Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells.
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.
Sawamukai
Norifumi
N
First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. sawa@med.uoeh-u.ac.jp
Saito
Kazuyoshi
K
Yamaoka
Kunihiro
K
Nakayamada
Shingo
S
Ra
Chisei
C
Tanaka
Yoshiya
Y
D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D003437:Crotonates; D000090722:Dihydroorotate Dehydrogenase; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006885:Hydroxybutyrates / Q000494:pharmacology / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077339:Leflunomide; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology* / Q000276:immunology; D009570:Nitriles; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013583:Synovial Membrane / Q000201:enzymology / Q000276:immunology; D013585:Synovitis / Q000201:enzymology / Q000276:immunology; D014052:Toluidines; D014529:Uridine / Q000494:pharmacology
D000814:Aniline Compounds; D003437:Crotonates; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D006885:Hydroxybutyrates; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D007555:Isoxazoles; D009570:Nitriles; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014052:Toluidines; C527525:teriflunomide; D044925:Oxidoreductases Acting on CH-CH Group Donors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077339:Leflunomide; D014529:Uridine