This Article Full Text Full Text (PDF) All Versions of this Article: 23/11/2034    most recent 01.ATV.0000094234.60166.78v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murakami, R. Articles by Seo, H. Search for Related Content PubMed PubMed Citation Articles by Murakami, R. Articles by Seo, H. Related Collections Cell signalling/signal transduction Gene expression Gene regulation Growth factors/cytokines Smooth muscle proliferation and differentiation

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:2034.)
© 2003 American Heart Association, Inc.

Vascular Biology

Cyclosporin A Enhances Interleukin-8 Expression by Inducing Activator Protein-1 in Human Aortic Smooth Muscle Cells

Ryuichiro Murakami; Fukushi Kambe; Hirohito Mitsuyama; Kenji Okumura; Toyoaki Murohara; Satoru Niwata; Ryohei Yamamoto; Hisao Seo

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.

Correspondence to Fukushi Kambe, MD, PhD, Department of Endocrinology and Metabolism, Division of Molecular and Cellular Adaptation, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. 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

This article has been cited by other articles:

				M.-R. Du, W.-H. Zhou, L. Dong, X.-Y. Zhu, Y.-Y. He, J.-Y. Yang, and D.-J. Li Cyclosporin A Promotes Growth and Invasiveness In Vitro of Human First-Trimester Trophoblast Cells Via MAPK3/MAPK1-Mediated AP1 and Ca2+/Calcineurin/NFAT Signaling Pathways Biol Reprod, June 1, 2008; 78(6): 1102 - 1110. [Abstract] [Full Text] [PDF]

				K. Yokouchi, Y. Numaguchi, R. Kubota, M. Ishii, H. Imai, R. Murakami, Y. Ogawa, T. Kondo, K. Okumura, D. E. Ingber, et al. l-Caldesmon Regulates Proliferation and Migration of Vascular Smooth Muscle Cells and Inhibits Neointimal Formation After Angioplasty Arterioscler Thromb Vasc Biol, October 1, 2006; 26(10): 2231 - 2237. [Abstract] [Full Text] [PDF]

				A. Bostrom, H. Bharath, A. Saulewicz, and A.S. Narayanan Cyclosporin A Affects Signaling Events Differentially in Human Gingival Fibroblasts Journal of Dental Research, June 1, 2005; 84(6): 532 - 536. [Abstract] [Full Text] [PDF]

				J. C. Mason, R. Steinberg, E. A. Lidington, A. R. Kinderlerer, M. Ohba, and D. O. Haskard Decay-accelerating Factor Induction on Vascular Endothelium by Vascular Endothelial Growth Factor (VEGF) Is Mediated via a VEGF Receptor-2 (VEGF-R2)- and Protein Kinase C-{alpha}/{epsilon} (PKC{alpha}/{epsilon})-dependent Cytoprotective Signaling Pathway and Is Inhibited by Cyclosporin A J. Biol. Chem., October 1, 2004; 279(40): 41611 - 41618. [Abstract] [Full Text] [PDF]

				S.-W. Ryoo, D.-U. Kim, M. Won, K.-S. Chung, Y.-J. Jang, G.-T. Oh, S.-K. Park, P.-J. Maeng, H.-S. Yoo, and K.-L. Hoe Native LDL induces interleukin-8 expression via H2O2, p38 Kinase, and activator protein-1 in human aortic smooth muscle cells Cardiovasc Res, April 1, 2004; 62(1): 185 - 193. [Abstract] [Full Text] [PDF]