HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sawamukai, N. Articles by Tanaka, Y. Search for Related Content PubMed PubMed Citation Articles by Sawamukai, N. Articles by Tanaka, Y.

Leflunomide Inhibits PDK1/Akt Pathway and Induces Apoptosis of Human Mast Cells¹

Norifumi Sawamukai^2,*, Kazuyoshi Saito^*, Kunihiro Yamaoka^*, Shingo Nakayamada^*, Chisei Ra and Yoshiya Tanaka^*

^* First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan; and Division of Molecular Cell Immunology and Allergology, Nihon University Graduate School of Medical Science, Tokyo, Japan

Mast cells release many inflammatory mediators that play an important role not only in allergic diseases but also in chronic inflammatory diseases, autoimmune diseases, and others. A lot of mast cells exist in synovium of rheumatoid arthritis, and it is known that synovitis does not occur in mast cell-deficient mice. Thus, it is thought that mast cells play a very important role in rheumatoid arthritis pathogenesis. Leflunomide is a drug used clinically in the treatment of rheumatoid arthritis. We used clinical doses of 2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)-butenamide (A77 1726), which is an active metabolite of leflunomide, and decreased the number of viable human primary mast cells in a concentration-dependent manner. This decrease was not reversed by uridine. Inhibition of pyrimidine synthesis by dihydro-orotic acid dehydrogenase inhibition, which is the primary mechanism of action of A77 1726, was not involved. A77 1726 dramatically induced apoptosis of human mast cells and inhibited the phosphorylation of Akt, an important survival signal of mast cells, in a concentration-dependent manner. Caspases 3 and 9, downstream molecules of Akt survival pathway, were also fragmented by A77 1726. In addition, it became evident for the first time that the mechanism involved in this result was the concentration-dependent inhibition of PDK1 phosphorylation, which controls the activation of Akt. These results indicate a new way of controlling mast cells and may therefore be the basis for innovative approaches to the treatment of various diseases related to mast cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Research Grant-in-Aid for Scientific Research by the Ministry of Health, Labor and Welfare of Japan, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the University of Occupational and Environmental Health, Japan.

² Address correspondence and reprint requests to Dr. Norifumi Sawamukai, First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi, Kitakyushu 807-8555 Japan. E-mail address: sawa{at}med.uoeh-u.ac.jp

³ Abbreviations used in this paper: LEF, leflunomide; RA, rheumatoid arthritis; A77 1726, 2-cyano-3-hydroxy-N-(4-trifluoromethylphenyl)-butenamide; DHODH, dihydro-orotic acid dehydrogenase; CBMC, cord blood-derived mast cell; SCF, stem cell factor; GSK3β, glycogen synthase kinase-3β; PI, propidium iodide.