Stimulation of Proliferation of Rat Hepatic Stellate Cells by Galectin-1 and Galectin-3 through Different Intracellular Signaling Pathways

Abstract

We found that the expression of galectin-1 and galectin-3 was significantly up-regulated in hepatic stellate cells (HSCs) both in the course of their transdifferentiation into myofibroblasts, a process of “self-activation,” and in the fibrosis of liver tissues. Recombinant galectin-1 and galectin-3 stimulated the proliferation of cultured HSCs via the MEK1/2-ERK1/2 signaling pathway. However, galectin-3 utilized protein kinases C and A to induce this process, whereas galectin-1 did not. We also found that thiodigalactoside, a potent inhibitor of β-galactoside binding, attenuated the effects of both galectins. In addition, galectin-1, but not galectin-3, promoted the migration of HSCs. Thus, it appears that galectin-1 and galectin-3, generated by activated HSCs, could participate in β-galactoside binding and induce different intracellular signaling pathways leading to the proliferation of HSCs. We found that the expression of galectin-1 and galectin-3 was significantly up-regulated in hepatic stellate cells (HSCs) both in the course of their transdifferentiation into myofibroblasts, a process of “self-activation,” and in the fibrosis of liver tissues. Recombinant galectin-1 and galectin-3 stimulated the proliferation of cultured HSCs via the MEK1/2-ERK1/2 signaling pathway. However, galectin-3 utilized protein kinases C and A to induce this process, whereas galectin-1 did not. We also found that thiodigalactoside, a potent inhibitor of β-galactoside binding, attenuated the effects of both galectins. In addition, galectin-1, but not galectin-3, promoted the migration of HSCs. Thus, it appears that galectin-1 and galectin-3, generated by activated HSCs, could participate in β-galactoside binding and induce different intracellular signaling pathways leading to the proliferation of HSCs. Hepatic stellate cells (HSCs), 1The abbreviations used are: HSCs, hepatic stellate cells; ECMs, extracellular matrix materials; PDGF, platelet-derived growth factor; r-PDGF-BB, recombinant rat platelet-derived growth factor-BB; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-hydroxykinase; TAA, thioacetamide; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; SAPK, stress-activated protein kinase; JNK, c-Jun N-terminal kinase; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; r-galectin, recombinant human galectin; RT, reverse transcription; PKC, protein kinase C; PKA, protein kinase A; TDG, thiodigalactoside.1The abbreviations used are: HSCs, hepatic stellate cells; ECMs, extracellular matrix materials; PDGF, platelet-derived growth factor; r-PDGF-BB, recombinant rat platelet-derived growth factor-BB; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-hydroxykinase; TAA, thioacetamide; ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; SAPK, stress-activated protein kinase; JNK, c-Jun N-terminal kinase; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; r-galectin, recombinant human galectin; RT, reverse transcription; PKC, protein kinase C; PKA, protein kinase A; TDG, thiodigalactoside. liver-specific pericytes, play a pivotal role in hepatic fibrogenesis (1Friedman S.L. N. Engl. J. Med. 1993; 328: 1828-1835Crossref PubMed Scopus (0) Google Scholar). In liver injury, HSCs undergo proliferation and migration and generate a large amount of extracellular matrix materials (ECMs), including fibril-forming collagens, fibronectin, and proteoglycans, resulting in the formation of septa in chronically damaged liver (2Friedman S.L. J. Biol. Chem. 2000; 275: 2247-2250Abstract Full Text Full Text PDF PubMed Scopus (1867) Google Scholar, 3Gressner A.M. Bachem M.G. Digestion. 