Mitogenic activity of interferon gamma on growth-arrested human vascular smooth muscle cells

Tasuku Yokota, Kentaro Shimokado, Chiya Kosaka, Toshiyuki Sasaguri, Junichi Masuda, Jun Ogata

研究成果: ジャーナルへの寄稿記事

28 引用 (Scopus)

抄録

Interferon gamma (IFN-γ) is a multifunctional lymphokine secreted by activated T lymphocytes, which are found in atherosclerotic lesions. IFN-γ has been reported to suppress the proliferation of vascular smooth muscle cells (SMCs). However, as we report in this paper, IFN-γ is mitogenic for vascular SMCs under certain circumstances. Recombinant human IFN-γ (1-100 units/ml), in a dose-dependent fashion, stimulated cell multiplication and [3H]thymidine and 5-bromo-2′-deoxyuridine incorporation into DNA by cultured arterial SMCs that had been growth arrested by culturing in 1% plasma-derived serum for 5 days. IFN-γ also accentuated the mitogenic activity of platelet-derived growth factor (PDGF)-BB. A time-course study revealed that there was a time lag of 4-6 hours between the G1→S transition of quiescent SMCs stimulated by IFN-γ and that of SMCs stimulated by PDGF-BB. A synergistic effect of IFN-γ on the mitogenicity of PDGF became apparent after a similar time lag, suggesting that the IFN-γ-related mitogenicity is mediated by a substance(s) secreted by IFN-γ-treated SMCs. In fact, conditioned medium of IFN-γ-treated SMCs was mitogenic for SMCs. Mitogenic activity in the conditioned medium was also detected by an assay using Swiss 3T3 cells, which originate from mice and, therefore, are not responsive to human IFN-γ. The production of the mitogenic factor was blocked by anti-IFN-γ antibody. Mitogenicity of the conditioned medium was not eliminated by addition of neutralizing antibody against PDGF, indicating that any autocrine growth factor(s) secreted by IFN-γ-treated SMCs was not PDGF. This was supported by the fact that 125I-PDGF-AA binding to SMCs was not decreased by prior treatment with IFN-γ. Contrary to the lack of effects on the PDGF α-receptor, IFN-γ treatment increased 125I-PDGF-BB binding to SMCs by 20-50%. Scatchard plot analysis revealed that this increase in 125I-PDGF-BB binding was due to increased binding sites on the cell surface. Northern blot analysis showed that the increase of the PDGF β-receptor was regulated at the level of mRNA. Based on these observations, we conclude that IFN-γ under certain circumstances stimulates proliferation of vascular SMCs by both inducing production of an autocrine growth factor(s) and upregulating PDGF β-receptor expression. The mitogenic activity of IFN-γ may play a role in atherogenesis and other inflammatory processes.

元の言語英語
ページ(範囲)1393-1401
ページ数9
ジャーナルArteriosclerosis, thrombosis, and vascular biology
12
発行部数12
DOI
出版物ステータス出版済み - 1 1 1992

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Vascular Smooth Muscle
Interferon-gamma
Smooth Muscle Myocytes
Growth
Platelet-Derived Growth Factor
Platelet-Derived Growth Factor Receptors
Conditioned Culture Medium
Intercellular Signaling Peptides and Proteins
Swiss 3T3 Cells
Lymphokines
Bromodeoxyuridine
Neutralizing Antibodies
Northern Blotting
Thymidine
Atherosclerosis
Binding Sites

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

これを引用

Mitogenic activity of interferon gamma on growth-arrested human vascular smooth muscle cells. / Yokota, Tasuku; Shimokado, Kentaro; Kosaka, Chiya; Sasaguri, Toshiyuki; Masuda, Junichi; Ogata, Jun.

:: Arteriosclerosis, thrombosis, and vascular biology, 巻 12, 番号 12, 01.01.1992, p. 1393-1401.

