, much light has been shed on hepatic fibrosis, and the activation / proliferation of Ito cells (IC) emerged to play a central role. Therefore, it is essential to have solid quantitative data in nonpathological statuses; yet, this data is scarce and confined to "number per area" or semiquantitative information. Moreover, the supposed heterogeneous distribution of IC in the hepatic lobule was never analysed with design-based (unbiased) stereology. In the present study, the total number (N) of IC in rat liver was estimated for the first time, by combining immunocytochemistry with the optical fractionator. Quantification was extended to the hepatocytes, to disclose the IC index, an often-used ratio in hepatology. Systematic uniform random liver sections were obtained from male Wistar rats (n = 3), and immunostained against glial fibrillary acidic protein (GFAP), a known specific marker for hepatic IC. For the first time, these were marked against GFAP in thick (30 μm) paraffin sections. The estimated N of IC was 224E06; with a coefficient of error of 0.04 or 0.06, depending on the particular equation used (based on the so-called "quadratic approximation"). The IC index was 91 IC/1000 hepatocytes. Concerning the lobular heterogeneity, it was proved the liver harbours a larger total number of periportal IC and hepatocytes.

IL-18 Downregulates Collagen Production in Human Dermal Fibroblasts via the ERK Pathway

Excessive accumulation of collagen contributes to the fibrotic process. Several experimental studies have shown that IFN-gamma is effective in preventing fibrogenesis. IL-18, originally identified as an IFN-gamma-inducing factor, is a key mediator of inflammation and host defense responses. In this study, we investigated the regulatory effect of IL-18 on the expression of type I and III collagen genes in dermal fibroblasts. The exposure of human dermal fibroblasts (HDFs) to IL-18 resulted in a reduction of collagen gene expression and production. Also, IL-18 inhibited the fibrogenic cytokine transforming growth factor (TGF)-beta-induced collagen gene expression. Next, to determine the molecular mechanism involved in this regulation, we showed that IL-18-regulated collagen expression was blocked by small interfering RNA (siRNA)-mediated Ets-1 knockdown. Furthermore, we showed that IL-18 induced phosphorylation of extracellular signal-regulated kinase (ERK) within 10 minutes and that the ERK inhibitor PD98059 blocked the inhibitory effect of IL-18. IL-18 also inhibited the production of collagen in systemic sclerosis (SSc) dermal fibroblasts. Our data indicate that IL-18 downregulates collagen production in HDF directly via Ets-1 and the ERK pathway, suggesting that IL-18 may exert antifibrotic activities in dermal fibroblasts.

Neoplasm of hepatic stellate cells (spongiotic pericytoma): A new tumor entity in human liver

The purpose of this investigation was to classify a previously unknown tumor entity in human liver observed in a 35-year-old woman. It was characterized by an unusual accumulation of fusiform CD34-positive cells and was initially misconceived as a tumor of the liver sinusoids. The tissue was examined by light and electron microscopy and by immunocytochemical techniques with a broad spectrum of antibodies. The polycyclic tumor contained multiple nodular cell aggregates. The tumor cells possessed extensive cytoplasmic processes, rough endoplasmic reticulum, a prominent Golgi complex, and, in isolated cases, fat droplets. They expressed vimentin, CD34, CD105, CD99, CD56, and sm-actin. The matrix surrounding these cells was reactive for collagen types I, III and V, and fibronectin. The unusual aspect of this tumor is that it contained collections of cells that appeared to be hepatic stellate cells (Ito cells). It also contained hepatic cells arranged in plates, lobules, and capillarized sinuses. These findings suggest that the tumorous proliferation of hepatic stellate cells is functionally linked to the hepatocytes. It is unclear whether there is a link between the tumor and the patient's use of oral contraceptives. Referring to animal studies, different hepatocarcinogens may cause neoplastic Ito cell proliferation. The patient has remained recurrence-free during the 12 months since operation.

