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Glucocorticoid and cytokine regulation of genes involved in chronic inflammation
Başlık:
Glucocorticoid and cytokine regulation of genes involved in chronic inflammation
Yazar:
Alourfi, Zaynab, author.
ISBN:
9780355978483
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (202 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 76-08C.
Özet:
Macrophage migration inhibitory factor (MIF) is a ubiquitous and pleiotropic cytokine. A single nucleotide polymorphism (SNP), a G to C transition at position -173 and a CATT tetranucleotide repeat, starting at -794 relative to the transcription start site have been described in the 5'flanking region of MIF gene. Using luciferase-based reporter gene assays in CEMC7A (a human T lymphoblasts) the expression of MIF -173*C-luc was shown to be significantly higher than the expression of MIF -173*G-luc (P=0.013). Analysis of the haplotypic constructs that cover -794 CATT repeats (5-7) in combination with the -173*G/C showed a haplotypic effect on MIF promoter activity in a cell type specific manner. Specifically, in CEMC7A cells the extended CATT repeat increased the promoter activity of the MIF-173*C allele (P=0.007 for CATT (7)-MIF-173*C compared with CATT (5rMIF-173*C). However, there was no interaction between the CATT repeat and MIF-173*G. In A549 (a human epithelial cell lines) the CATT repeats interacted with MIF-173*C and significantly increased the reporter gene activity (P<0.001 for CATT (7)- MIF-173*C compared with CATT (5)-MIF-173*C). In addition, the repeat also interacted with MIF -173*G, but an extended CATT repeat decreased the promoter activity of the MIF-173*G allele (P=0.014 for CATT (7)-MIF-173*C compared with CATT (5)-MIF-173*G). There was no induction of the MIF haplotypic reporter constructs with either cpt cAMP or TNF?, but a significant induction of all constructs was found with Phorbol myristate acetate (PMA). Transient transfection studies showed that the MW promoter was repressed by dexamethasone (Dex) (10nM) in CEM C7A cells, with up to 50% suppression by 100nM. Furthermore, the Dex repression was independent of the haplotypes. No regulation of the MIF promoter by Dex was observed in A549 cells. Optimization of a MW ELISA was carried out. Utilizing this, sub-nanomolar concentrations of Dex were found to suppress MW secretion by 80% in both CEM C7A and A549. Endogenous MIF mRNA was also found to be repressed by Dex in CEM C7A cells, as measured by a quantitative RT-PCR assay, but there was no such regulation in the A549 cells. This suggests that GC affects translation rather than transcription of MIF in A549 cells. Dex regulation of MIF secretion in the rodent RAW 264.7 cells was also analyzed but no Dex effect was found, which is contrary to earlier findings. There was also no Dex regulation on MIF mRNA from this rodent cell line as measured by q RT-PCR. Understanding how GC regulates MIF in a cell-type dependent manner may give insights to glucocorticoid refractory human inflammatory diseases.
Notlar:
School code: 1543
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(683884.1) | 683884-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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