Transforming Growth Factor β (TGF-β)Inhibits Expression of Fibrinogen and Factor VII in a Hepatoma Cell Line

Summary

We have investigated the effect(s) of transforming growth factor (TGF)-β1 and interleukin (IL)-6 on the expression of fibrinogen and blood coagulation factors VII, IX, X mRNAs in a hepatoma cell line (Hep 3B). The results indicate that TGF-β induces a decrease of the basal level of fibrinogen and factor VII mRNAs, but does not affect factor X expression. Furthermore, TGF-β efficiently antagonizes the IL-6 induction of fibrinogen mRNA at late (12-48 h) but not early (6 h) times: this effect is apparently mediated by posttranscriptional mechanism(s). These findings, together with previously reported data on the inhibitory effect of TGF-β on acute phase genes (e.g., ApoAl and albumin), suggest a role for TGF-β in the regulation of liver genes expression. The early stimulatory and late inhibitory effect exerted by IL-6 and TGF-β respectively on fibrinogen mRNA level may play a role in the regulatory mechanism(s) of clot formation in a variety of conditions.

• References

• 1 Moses HL, Tucker RF, Leof EB, Coffey RJ, Halper J, Shipley GD. Type beta transforming growth factor is a growth stimulator and a growth inhibitor. In: Cancer Cells 3. Feramisco J, Ozanne B, Stiles C. eds Cold Spring Harbor Laboratory; Cold Spring Harbor, N Y: 1985. pp 65-71
• 2 Tucker RF, Shipley GD, Moses HL, Holley RW. Transforming growth factor-beta: biological function and chemical structure. Science 1984; 226: 705-707
• 3 Heimark RL, Twardzik DR, Schwartz SM. Inhibition of endothelial regeneration by type-beta transforming growth factor from platelets. Science 1986; 233: 1078-1080
• 4 Takehara K, Le Roy EC, Grotendorst GR. TGF-β inhibition of endothelial cell proliferation: alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression. Cell 1987; 49: 415-422
• 5 Sorrentino V, Bandyopadhyay S. TGF-β inhibits Go/S-phase transition in primary fibroblasts. Loss of response to the antigrowth effect of TGF-β is observed after immortalization. Oncogene 1989; 4: 569-574
• 6 Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci USA 1987; 84: 5788-5792
• 7 Lund LR, Riccio A, Andreasen PA, Nielsen LS, Kristenser P, Laiho M, Saksela O, Blasi F, Dano K. Transforming growth factor-beta is a strong and fast acting positive regulator of the level of type-1 plasminogen activator inhibitor mRNA in WI-38 human lung fibroblast. EMBO J 1987; 6: 1281-1286
• 8 Rossi P, Karsenty G, Roberts AB, Roche NS, Sporn MB, de Cronbrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-beta. Cell 1988; 52: 405-414
• 9 Morrone G, Cortese R, Sorrentino V. Post-transcriptional control of negative acute phase genes by transforming growth factor beta. EMBO J 1989; 8: 3767-3771
• 10 Aen Dijke P, Hansen P, Iwata KK, Picler C, Faulkes JG. Identification of another member of the transforming growth factor type beta gene family. Proc Natl Acad Sci USA 1988; 85: 4715-4719
• 11 Sporn MB, Roberts AB, Wakefield LM, de Cronbrugghe B. Some recent advances in the chemistry and biology of transforming growth factor-beta. J Cell Biol 1987; 105: 1039-1045
• 12 Assoian RK, Kamoriya A, Meyers GA, Miller DM, Sporn MB. Transforming growth factor-beta in human platelets. J Biol Chem 1983; 258: 7155-7160
• 13 Cheifetz S, Weatherbee JA, Tsang ML-S, Anderson JK, Mole JE, Lucas R, Massagué J. The transforming growth factor-beta system, a complex pattern of cross-reactive ligands and receptors. Cell 1987; 48: 409-415
• 14 Assoian RK, Fleurdelys BE, Stevenson HC, Miller PJ, Madtes DK, Raines EW, Russell R, Sporn MB. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci USA 1987; 84: 6020-6024
• 15 Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine VI, Liotta LA, Falanga V, Kehrl JH, Fauci AS. Transforming growth factor type-beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 1986; 83: 4167-4171
• 16 Robey PG, Young MF, Flanders KC, Roche NS, Kondaiah P, Reddi AH, Termine JD, Sporn MB, Roberts AB. Osteoblasts synthesize and respond to TGF-β in vitro. J Cell Biol 1987; 105: 457-463
• 17 Rappolee DA, Mark D, Banda MJ, Werb Z. Wound macrophages express TGF-alpha and other growth factors in vivo/analysis by mRNA phenotyping. Science 1988; 241: 708-711
• 18 Padgett RW, Johnston RD, Gelbart WM. A transcript from Drosophila pattern gene predicts a protein homologous to the transforming growth factor-beta family. Nature 1987; 325: 81-84
• 19 Mackiewics A, Ganapathi MK, Schultz D, Brabenec A, Weinstein J, Kelley MF, Kuschner I. Transforming growth factor beta 1 regulates production of acute phase proteins. Proc Natl Acad Sci USA 1990; 87: 1491-1495
