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Leflunomide, a novel immunosuppressive drug, is able to prevent
and reverse allograft and xenograft rejection in rodents, dogs, and
monkeys. It is also effective in the treatment of several rodent models
of arthritis and autoimmune disease. In vitro studies indicate
that leflunomide is capable of inhibiting anti-CD3- and interleukin-2
(IL-2)-stimulated T cell proliferation. However, the biochemical
mechanism for the inhibitory activity of leflunomide has not been
elucidated. In this study, we characterized the inhibitory effects of
leflunomide on Src family (p56
Volume 270,
Number 21,
Issue of May 26, pp. 12398-12403, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
and
p59
)-mediated protein tyrosine phosphorylation.
Leflunomide was able to inhibit p59
and
p56
activity in in vitro tyrosine
kinase assays. The IC
values for p59
(immunoprecipitated from either Jurkat or CTLL-4 cell lysate)
autophosphorylation and phosphorylation of the exogenous substrate,
histone 2B, were 125-175 and 22-40 µM
respectively, while the IC
values for p56
(immunoprecipitated from Jurkat cell lysates) autophosphorylation
and phosphorylation of histone 2B were 160 and 65 µM
respectively. We also demonstrated the ability of leflunomide to
inhibit protein tyrosine phosphorylation induced by anti-CD3 monoclonal
antibody in Jurkat cells. The IC
values for total
intracellular tyrosine phosphorylation ranged from 5 to 45
µM, with the IC
values for the
chain
and phospholipase C isoform
1 being 35 and 44 µM
respectively. Leflunomide also inhibited Ca
mobilization in Jurkat cells stimulated by anti-CD3 antibody but
not in those stimulated by ionomycin. Distal events of anti-CD3
monoclonal antibody stimulation, namely, IL-2 production and IL-2
receptor expression on human T lymphocytes, were also inhibited by
leflunomide. Finally, tyrosine phosphorylation in CTLL-4 cells
stimulated by IL-2 was also inhibited by leflunomide. These data
collectively demonstrate the ability of leflunomide to inhibit tyrosine
kinase activity in vitro, and suggest that inhibition of
tyrosine phosphorylation events may be the mechanism by which
leflunomide functions as an immunosuppressive agent.
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