1995; 56: 335-346Crossref PubMed Scopus (222) Google Scholar). Resident macrophages (Kupffer cells), infiltrating macrophages, platelets, and sinusoidal endothelial cells secrete growth factors at the inflammatory sites, such as transforming growth factor-β and platelet-derived growth factor (PDGF). These growth factors trigger the proliferation and the secretion of ECMs by HSCs. Recent studies have elucidated that MAPK and phosphatidylinositol 3-kinase (PI3K) are key signaling pathways involved in the growth factor-induced stimulation of HSCs (4Pinzani M. Marra F. Carloni V. Liver. 1998; 18: 2-13Crossref PubMed Scopus (231) Google Scholar, 5Marra F. Gentilini A. Pinzani M. Choudhury G.G. Parola M. Herbst H. Dianzani M.U. Laffi G. Abboud H.E. Gentilini P. Gastroenterology. 1997; 112: 1297-1306Abstract Full Text PDF PubMed Scopus (185) Google Scholar). Galectins form a group of β-galactoside-binding animal lectins (6Sharon N. Lis H. Science. 1989; 246: 227-234Crossref PubMed Scopus (1061) Google Scholar, 7Barondes S.H. Castronovo V. Cooper D.N. Cummings R.D. Drickamer K. Feizi T. Gitt M.A. Hirabayashi J. Hughes C. Kasai K.-i. Leffler H. Liu F. Lotan R. Mercurio A.M. Monsigni M. Pillai S. Poirer F. Raz A. Rigby P.W.J. Rini J.M. Wang J.L. Cell. 1994; 76: 597-598Abstract Full Text PDF PubMed Scopus (1074) Google Scholar, 8Kasai K.-i. Hirabayashi J. J. Biochem. 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Cell Biol. 1991; 115: 1437-1448Crossref PubMed Scopus (212) Google Scholar, 29Kuwabara I. Liu F.T. J. Immunol. 1996; 156: 3939-3944PubMed Google Scholar). Over such a wide range of influences, galectins are thought to modulate cell signaling by cross-linking with target molecules through their β-galactoside-containing glycoconjugates (30Perillo N.L. Marcus M.E. Baum L.G. J. Mol. Med. 1998; 76: 402-412Crossref PubMed Scopus (578) Google Scholar, 31Sacchettini J.C. Baum L.G. Brewer C.F. Biochemistry. 2001; 40: 3009-3015Crossref PubMed Scopus (273) Google Scholar). There have been a few reports on the function of galectins in the physiologic and pathologic processes of the liver (23Shimonishi T. Miyazaki K. Kono N. Sabit H. Tuneyama K. Harada K. Hirabayashi J. Kasai K.-i. Nakanuma Y. Hum. Pathol. 2001; 32: 302-310Crossref PubMed Scopus (75) Google Scholar, 32Kristensen D.B. Kawada N. Imamura K. Miyamoto Y. Tateno C. Seki S. Kuroki T. Yoshizato K. 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Pathol. 2001; 32: 302-310Crossref PubMed Scopus (75) Google Scholar). A study on concanavalin A-induced acute liver injury showed that galectin-1 administration protects mice from liver injury by selectively eliminating activated T cells and preventing the synthesis of proinflammatory Th1-derived cytokines (34Santucci L. Fiorucci S. Cammilleri F. Servillo G. Federici B. Morelli A. Hepatology. 2000; 31: 399-406Crossref PubMed Scopus (138) Google Scholar). Our previous proteome analysis of rat HSC proteins revealed that the amount of galectin-1 is greatly increased in activated HSCs compared with quiescent HSCs; the secretion of galectin-1 is also much enhanced by activated HSCs (32Kristensen D.B. Kawada N. Imamura K. Miyamoto Y. Tateno C. Seki S. Kuroki T. Yoshizato K. Hepatology. 2000; 32: 268-277Crossref PubMed Scopus (200) Google Scholar). Although a detailed analysis has not yet been performed, these results suggest that an enhanced level of galectin-1 modifies the function of HSCs themselves as well as other hepatic constituent cells in chronically injured liver. In this study, we investigated in detail the expression pattern of galectin-1 and galectin-3 in HSCs and in fibrotic liver tissues. We further demonstrated that both types of galectins activate MAPK pathways presumably by cross-linking with target molecules through their β-galactoside-containing glycoconjugates, leading to the proliferation of HSCs. Materials—Collagenase, thioacetamide (TAA), isopropyl-β-d-thiogalactopyranoside, Me2SO, and 3,3′-diaminobenzidine tetrahydrochloride) were purchased from Wako Pure Chemical Co. (Osaka, Japan). Pronase E was from Merck (Darmstadt, Germany). Rat PDGF-BB was from R&D Systems (Minneapolis, MN). Rat hepatocyte growth factor was from Toyobo Co. (Japan). Polyclonal antibodies against ERK1/2, phospho-ERK1/2 (Thr202/Tyr204), MEK1/2, MAPK, MAPK and were from Cell and against were from antibodies against were purchased from and against galectin-3 purchased from Polyclonal antibodies against galectin-1 were generated in as J. H. G. Kasai K.