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Am. J. Respir. Cell Mol. Biol., Volume 22, Number 1, January, 2000 51-60

Interleukin-8 Gene Repression by Clarithromycin Is Mediated by the Activator Protein-1 Binding Site in Human Bronchial Epithelial Cells

Shuichi Abe, Hidenori Nakamura, Sumito Inoue, Hiroaki Takeda, Hiroshi Saito, Shuichi Kato, Naofumi Mukaida, Kouji Matsushima, and Hitonobu Tomoike

First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata; Department of Pharmacology, Cancer Research Institute, Kanazawa University, Kanazawa; and Department of Molecular Preventive Medicine, Tokyo University Faculty of Medicine, Tokyo, Japan

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 having antimicrobial activities, macrolides have antiinflammatory effects, such as the inhibition of cytokine production. In the present study we investigated the effects of clarithromycin (CAM) on interleukin (IL)-8 gene expression and protein levels, using the human bronchial epithelial cell line BET-1A. Northern blot analyses showed that CAM inhibited tumor necrosis factor (TNF)-alpha -induced IL-8 gene expression in a dose- and incubation time-dependent manner. The half-life of IL-8 messenger RNA transcripts in TNF-alpha -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 potent promoter activity in a 174-bp segment (-130 to +44 bp relative to the transcription start site). This segment includes activator protein (AP)-1 and nuclear factor (NF)-kappa B-like sites, and exhibited its strongest response to TNF-alpha . TNF-alpha -induced promoter activity in this segment showed a significant repression by CAM. However, a 156-bp segment (-112 to +44 bp) that does not include an AP-1 site but includes an NF-kappa B-like site did not show a significant repression of TNF-alpha -induced promoter activity by CAM. Mutation of the AP-1 binding site abrogated the suppression by CAM of TNF-alpha -induced enhancement of luciferase activity. In accord with promoter analyses, an electrophoretic mobility shift assay showed that CAM repressed AP-1 binding in TNF-alpha -treated BET-1A cells; however, TNF-alpha induced both AP-1 and NF-kappa B binding activities in BET-1A cells. These data suggest that macrolides such as CAM repress IL-8 gene transcription mainly via the AP-1 binding site in human bronchial epithelial cells. Our findings provide a novel mechanism for the antiinflammatory function of macrolides, implicating a target for the development of new drugs for treating chronic airway inflammation.




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