1998 Fiscal Year Final Research Report Summary
Interleukin-8 Gene Repression by Clarithromycin is mediated by AP-1 Binding Site in Human Bronchial Epithelial Cells
| Project/Area Number |
09670597
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | YAMAGATA UNIVERSITY |
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Principal Investigator |
NAKAMURA Hidenori Yamagata University School of Medicine, Associate Professor, 医学部, 講師 (30240675)
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| Co-Investigator(Kenkyū-buntansha) |
KATO Shuichi Yamagata University School of Medicine, Instructor, 医学部, 助手 (90260463)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Interleukin-8 / Bronchial Epithelial Cells / Macrolide Antibiotics / Promoter / Transcription Factors |
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| Research Abstract |
Macrolide antibiotics are known to be effective for the treatment of chronic inflammatory airway diseases including diffuse panbronchiolitis, chronic bronchitis and bronchial asthma. Other than anti-microbial activities, macrolides have "anti-inflammatory" effects, such as the inhibition of cytokine production. In the present study, we investigated the effects of clarithromycin (CAM) on the interleukin-8 (IL-8) gene expression and its protein levels using a human bronchial epithelial cell line, BET-1A cells. Northern analyses demonstrated that CAM inhibited the tumor necrosis factor alpha (TNF)-induced IL-8 gene expression in dose and incubation time-dependent fashions. The half-life of IL-8 mRNA transcripts in TN F-treated BET-1A cells did not change with CAM.Transfection studies with BET-1A cells, using fusion genes composed of the 5'-flanking sequences of the IL-8 gene and a luciferase reporter gene, demonstrated a potent promoter activity in a 174.bp segment (-130 to +44 bp relative to the transcription start site). This segment includes AP-1 and NF-_<lambda>B-like sites, and exhibited a strongest response to TNF.TNF-induced promoter activity in this segment showed a significant repression by CAM.However, a 156-bp segment (-112 to +44 bp), which does not include an AP-1 site but includes a NF-_<lambda>B-like site, did not show a significant repression of TNF-induced promoter activity by CAM.Consistent with promoter analyses, an electrophoretic mobility shift assay demonstrated that CAM repressed the AR-1 binding in TNF-treated BET-1A cells, however, TNF induced both AP-1 and NF-_<lambda>B binding activities in BET-1A cells. These data suggest that macrolidessuch as CAM repress the IL-8 gene transcription mainly via the AP-1 binding site in human bronchial epithelial cells. Our findings provide a novel mechanism of the anti-inflammatory function of macrolides, implicating a target for the development of a new drug for the treatment of chronic airway inflammation.
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[Publications] Kawasaki S,Takizawa H,Ohtoshi T,Takeuchi N,Kohyama T,Nakamura H,Kasama T,Kobayashi K,Kasahara K,Morita Y,Yamamoto K.: "Roxithromycin inhibits cytokine production by and neutrophil attachment to human bronchial epithelial cells in vitro." Antimicrob Agents Chem. 42. 1499-1502 (1998)
Description
「研究成果報告書概要(欧文)」より
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