The role of TGF-β1 and cytokines in the modulation of liver fibrosis by Sho-saiko-to in rat's bile duct ligated model

Liver fibrosis is an over-accumulation of extra-cellular matrix (ECM) and the hepatic stellate cell (Ito cell) play a central role in the pathogenesis of liver fibrosis. There are a lot of growth factors and cytokines involved in the activation of hepatic stellate cell, including of transforming growth factor (TGF-α, TGF-β1), platelet-derived growth factor (PDGF), interleukin (IL-1α,β, IL-6) and tumor necrosis factor (TNF-α). Sho-saiko-to (TJ-9; Xiao-Chai-Hu-Tang in Chinese) was the most popular herbal medicine for the treatment of chronic liver disease in Chinese and Japanese. Our aim of the current study was to examine whether TJ-9 regulated the growth factors and cytokines in the fibrogenesis of bile duct ligated model. Therefore, we assessed the TJ-9's potential in regulating TGF-β1, PDGF mRNA expression, the amount of IL-1α, IL-1β, IL-6, TNF-α and the fibrotic marker “PIII NP” in the serum. Then, using the immunohistochemical stain to observe the TGF-β1 expression in the tissue. Our results showed that TJ-9 at a dose of 0.5 g/(kg day) significantly reduced the serum level of PIII NP, the mRNA expression of TGF-β1 and PDGF. For the cytokines involved in the activation of Ito cell, TJ-9 at a dose of 0.5 g/(kg day) significantly suppressed the increasing tendency of IL-1β and enhanced the production of TNF-α. Finally, we concluded that: (1) TJ-9 at a dose of 0.5 g/(kg day) significantly reduced the serum fibrotic marker PIII NP in the bile duct ligated model, and its mechanism was partly by means of downregulating the mRNA of TGF-β1 and PDGF. These results also confirmed by the immunohistochemical staining of TGF-β1. (2) TJ-9 at a dose of 0.5 g/(kg day) suppressed the increasing tendency of IL-1β and stimulated the production of TNF-α to inhibit Ito cell proliferation and collagen formation.

Alteration of the liver in rats with experimental dysbiosis.

We evaluated the relationship between pathological changes in the liver and the state of intestinal microflora in rats with experimental dysbiosis. Changes in the intestinal microflora were accompanied by alteration of the morphological structure in the liver. Enhanced proliferation of Ito cells served as an indirect evidence of damage to the liver. Ito cells did not undergo transformation into myofibroblasts that excluded the possibility of fibrosis.

Possible participation of endotoxin of gram-negative bacteria in pathogenesis of liver damage during viral hepatitis.

Possible role of gram-negative bacteria in the genesis of hepatic damage during chronic viral hepatitis B and C was studied. Histological activity, hepatocyte proliferative activity, and expression of alpha-smooth muscle actin were compared with the severity of endotoxemia in patients with chronic hepatitis B and C. The study revealed a correlation between the degree of intralobular necroses, hepatocyte proliferation, and myofibroblast transdifferentiation of Ito cells with endotoxin concentration in the blood.

Immunohistochemical and ultrastructural study of ito cells (fat-storing cells) in response to extrahepatic bile duct ligation in broiler chickens.

The Ito cell (fat-storing cell) lies in perisinusoidal space of liver and has a variety of functions. We investigated the immunohistochemistry and ultrastructure of Ito cells in normal and cholestatic livers of broiler chickens. Immunohistochemistry demonstrated that Ito cells expressed HHF35 muscle actin, vimentin, desmin, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), chromogranin A and cytokeratins in normal livers. These cells were diffusely scattered throughout the lobules. Livers treated with extrahepatic bile duct ligation (BDL) showed cholestasis, fibrosis, proliferation of biliary ductules and Ito cells. The Ito cells were frequently found in fibrotic areas and were larger in size with more extensive immunoreactivity than those of normal livers. Ultrastructural study demonstrated that Ito cells were closely associated with the production of collagen fibers in BDL livers. These findings suggest that Ito cells actively react against hepatocytic injuries and play a major role in the hepatic fibrogenesis of cholestatic livers of chickens.

The effect of retinoic acid on Ito cell proliferation and content of DNA and RNA.

The development of liver fibrosis is due to an imbalance between synthesis and degradation of extracellular matrix. Recent studies have shown that Ito cells which are located along the sinuses of liver, can store and metabolize Vit A, and are the main cells that produce collagen, among which type I, III and IV and laminin, account for 80%-95% of the total hepatic collagen[1]. Ito cells in the course of proliferation and synthesis of collagen showed a reduction of Vit A contents and retinoic acid receptors[2]. This study was designed to investigate the effect of retinoic acid on Ito cell proliferation and the contents of DNA/RNA and to analyse further its mechanism or pathways.