• 20 Baumann H, Hill RE, Sauder DN, Jahreis GP. Regulation of major acute phase plasma protein by hepatocyte stimulating factors of human squamous carcinoma cells. J Cell Biol 1986; 102: 370-383
• 21 Perlmutter DH, Godberger G, Dinarello CA, Mizel SB, Colten HR. Regulation of Class III major histocompatibility complex gene products by interleukin-1. Science 1986; 232: 850-852
• 22 Darlington GJ, Wilson DR, Lachman LB. Monocyte-conditioned medium interleukin-1 and tumor necrosis factor stimulate the acute phase response in human hepatoma cells in vitro. J Cell Biol 1986; 103: 787-793
• 23 Gauldie J, Richards C, Harmish D, Landsdap P, Baumann H. Interferon B2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA 1987; 84: 7251-7255
• 24 Morrone G, Ciliberto G, Oliviero S, Arcone R, Dente L, Content J, Cortese R. Recombinant interleukin-6 regulates the transcriptional activation of a set of human acute phase genes. J Biol Chem 1988; 263: 12554-12558
• 25 Evans E, Courtois GM, Kilian PL, Fuller GM, Crabtree GR. Induction of fibrinogen and a subset of acute phase response genes involves a novel monokine which is mimicked by phorbol esters. J Biol Chem 1987; 262: 10850-10854
• 26 Baumann H, Richards C, Gauldie J. Interaction among hepatocyte-stimulating factors, interleukin 1 and glucocorticoids for regulation of acute phase plasma proteins in human hepatoma (Hep G2) cells. J Immunol 1987; 139: 4122-4128
• 27 Baumann H, Isseroff H, Latimer JJ, Jahreis GP. Phorbol ester modulates interleukin 6- and interleukin 1-regulated expression of acute phase plasma proteins in hepatoma cells. J Biol Chem 1988; 263: 17390-17396
• 28 Darlington GL. Liver cell lines. Methods Enzymol 1987; 151: 19-38
• 29 Baumann H, Jahreis GP, Sauder DN, Koj A. Human keratinocytes and monocytes release factors which regulate the synthesis of major acute-phase plasma proteins in hepatic cells from man, rat and mouse. J Biol Chem 1984; 259: 7331-7342
• 30 Darlington GJ, Wilson DR, Lachman LB. Monocytes-conditioned medium, interleukin 1, and tumor necrosis factor stimulate the acute phase response in human hepatoma cells in vitro. J Cell Biol 1986; 103: 787-793
• 31 Bloom AL, Thomas DF. Hemostasis and Thrombosis. Churchill Livingstone; Edinburgh: 1981
• 32 Knowles BB, Howe CC, Aden DP. Human hepatocellular carcinoma cell lines secrete the major plasma proteins and hepatitis B surface antigen. Science 1980; 209: 497-499
• 33 Fair DS, Bahnak BR. Human hepatoma cells secrete single chain factor X, prothrombin, and antithrombin III. Blood 1984; 67: 194-197
• 34 Fair DS, Marlar RA. Biosynthesis and secretion of factor VII, protein C, protein S, and the protein C inhibitor from a human hepatoma cell line. Blood 1986; 67: 64-68
• 35 Hassan HJ, Leonardi A, Chelucci C, Mattia G, Macioce G, Guerriero R, Russo G, Mannucci PM, Peschle C. Blood coagulation factors in human embryonic-fetal development: preferential expression of the tissue factor/factor VII pathway. Blood 1990; 76: 1158-1164
• 36 Gabbianelli M, Pelosi E, Bassano E, Labbaye C, Petti S, Rocca E, Tritarelli E, Miller BA, Valtieri M, Testa U, Peschle C. Granulo-cytemacrophage colony-stimulating factor reactives fetal hemoglobin synthesis in erythroblast clones from normal adult. Blood 1989; 74: 2657-2667
• 37 Chirgwin JM, Prebyla AE, MacDonald RJ, Rutter WJ. Isolation of biological active ribonucleic acid from sources enriched in ribo-nucleose. Biochemistry 1979; 18: 5294-5299
• 38 Chung DW, Que BG, Rixon MW, Mace Jr M, Davie EW. Characterization of complementary deoxyribonucleid acid and genomic deoxyribonucleic acid for the beta chain of human fibrinogen Biochemistry 1983; 22: 3244-3250
• 39 Rixon MW, Chan W-Y, Davie EW, Chung DW. Characterization of a complementary deoxyribonucleic acid coding for the alpha chain of human fibrinogen. Biochemistry 1983; 22: 3237-3244
• 40 Chung DW, Chan W-Y, Davie EW. Characterization of a complementary deoxyribonucleic acid coding for the gamma chain of human fibrinogen. Biochemistry 1983; 22: 3250-3256
• 41 Choo KH, Gould KG, Rees DJG, Brownlee GG. Molecular cloning of the gene for human anti haemophilic factor IX. Nature 1982; 299: 178-180
• 42 Leytus SP, Chung DW, Kisiel W, Kurachi K, Davie EW. Characterization of cDNA coding for human factor X. Proc Natl Acad Sci USA 1984; 81: 3699-3702
• 43 Ramadori G, Van Damme J, Reter H, Meyer-zum-Buschenfelte HM. Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 beta and tumor necrosis -factor-alpha. Eur J Immunol 1988; 18: 1259-1264