on September 4, 2003
Published online before print September 4, 2003, doi: 10.1161/01.ATV.0000094234.60166.78
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Submitted on July 17, 2003
Accepted on August 10, 2003
Cyclosporin A Enhances Interleukin-8 Expression by Inducing Activator Protein-1 in Human Aortic Smooth Muscle Cells
Ryuichiro Murakami ;
From the Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine (R.M., F.K., H.M., H.S.) and Department of Cardiology, School of Medicine (R.M., K.O., T.M.), Nagoya University, and Technical Research Laboratory (S.N., R.Y.), Kurabo Industries Ltd, Osaka, Japan.
* To whom correspondence should be addressed. E-mail: kambe{at}riem.nagoya-u.ac.jp.
Objective--Cyclosporin A (CsA) and tacrolimus (FK506) are widely used as immunosuppressants. However, their use has been hampered by various adverse effects, such as acceleration of atherosclerosis. Interleukin (IL)-8, a chemotactic cytokine, plays an important role in pathogenesis of atherosclerosis. We thus investigated whether synthesis of IL-8 from primary human aortic smooth muscle cells is influenced by CsA and FK506.
Methods and Results--Northern blot analysis revealed that CsA increased IL-8 mRNA level and enhanced its increase by epidermal growth factor or tumor necrosis factor-
. In contrast, FK506 had no effect on the mRNA level. IL-8 accumulation in culture media was also increased by CsA. Stability of IL-8 mRNA was not affected by CsA, whereas luciferase reporter gene assay using the human IL-8 promoter revealed that CsA significantly augmented the promoter activity. Electrophoretic mobility shift assay showed that binding activity of activator protein (AP)-1 was increased by CsA, and introduction of a mutation into the AP-1 site in the promoter abolished its CsA-dependent activation. The increased AP-1 binding activity was accompanied by c-Fos synthesis.
Conclusions--CsA stimulates synthesis of IL-8 via activation of AP-1 in human aortic smooth muscle cells, providing a novel aspect of biological effects of CsA on the cells.
Key words: Cyclosporin A • tacrolimus • interleukin-8 • activator protein-1 • human aortic smooth muscle cells
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