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Differential Effects of Transforming Growth Factor-β1, a Fibrogenic Factor, on Macrophage-Like Cells (HS-P) and Myofibroblastic Cells (MT-9) In Vitro

Department of Veterinary Pathology, Graduate School of Agriculture and Biological Science, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan, yamate{at}vet.osakafu-u.ac.jp

Masaru Maeda

Department of Veterinary Pathology, Graduate School of Agriculture and Biological Science, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan

Sally J. Benn

Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G2W1, Canada

James E. Laithwaite

Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G2W1, Canada

Alison Allan

Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G2W1, Canada

Mika Ide

Department of Veterinary Pathology, Graduate School of Agriculture and Biological Science, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan

Mitsuru Kuwamura

Department of Veterinary Pathology, Graduate School of Agriculture and Biological Science, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan

Takao Kotani

Department of Veterinary Pathology, Graduate School of Agriculture and Biological Science, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan

Sadashige Sakuma

Department of Veterinary Pathology, Graduate School of Agriculture and Biological Science, Osaka Prefecture University, Gakuencho 1-1, Sakai, Osaka 599-8531, Japan

Jonathan Lamarre

Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, N1G2W1, Canada

Transforming growth factor- β1 (TGF-β1) produced by infiltrating macrophages plays a role in fibrotic disorders through the induction of myofibroblasts. To explore possible mechanisms by which TGF-β1 may act in this context, we investigated effects of TGF-β1 on macrophage-like (HS-P) and myofibroblastic (MT-9) cells, two novel cell lines developed by us. Immunocytochemicall y, the addition of TGF-β1 (0, 0.1, 0.5, and 1.0 ng/ml) dose-dependently suppressed the expressions of antigens recognized by macrophage/histiocyte-specific antibodies (ED1 and ED2) in HS-P cells, whereas the addition concomitantly increased the number of anti--smooth muscle actin antibody-positive myofibroblastic cells, suggesting a possible phenotypical modulation of macrophages into myofibroblasts in the fibrotic lesions. By contrast, MT-9 cells did not show such immunophenotypica l changes following TGF-β1 addition. DNA synthesis, measured by tritiated thymidine-incorporation , was inhibited in a dose-dependen tmanner in MT-9 cells by TGF-β1 addition (0, 0.1, 0.2, 0.5, 1.0, 5, and 10 ng/ml), but that in HS-P cells was unchanged. Northern blot analysis revealed that expressions of cell cycle-related early genes, c-jun and c-myc, were increased in HS-P cells after TGF- β1 (1 ng/ml) addition, with c-jun showing peak expression prior to c-myc. By contrast, the peak expressions of c-jun and c-myc were delayed in TGF-β1 (1 ng/ml)-added MT-9 cells, and their levels were less in MT-9 cells than in HS-P cells. Furthermore, TGF-β1 (1 and 10 ng/ml) induced DNA laddering in MT-9 cells, but did not in HS-P cells. Based on these findings, it was speculated that TGF- β1 could have induced G1 arrest in cell cycle and apoptosis in MT-9 cells. The present study showed that there were significant differences in the effects of TGF-β1 between macrophage-like HS-P cells and myofibroblastic MT-9 cells, presumably depending on divergent susceptibilities to TGF- β1 between both cell types. Because such cell types are key cells in the fibrogenesis, HS-P and MT-9 might be useful models for investigating the pathogenesis of fibrosis in vitro.

Key Words: Apoptosis • fibrosis • immediate early genes • macrophage-like cells • myofibroblastic cells • TGF-β1.

Toxicologic Pathology, Vol. 29, No. 4, 483-491 (2001)
DOI: 10.1080/01926230152500103


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