-i. 1989; PubMed Scopus Google Scholar, Y. Leffler H. Y. Kasai K.-i. Barondes S.H. 1991; PubMed Scopus Google Scholar, J. Kasai K.-i. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar). the and were purchased from and were purchased from Dulbecco's modified Eagle's and fetal bovine were purchased from E was from was from Japan). were of (Tokyo). The was from and were from (Tokyo). were from was from was from Co. were from Cell was from other were purchased from and were in The of in the was did not the function of cultured HSCs. were from Japan). were at a and with and of Recombinant Galectin-1 and human galectin-1 and were generated in as J. H. G. 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PubMed Scopus Google Scholar). were 3,3′-diaminobenzidine and were an Cell HSCs were cultured on in and in were cultured on in E and in E. The cells were stimulated with and with the The was by as H. Y. Kawada N. Seki S. D.B. Yoshizato K. N. Y. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). In HSCs were in in and in The cells were stimulated with were in and with a The of HSCs was in a at a of were migration of HSCs was cell as K. T. Wang H. Kawada N. K. Hepatology. 1999; PubMed Scopus Google Scholar). HSCs cultured were from the in of into the and to to the surface of the HSCs were in Recombinant rat PDGF-BB was into the of the was to the were in and with a The of HSCs on the surface of the was at a of and that on the surface was by the were The of cells migration was as migration of cells on surface of on and of as are of analysis was by at a level of of Galectin-1 and Galectin-3 in Rat Hepatic and and sinusoidal endothelial cells were from rat The expression of galectin-1 and galectin-3 was by Galectin-1 was not in of the whereas galectin-3 was in and sinusoidal endothelial cells apoptosis a few of as R. Y. K. A. K. J. S. Exp. Cell Res. 1994; PubMed Scopus Google Scholar, Y. S. Y. M. H. Chen A. H. T. K. Kawada N. K. J. 1995; PubMed Scopus Google Scholar). In HSCs increased in and into of The expression of both galectin-1 and galectin-3 was increased in HSCs in a as revealed by and analysis revealed that the protein of galectin-1 and galectin-3 increased in a course to that the expression of and well activated HSCs. In with these on in activated HSCs, in activated HSCs from fibrotic and proteins galectin-1 and galectin-3, both of were in quiescent HSCs from showed that galectin-1 was in liver tissues whereas in the septa of fibrotic activated HSCs were it was Galectin-3 was in cells in was and septa in fibrotic These the results with HSCs and cells from and fibrotic showed that the of both galectin-1 and galectin-3 were up-regulated in of liver the by administration and the by These results that the expression of galectin-1 and galectin-3 is in activated HSCs. of Galectin-1 and Galectin-3 on HSC the role of galectin-1 and galectin-3 in the process of liver we examined their effects on the proliferation of HSCs and in both galectin-1 and galectin-3 were found to synthesis in HSCs in a with the stimulation by the that by the at was that at the potent HSCs (4Pinzani M. Marra F. Carloni V. Liver. 1998; 18: 2-13Crossref PubMed Scopus (231) Google Scholar, 5Marra F. Gentilini A. Pinzani M. 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Med. 1998; 76: 402-412Crossref PubMed Scopus (578) Google and the of the cell In study has that the expression of galectin-1 and galectin-3 is induced in activated HSCs and fibrotic These galectins with β-galactoside-containing glycoconjugates on the cell the MEK1/2-ERK1/2 signaling pathway. to the of the proliferation of HSCs. Thus, the of galectin-1 and galectin-3 in activated HSCs to play an role in the of liver fibrosis via this We and and and We also in the