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B, Activator Protein-1, c-Jun N-Terminal Protein Kinase, and Apoptosis1
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
Leflunomide is a pyrimidine biosynthesis inhibitor that
has recently been approved for treatment of rheumatoid arthritis.
However, the mechanism of leflunomide’s antiarthritis activity and is
not fully understood. The critical role that TNF plays in rheumatoid
arthritis led us to postulate that leflunomide blocks TNF signaling.
Previously, we have demonstrated that leflunomide inhibits TNF-induced
NF-
B activation by suppressing I-B
(inhibitory subunit of
NF-B) degradation. We in this study show that leflunomide also
blocks NF-B reporter gene expression induced by TNFR1,
TNFR-associated factor 2, and NF-B-inducing kinase (NIK), but not
that activated by the p65 subunit of NF-B, suggesting that
leflunomide acts downstream of NIK. Leflunomide suppressed TNF-induced
phosphorylation of I-B, as well as activation of I-B
kinase-
located downstream to NIK. Leflunomide also inhibited
TNF-induced activation of AP-1 and the c-Jun N-terminal protein kinase
activation. TNF-mediated cytotoxicity and caspase-induced
poly(ADP-ribose) polymerase cleavage were also completely abrogated by
treatment of Jurkat T cells with leflunomide. Leflunomide suppressed
TNF-induced reactive oxygen intermediate generation and lipid
peroxidation, which may explain most of its effects on TNF signaling.
The suppressive effects of leflunomide on TNF signaling were completely
reversible by uridine, indicating a critical role for pyrimidine
biosynthesis in TNF-mediated cellular responses. Overall, our results
suggest that suppression of TNF signaling is one of the possible
mechanisms for inhibitory activity of leflunomide against rheumatoid
arthritis.
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