1991 Fiscal Year Final Research Report Summary
The Effect of IFN-gamma on Proliferation of Vascular SMCS.
| Project/Area Number |
02670386
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
SHIMOKADO Kentaro NCVC Research Institute, 循環動熊機能部・機能評価研究室, 研究員 (30192115)
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| Co-Investigator(Kenkyū-buntansha) |
MASUDA Junichi NCVC Research Institute, 疫学部, 室長 (70173747)
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| Project Period (FY) |
1990 – 1991
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| Keywords | Atherosclerosis / Cytokines / Interferon Gamma / Smooth Muscle Cells / Proliferation / Autocrine / PDGF |
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| Research Abstract |
Interferon gamma(IFN-gamma)is a, multifunctional lymphokne secreted by activated T lymphocytes which are found in atherosclerotic lesions. It has been reported to suppress the proliferation of vascular smooth muscle cells(SMCs). However, as we report in this paper, IFN-gamma is mitogenic for vascular smooth muscle cells under certain circumstances.
Recombinant human IFN-gamma(1-100 U/ml)stimulated, in a dose dependent fashion, cell multiplication and[ ^3H]thymidine(TdR)incorporation into DNA by cultured arterial SMCs which had been growth-arrested by culturing in I %plasma-derived serum for 5 days. It also accentuated the mitogenic activity of platelet-derived growth factor(PDGF)-BB. Time course study revealed that there was a time lag of 4-6 hours between the Gl-S transition of quiescent SMCs stimulated by IFNgamma and that of SMCs stimulated by PDGF-BB. A synergistic effect of IFN-gamma upon the mitogenicity of PDGF became apparent after a similar time lag, suggesting that the IFN-gam
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ma-related mitogenicity is mediated by a substance(s)secreted by IFN-treated SMCs. In fact, conditioned medium of IFN-treated SMCs was mitogenic for SMCS. Mjtogenic activity in the conditioned medium was also detected by an assay using Swiss 3T3 cells which originated from mice and were therefore not responsive to human IFN. The production of mitogenic factor was blocked by anti-IFN-gamma 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-treated SMCs was not PDGF. This was supported by the fact that ^<125>I-PDGF-AA binding to SMCs was not decreased by prior treatment with IFN-gamma. Contrary to the lack of effects on the PDGF et receptor, IFNtreatment increased ^<125>I-PDGF-BB binding to SMCs by 20-50%. Scatchard plot analysis revealed that this increase in ^<125>I- PDGF-BB binding was due to increased binding sites on the cell surface. Nonhem blot analysis showed that the increase of PDGF beta receptor was regulated at transcriptional level. Based of these observation, we conclude that IFN-gamma, under certain circumstances, stimulates proliferation of vascular SMCs both by inducing production of an autocrine growth factor(s)and by upregulating PDGF beta recptor expression. The mitogenic activity of IFN-gamma may play a role in atherogenesis and other inflammatory processes. Less
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