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dc.contributor.authorTeng, Xingwu
dc.date.accessioned2020-10-15T17:36:49Z
dc.date.available2020-10-15T17:36:49Z
dc.date.issued2000-04
dc.identifier.urien
dc.identifier.urihttp://hdl.handle.net/10675.2/623595
dc.descriptionThe file you are attempting to access is currently restricted to Augusta University. Please log in with your NetID if off campus.
dc.description.abstractThe aim of this study is to investigate the molecular mechanisms of inducible nitric oxide synthase (NOS) induction by interferon-γ (IFN-γ) in rat aortic smooth muscle cells (RASMC) and the interactions between transcription factors and the rat NOS promoter that are responsible for the IFN-γ-induced NOS expression. Measurements of NOS activity levels (nitrite accumulation), NOS protein levels and NOS promoter activity demonstrated that IFN-γ enhanced the interleukin-1β, (IL-1β)-induced NOS expression in RASMC, but that IFN-γ alone had no effect. By electrophoretic mobility shift assay (EMSA), IFN-γ was shown to activate interferon regulatory factor I (IRF-1) and signal transducers and activators of transcription 1 (Stat1). However, it had no effect on nuclear factor kappa B (NF-κB) or CCAAT box/enhancer binding protein (C/EBP) activation. Conversely, IL-1β activated NF-κB and C/EBP, but had no effect on IRF-1 or Stat1 activation. Deletion of a gamma interferon activated site (GAS site, −936 to −928 bp) increased the IL-1β-induced promoter activity, but did not significantly change the iNOS promoter induction by IFN-γ+IL-1β. The IFN-γ enhancement was partially abolished by the GAS site deletion, suggesting that the GAS site participates in the IFN-γ-enhanced NOS expression. Mutations of a reverse IRF site (−918 to −907 bp) completely abolished the NOS induction by IFN-γ, but it did not decrease the IL-1β-induced NOS promoter activity. These results suggest that the reverse IRF site is responsible for at least part of NOS induction by IFN-γ in RASMC. Deletion mutations that disrupted both the IRF site and the overlapping C/EBP site (−910 to −902 bp) abolished both the IL-1β-induced promoter activity and the IFN-γ enhancement, suggesting that the C/EBP site participates in the IL-1β-induced NOS expression. Mutations of a reverse NF-κB site (−901 to −892 bp) abolished the IL-1β-induced promoter activity, but not the IFN-γ enhancement, suggesting that the NF-κB binding mediates the IL-1β-induced, but not the IFN-γ-enhanced, NOS expression in RASMC. In summary, this study demonstrates that, in RASMC, IRF-1 and Stat1 activation mediates NOS induction by IFN-γ, and that the NF-κB and C/EBP activation mediates NOS induction by IL-1β, but not by IFN-γ.en_US
dc.language.isoen_USen_US
dc.publisherMedical College of Georgiaen_US
dc.relation.urlhttps://search.proquest.com/docview/304644914?accountid=12365
dc.rightsCopyright protected. Unauthorized reproduction or use beyond the exceptions granted by the Fair Use clause of U.S. Copyright law may violate federal law.en_US
dc.subjectHealth and environmental sciencesen_US
dc.subjectBiological sciencesen_US
dc.subjectAortic smooth muscleen_US
dc.subjectInterferon gammaen_US
dc.subjectNitric oxide synthaseen_US
dc.titleMolecular mechanisms of inducible nitric oxide synthase induction by interferon-γ in rat aortic smooth muscle cellsen_US
dc.typeDissertationen_US
dc.contributor.departmentDepartment of Pharmacology and Toxicologyen_US
dc.description.advisorCatravas, John D
dc.description.degreeDoctor of Philosophy with a Major in Pharmacologyen_US
dc.description.committeeFuchs, Leslie C
dc.description.committeeMills, Thomas M
dc.description.committeeVenema, Richard C
dc.description.committeeZhang, Hanfang
dc.embargoen
refterms.dateFOA2020-10-15T17:36:49Z


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