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B Activation and Gene Expression1
Cytokine Research Laboratory, Department of Molecular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
Leflunomide is a novel immunosuppressive and antiinflammatory
agent currently being tested for treatment of autoimmune diseases and
transplant rejection. NF-
B is a transcription factor activated in
response to a wide variety of inflammatory stimuli, including TNF, but
whether leflunomide blocks NF-B activation is not known. In the
present report we demonstrate that treatment of a human T cell line
(Jurkat) with leflunomide blocks TNF-mediated NF-B activation in a
dose- and time-dependent manner, with maximum inhibition at 5–10 µM.
Inhibition was not restricted to TNF-induced activation, because
leflunomide also inhibited NF-B activation induced by other
inflammatory agents, including phorbol ester, LPS,
H2O2, okadaic acid, and ceramide. Leflunomide
blocked the degradation of IB
and subsequent nuclear
translocation of the p65 subunit, steps essential for NF-B
activation. This correlated with inhibition of dual
specificity-mitogen-activated protein kinase kinase as well as an Src
protein tyrosine kinase, p56lck, by
leflunomide. Reducing agents did not reverse the effect of leflunomide.
Leflunomide also suppressed the TNF-activated NF-B-dependent
reporter gene expression. Our results thus indicate that leflunomide is
a potent inhibitor of NF-B activation induced by a wide variety of
inflammatory stimuli, and this provides the molecular basis for its
anti-inflammatory and immunosuppressive
effects.
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