Serum pharmacological effects of Fuzheng Huayu Decoction"Equation missing" on Ito cell proliferation and collagen synthesis in rats) on Ito cell proliferation and collagen synthesis in rats

Objective: To explore mechanism of the effect of Fuzheng Huayu Decoction on Ito cell proliferation and collagen synthesis.Methods: Biological effects of the drug serum taken from rats fed with Fuzheng Huayu decoction (FZHYD) on cell proliferation and collagen synthesis of Ito cell line were observed. Serum collected from rats at various times (1, 2 or 3 hours) after animals were fed with FZHYD once (It) or twice (2t, 2nd time repeated with the same dose), was incubated with Ito cell.Results: The lt-2h serum in 0. 46 g/kg FZHYD group, it seems to prevent cell proliferation, but had no significant difference. While all 2t drug serum could inhibit cell proliferation. The 2t-lh drug serum had no obvious effects on Ito cell morphology, but could improve cell viability, its effect on cell proliferation was dose and serum concentration dependent. Also the 2t-lh drug serum in all doses could inhibit Ito cells both intracellular and extracellular collagen production, the drug serum of 0.46 g/kg group had inhibitory effect in serum concentration dependent manner and similar effect as colchicine.Conclusion: Inhibition of Ito cells proliferation and collagen synthesis is perhaps one of main mechanism of FZHYD in antifibrotic action.

Retinoids may increase fibrotic potential of TGF-β: Crosstalk between two multi-functional effectors

HepatologyVolume 26, Issue 4 p. 1067-1068 EditorialFree Access Retinoids may increase fibrotic potential of TGF-β: Crosstalk between two multi-functional effectors R Blomhoff, R BlomhoffSearch for more papers by this author R Blomhoff, R BlomhoffSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1002/hep.510260439Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1 Wake K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 1980; 66: 303– 353. 2 Blomhoff R, Wake K. Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J 1991; 5: 271– 277. 3 Friedman SL. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 1993; 328: 1828– 1835. 4 Davis BH, Kramer RT, Davidson NO. Retinoic acid modulates rat Ito cell proliferation, collagen, and transforming growth factor beta production. J Clin Invest 1990; 86: 2062– 2070. 5 Davis BH, Vucic A. The effect of retinol on Ito cell proliferation in vitro. Hepatology 1988; 8: 788– 793. 6 Sato T, Kato R, Tyson CA. Regulation of differentiated phenotype of rat hepatic lipocytes by retinoids in primary culture. Exp Cell Res 1995; 217: 72– 83. 7 Senoo H, Wake K. Suppression of experimental hepatic fibrosis by administration of vitamin A. Lab Invest 1985; 52: 182– 194. 8 Seifer WF, Bosma A, Hendriks HF, van Leeuwen RE, van Thil-de Ruiter GC, Seifert-Bock I, Knock DL, et al. Beta-carotene (provitamin A) decreases the severity of CCl4-induced hepatic inflammation and fibrosis in rats. Liver 1995; 15: 1– 8. 9 Seifer WF, Bosma A, Brouwer A, Hendriks HF, Roholl PJ, van Leeuwen RE, Ruiter GC van Thil-de, et al. Vitamin A deficiency potentiates carbon tetrachloride-induced liver fibrosis in rats. Hepatology 1994; 19: 193– 201. 10 Okuno M, Moriwaki H, Imai S, Muto Y, Kawada N, Suzuki Y, Kojima S. Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-β in liver stellate cells. Hepatology 1997; 26: 918– 926. 11 Blomhoff R. Vitamin A in Health and Disease. New York: Marcel Dekker, Inc., 1994: 1– 677. 12 Blomhoff R, Green MH, Berg T, Norum KR. Transport and storage of vitamin A. Science 1990; 250: 399– 404. 13 Blomhoff R, Helgerud P, Rasmussen M, Berg T, Norum KR. In vivo uptake of chylomicron retinyl ester by rat liver: evidence for retinol transfer from parenchymal to nonparenchymal cells. Proc Natl Acad Sci U S A 1982; 79: 7326– 7330. 14 Blomhoff R, Rasmussen M, Nilsson A, Norum KR, Berg T, Blaner WS, Kato M, et al. Hepatic retinol metabolism, distribution of retinoids, enzymes, and binding proteins in isolated rat liver cells. J Biol Chem 1985; 260: 13560– 13565. 15 Blaner WS, van Bennekum AM, Brouwer A, Hendriks HF. Distribution of lecithin-retinol acyltransferase activity in different types of rat liver cells and subcellular fractions. FEBS Lett 1990; 274: 89– 92. 16 Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schütz G, Kastner P, Mark M, et al. The nuclear receptor superfamily: the second decade. Cell 1995; 83: 835– 839. 17 Ohata M, Lin M, Satre M, Tsukamoto H. Diminished retinoic acid signaling in hepatic stellate cells in cholestatic liver fibrosis. Am J Physiol 1997; 272: G589– G596. 18 Takahashi N, Bretiman TR. Retinoylation of proteins in mammalian cells, pp. 257– 273. In: R Blomhoff, ed. Vitamin A in Health and Disease. New York: Marcel Dekker, Inc., 1994: 257–273. 19 Koga H, Fujita I, Miyazaki S. Effects of all-trans retinoic acid on super-oxide generation in intact neutrophils and a cell-free system. Br J Haematol 1997; 97: 300– 305. 20 Buck J, Derguini F, Levy E, Nakanishi K, Hmmerling U. Intracellular signalling by 14-hydroxy-4, 14-retro-retinol. Science 1991; 254: 1654– 1656. 21 Achkar CC, Derguini F, Blumberg B. 4-oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors. Proc Natl Acad Sci USA 1996; 93: 4879– 4884. Citing Literature Volume26, Issue4October 1997Pages 1067-1068 ReferencesRelatedInformation

