Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells

Norifumi Sawamukai, Kazuyoshi Saito, Kunihiro Yamaoka, Shingo Nakayamada, Chisei Ra, Yoshiya Tanaka

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6479-6484
Number of pages6
JournalJournal of Immunology
Volume179
Issue number10
Publication statusPublished - 2007 Nov 15
Externally publishedYes

Fingerprint

leflunomide
Mast Cells
A 771726
Apoptosis
Rheumatoid Arthritis
Phosphorylation
Orotic Acid
Synovitis
Survival
Caspase 9
Synovial Membrane
Uridine

ASJC Scopus subject areas

  • Immunology

Cite this

Sawamukai, N., Saito, K., Yamaoka, K., Nakayamada, S., Ra, C., & Tanaka, Y. (2007). Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells. Journal of Immunology, 179(10), 6479-6484.

Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells. / Sawamukai, Norifumi; Saito, Kazuyoshi; Yamaoka, Kunihiro; Nakayamada, Shingo; Ra, Chisei; Tanaka, Yoshiya.

In: Journal of Immunology, Vol. 179, No. 10, 15.11.2007, p. 6479-6484.

Research output: Contribution to journalArticle

Sawamukai, N, Saito, K, Yamaoka, K, Nakayamada, S, Ra, C & Tanaka, Y 2007, 'Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells', Journal of Immunology, vol. 179, no. 10, pp. 6479-6484.
Sawamukai N, Saito K, Yamaoka K, Nakayamada S, Ra C, Tanaka Y. Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells. Journal of Immunology. 2007 Nov 15;179(10):6479-6484.
Sawamukai, Norifumi ; Saito, Kazuyoshi ; Yamaoka, Kunihiro ; Nakayamada, Shingo ; Ra, Chisei ; Tanaka, Yoshiya. / Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells. In: Journal of Immunology. 2007 ; Vol. 179, No. 10. pp. 6479-6484.
@article{c4d279c2ac254c67872da294993df094,
title = "Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells",
abstract = "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.",
author = "Norifumi Sawamukai and Kazuyoshi Saito and Kunihiro Yamaoka and Shingo Nakayamada and Chisei Ra and Yoshiya Tanaka",
year = "2007",
month = "11",
day = "15",
language = "English",
volume = "179",
pages = "6479--6484",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "10",

}

TY - JOUR

T1 - Leflunomide inhibits PDK1/Akt pathway and induces apoptosis of human mast cells

AU - Sawamukai, Norifumi

AU - Saito, Kazuyoshi

AU - Yamaoka, Kunihiro

AU - Nakayamada, Shingo

AU - Ra, Chisei

AU - Tanaka, Yoshiya

PY - 2007/11/15

Y1 - 2007/11/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=38449123007&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38449123007&partnerID=8YFLogxK

M3 - Article

C2 - 17982036

AN - SCOPUS:38449123007

VL - 179

SP - 6479

EP - 6484

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 10

ER -