Sk. Manna et al., Leflunomide suppresses TNF-induced cellular responses: Effects on NF-kappaB, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis, J IMMUNOL, 165(10), 2000, pp. 5962-5969
Leflunomide is a pyrimidine biosynthesis inhibitor that has recently been a
pproved for treatment of rheumatoid arthritis. However, the mechanism of le
flunomide's antiarthritis activity and is not fully understood. The critica
l role that TNF plays in rheumatoid arthritis led us to postulate that lefl
unomide blocks TNF signaling, Previously, we have demonstrated that lefluno
mide inhibits TNF-induced NF-kappaB activation by suppressing I-kappaB alph
a (inhibitory subunit of NF-kappaB) degradation. We in this study show that
leflunomide also blocks NF-kappaB reporter gene expression induced by TNFR
1, TNFR-associated factor 2, and NF-kappaB-inducing kinase (NIK), but not t
hat activated by the p65 subunit of NF-kappaB, suggesting that leflunomide
acts downstream of NIK, Leflunomide suppressed TNF-induced phosphorylation
of I-kappaB alpha, as well as activation of I-kappaB alpha kinase-beta loca
ted downstream to NIK, Leflunomide also inhibited TNF-induced activation of
AP-I and the c-Jun N-terminal protein kinase activation. TNF-mediated cyto
toxicity and caspase-induced poly(ADP-ribose) polymerase cleavage were also
completely abrogated by treatment of Jurkat T cells with leflunomide, Lefl
unomide 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 re
versible by uridine, indicating a critical role for pyrimidine biosynthesis
in TNF-mediated cellular responses. Overall, our results suggest that supp
ression of TNF signaling is one of the possible mechanisms for inhibitory a
ctivity of leflunomide against rheumatoid arthritis.