Seropharmalogical effects of Fuzheng Huayu decoction on rat Ito cell morphology and function in culture.

To investigate the mechanisms of anti-liver fibrosis actions of Fuzheng Huayu (FZHY) decoction, which acts to strengthen the body's resistance and promote blood circulation. Ito cells were isolated from rats and cultured. Serum samples were collected from healthy (normal) rats after administration of FZHY decoction and added to the subcultured cells. The effects of FZHY decoction on the Ito cells were investigated by contrast microscopy (to observe cell morphology), [(3)H]Pro incorporation assay (cell viability), [(3)H]TdR incorporation and MTT colorimetric assay (cell proliferation), and [(3)H]Pro incorporation and collagenase digestion (collagen synthesis rate). The rat sera samples from rats treated with FZHY decoction had no influence on Ito cell morphology, but improved cell viability and markedly inhibited cell proliferation and collagen synthesis. The magnitude of these effects showed dependence on treatment dosage and drug concentration in serum. The seropharmalogical method can be efficiently used to investigate the pharmacological mechanism of anti-fibrotic traditional Chinese herbs and formulae. Inhibition of Ito cell proliferation and collagen synthesis may be two of the major mechanisms underlying the anti-fibrosis actions of the FZHY decoction.

Differential effects between tauroursodeoxycholic and taurochenodeoxycholic acids in hepatic fibrosis: an assessment by primary cultured Ito and Kupffer cells from the rat liver.

The pathogenesis of hepatic fibrosis in cholestasis is still unknown, except for endotoxaemia. There is a possibility that the elevation of serum bile acids in cholestasis may play an important role in hepatic fibrogenesis due to a reaction to perisinusoidal cells, such as Ito or Kupffer cells. To assess the effects of bile acids, we investigated the cell proliferation and collagen formation of primary cultured Ito cells that were incubated with a Kupffer cell conditioned medium (KCCM) treated with either taurochenodeoxycholic acid (TCDCA) or tauroursodeoxycholic acid (TUDCA) in short-term (8 h) or long-term (48 h) cultures. KCCM treated with TCDCA (100 mumol/L) but not with TUDCA increased cell proliferation of Ito cells in short-term cultures and also partially elevated collagen formation by Ito cells in long-term cultures. The release of tumour necrosis factor-alpha (TNF alpha) from Kupffer cells was increased by TCDCA in short-term cultures, but not in long-term cultures. The release of transforming growth factor-beta 1 (TGF beta 1) from Kupffer cells was increased by TCDCA in long-term cultures, but not in the short-term cultures. TUDCA showed no significant effect on the release of TNF alpha and TGF beta 1 from Kupffer cells. TUDCA or TCDCA itself showed no direct effect on the cell proliferation and collagen formation of Ito cells. In conclusion, these findings are thus considered to show the potentially important role of TCDCA on the development of hepatic fibrosis in the early phase of cholestasis without endotoxaemia.

Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway.

Ito cells play a pivotal role in the development of liver fibrosis associated with chronic liver diseases. During this process, Ito cells acquire myofibroblastic features, proliferate, and synthesize fibrosis components. Considering the reported mitogenic properties of endothelin-1 (ET-1), we investigated its effects on the proliferation of human Ito cells in their myofibroblastic phenotype. Both ET receptor A (ETA: 20%) and ET receptor B (ETB: 80%) binding sites were identified, using a selective ETA antagonist, BQ 123, and a selective ETB agonist, sarafotoxin S6C (SRTX-C). ET-1 did not stimulate proliferation of myofibroblastic Ito cells. In contrast, ET-1 inhibited by 60% DNA synthesis and proliferation of cells stimulated with either human serum or platelet-derived growth factor -BB (PDGF-BB). PD 142893, a nonselective ETA/ETB antagonist totally blunted this effect. SRTX-C was as potent as ET-1, while BQ 123 did not affect ET-1-induced growth inhibition. Analysis of the intermediate steps leading to growth-inhibition by ET-1 revealed that activation of mitogen-activated protein kinase by serum or PDGF-BB was decreased by 50% in the presence of SRTX-C. In serum-stimulated cells, SRTX-C reduced c-jun mRNA expression by 50% whereas c-fos or krox 24 mRNA expression were not affected. We conclude that ET-1 binding to ETB receptors causes a potent growth inhibition of human myofibroblastic Ito cells, which suggests that this peptide could play a key role in the negative control of liver fibrogenesis. Our results also point out that, in addition to its well known promitogenic effects, ET-1 may also exert negative control of growth on specific cells.

Cyclosporin A and FK-506 in inhibition of rat ito cell activation in vitro

Ito cells are the primary matrix-producing cells in the liver. In hepatic fibrosis in vivo or culture on plastic, these cells undergo activation, a process characterized by cell proliferation, fibrogenesis, and smooth muscle alpha-actin expression. The cytosolic-binding proteins of cyclosporin A (CsA) and FK506 accelerate folding of various proteins including collagen and become inactivated by binding to those agents. CsA is shown to inhibit collagen synthesis in cultured fibroblasts. These findings prompted us to examine the effect of cyclosporin A and FK506 on Ito cell activation. CsA and FK506 reduced DNA synthesis in a dose-related manner, to 26% and 45% of controls at 5 mumol/L, respectively, without affecting total protein synthesis. CsA reduced collagen synthesis in a dose-related manner, to 70% of controls at 5 mumol/L without affecting noncollagenous protein synthesis, whereas FK506 changed neither collagen synthesis nor noncollagenous protein synthesis. Moreover, smooth muscle alpha-actin expression was reduced by 0.5 mumol/L CsA, but not by FK506. CsA merits consideration for the therapy of hepatic fibrosis. FK506 may also be a candidate for such therapy through inhibitory action on Ito cell proliferation.

Cyclosporin a and fk-506 in inhibition of rat ito cell activation in vitro

Ito cells are the primary matrix-producing cells in the liver. In hepatic fibrosis in vivo or culture on plastic, these cells undergo activation, a process characterized by cell proliferation, fibrogenesis, and smooth muscle α-actin expression. The cytosolic-binding proteins of cyclosporin A (CsA) and FK506 accelerate folding of various proteins including collagen and become inactivated by binding to those agents. CsA is shown to inhibit collagen synthesis in cultured fibroblasts. These findings prompted us to examine the effect of cyclosporin A and FK506 on Ito cell activation. CsA and FK506 reduced DNA synthesis in a dose-related manner, to 26% and 45% of controls at 5 μmol/L, respectively, without affecting total protein synthesis. CsA reduced collagen synthesis in a dose-related manner, to 70% of controls at 5 μmol/ L without affecting noncollagenous protein synthesis, whereas FK506 changed neither collagen synthesis nor noncollagenous protein synthesis. Moreover, smooth muscle α-actin expression was reduced by 0.5 μmol/L CsA, but not by FK506. CsA merits consideration for the therapy of hepatic fibrosis. FK506 may also be a candidate for such therapy through inhibitory action on Ito cell proliferation.