研究成果: ジャーナルへの寄稿記事

Yokota, Tasuku ; Shimokado, Kentaro ; Kosaka, Chiya ; Sasaguri, Toshiyuki ; Masuda, Junichi ; Ogata, Jun. / Mitogenic activity of interferon gamma on growth-arrested human vascular smooth muscle cells. :: Arteriosclerosis, thrombosis, and vascular biology. 1992 ; 巻 12, 番号 12. pp. 1393-1401.
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title = "Mitogenic activity of interferon gamma on growth-arrested human vascular smooth muscle cells",
abstract = "Interferon gamma (IFN-γ) is a multifunctional lymphokine secreted by activated T lymphocytes, which are found in atherosclerotic lesions. IFN-γ has been reported to suppress the proliferation of vascular smooth muscle cells (SMCs). However, as we report in this paper, IFN-γ is mitogenic for vascular SMCs under certain circumstances. Recombinant human IFN-γ (1-100 units/ml), in a dose-dependent fashion, stimulated cell multiplication and [3H]thymidine and 5-bromo-2′-deoxyuridine incorporation into DNA by cultured arterial SMCs that had been growth arrested by culturing in 1{\%} plasma-derived serum for 5 days. IFN-γ also accentuated the mitogenic activity of platelet-derived growth factor (PDGF)-BB. A time-course study revealed that there was a time lag of 4-6 hours between the G1→S transition of quiescent SMCs stimulated by IFN-γ and that of SMCs stimulated by PDGF-BB. A synergistic effect of IFN-γ on the mitogenicity of PDGF became apparent after a similar time lag, suggesting that the IFN-γ-related mitogenicity is mediated by a substance(s) secreted by IFN-γ-treated SMCs. In fact, conditioned medium of IFN-γ-treated SMCs was mitogenic for SMCs. Mitogenic activity in the conditioned medium was also detected by an assay using Swiss 3T3 cells, which originate from mice and, therefore, are not responsive to human IFN-γ. The production of the mitogenic factor was blocked by anti-IFN-γ antibody. Mitogenicity of the conditioned medium was not eliminated by addition of neutralizing antibody against PDGF, indicating that any autocrine growth factor(s) secreted by IFN-γ-treated SMCs was not PDGF. This was supported by the fact that 125I-PDGF-AA binding to SMCs was not decreased by prior treatment with IFN-γ. Contrary to the lack of effects on the PDGF α-receptor, IFN-γ treatment increased 125I-PDGF-BB binding to SMCs by 20-50{\%}. Scatchard plot analysis revealed that this increase in 125I-PDGF-BB binding was due to increased binding sites on the cell surface. Northern blot analysis showed that the increase of the PDGF β-receptor was regulated at the level of mRNA. Based on these observations, we conclude that IFN-γ under certain circumstances stimulates proliferation of vascular SMCs by both inducing production of an autocrine growth factor(s) and upregulating PDGF β-receptor expression. The mitogenic activity of IFN-γ may play a role in atherogenesis and other inflammatory processes.",
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AU - Yokota, Tasuku

AU - Shimokado, Kentaro

AU - Kosaka, Chiya

AU - Sasaguri, Toshiyuki

AU - Masuda, Junichi

AU - Ogata, Jun

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N2 - Interferon gamma (IFN-γ) is a multifunctional lymphokine secreted by activated T lymphocytes, which are found in atherosclerotic lesions. IFN-γ has been reported to suppress the proliferation of vascular smooth muscle cells (SMCs). However, as we report in this paper, IFN-γ is mitogenic for vascular SMCs under certain circumstances. Recombinant human IFN-γ (1-100 units/ml), in a dose-dependent fashion, stimulated cell multiplication and [3H]thymidine and 5-bromo-2′-deoxyuridine incorporation into DNA by cultured arterial SMCs that had been growth arrested by culturing in 1% plasma-derived serum for 5 days. IFN-γ also accentuated the mitogenic activity of platelet-derived growth factor (PDGF)-BB. A time-course study revealed that there was a time lag of 4-6 hours between the G1→S transition of quiescent SMCs stimulated by IFN-γ and that of SMCs stimulated by PDGF-BB. A synergistic effect of IFN-γ on the mitogenicity of PDGF became apparent after a similar time lag, suggesting that the IFN-γ-related mitogenicity is mediated by a substance(s) secreted by IFN-γ-treated SMCs. In fact, conditioned medium of IFN-γ-treated SMCs was mitogenic for SMCs. Mitogenic activity in the conditioned medium was also detected by an assay using Swiss 3T3 cells, which originate from mice and, therefore, are not responsive to human IFN-γ. The production of the mitogenic factor was blocked by anti-IFN-γ antibody. Mitogenicity of the conditioned medium was not eliminated by addition of neutralizing antibody against PDGF, indicating that any autocrine growth factor(s) secreted by IFN-γ-treated SMCs was not PDGF. This was supported by the fact that 125I-PDGF-AA binding to SMCs was not decreased by prior treatment with IFN-γ. Contrary to the lack of effects on the PDGF α-receptor, IFN-γ treatment increased 125I-PDGF-BB binding to SMCs by 20-50%. Scatchard plot analysis revealed that this increase in 125I-PDGF-BB binding was due to increased binding sites on the cell surface. Northern blot analysis showed that the increase of the PDGF β-receptor was regulated at the level of mRNA. Based on these observations, we conclude that IFN-γ under certain circumstances stimulates proliferation of vascular SMCs by both inducing production of an autocrine growth factor(s) and upregulating PDGF β-receptor expression. The mitogenic activity of IFN-γ may play a role in atherogenesis and other inflammatory processes.

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