Interferon alfa and gamma inhibit proliferation and collagen synthesis of human ito cells in culture

During the course of ongoing liver fibrogenesis, Ito cells acquire myofibroblastic features, proliferate, and synthesize increased amounts of extracellular matrix components. Interferon (IFN) alfa and IFN gamma have been shown to elicit antiproliferative and/or antifibrogenic effects in various cell cultures of mesenchymal origin. The aim of this study was to investigate the effects of IFN-alpha and IFN-gamma on cultured human myofibroblastic Ito cells (MFBIC) proliferation and collagen synthesis and secretion. Serum-stimulated incorporation of [3H]-thymidine into DNA of MFBIC was dose-dependently decreased by both cytokines. IFN-alpha (10(4) U/mL) and IFN-gamma (10(3) U/mL) decreased DNA synthesis by 69% and 66%, respectively. Inhibition of cell proliferation was confirmed by cell counting. Similar results were observed when cell growth was stimulated with platelet-derived growth factor (PDGF-BB, PDGF-AA) or transforming growth factor (TGF)-beta 1. Collagen secretion per cell was inhibited by both cytokines, as assessed by [3H]-hydroxyproline incorporation. After a 6-day treatment, IFN-gamma showed a greater potency than IFN-alpha in inhibiting secretion of newly synthetized collagen (41% and 4% of control in the presence of 10(2) U/mL of IFN-gamma and 10(4) U/mL of IFN-alpha, respectively). Both IFN-alpha and IFN-gamma concurrently decreased steady-state expression of type I and type III procollagen messenger RNAs (mRNAs) in quiescent MFBIC. Viability assays ruled out cytotoxic effects of the two molecules. Finally, both IFNs decreased smooth muscle alpha-actin (SM alpha-actin) expression, whether assayed by immunoblotting or by Northern blot analysis. We conclude that IFN-alpha and IFN-gamma inhibit proliferation as well as collagen synthesis in human MFBIC.

Interferon alfa and gamma inhibit proliferation and collagen synthesis of human ito cells in culture

During the course of ongoing liver fibrogenesis, Ito cells acquire myofibroblastic features, proliferate, and synthesize increased amounts of extracellular matrix components. Interferon (IFN) alfa and IFN gamma have been shown to elicit antiproliferative and/or antifibrogenic effects in various cell cultures of mesenchymal origin. The aim of this study was to investigate the effects of IFN-α and IFN-γ on cultured human myofibroblastic Ito cells (MFBIC) proliferation and collagen synthesis and secretion. Serum-stimulated incorporation of [ 3h]-thymidine into DNA of MFBIC was dose-dependently decreased by both cytokines. IFN-α (10 4U/mL) and IFN-γ (10 3U/mL) decreased DNA synthesis by 69% and 66%, respectively. Inhibition of cell proliferation was confirmed by cell counting. Similar results were observed when cell growth was stimulated with platelet-derived growth factor (PDGF-BB, PDGF-AA) or transforming growth factor (TGF)-βl. Collagen secretion per cell was inhibited by both cytokines, as assessed by [ 3h]hydroxyproline incorporation. After a 6-day treatment, IFN-γ showed a greater potency than IFN-α in inhibiting secretion of newly synthetized collagen (41% and 48% of control in the presence of 10 2 U/mL of IFN-γ and 10 4U/ mL of IFN-α, respectively). Both IFN-α and IFN-γ concurrently decreased steady-state expression of type I and type III procollagen messenger RNAs (mRNAs) in quiescent MFBIC. Viability assays ruled out cytotoxic effects of the two molecules. Finally, both IFNs decreased smooth muscle α-actin (SMα-actin) expression, whether assayed by immunobloting or by Northern blot analysis. We conclude that IFN-α and IFN-γ inhibit proliferation as well as collagen synthesis in human MFBIC.

Endothelin-1 inhibits proliferation of human myofibroblastic ito cells

Endothelin-1 inhibits proliferation of human myofibroblastic ito cells

Dexamethasone inhibits proliferation of human Ito cells and induces a morphological change

Dexamethasone inhibits proliferation of human Ito cells and induces a morphological change