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B Activation Through Inhibition of IB
Phosphorylation and Degradation1
Cytokine Research Laboratory, Department of Bioimmunotherapy, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030
Methotrexate (MTX), a folate antagonist, is a commonly used
anti-inflammatory, antiproliferative, and immunosuppressive drug
whose mode of action is not fully established. Due to the central role
of NF-
B in these responses, we postulated that MTX must mediate its
effects through suppression of NF-B activation. We investigated the
effects of MTX on NF-B activation induced by TNF in Jurkat cells.
The treatment of these cells with MTX suppressed TNF-induced NF-B
activation with optimum effects occurring at 10 µM MTX for 60 min.
These effects were not restricted to Jurkat cells because other cell
types were also inhibited. Besides TNF, MTX also suppressed the NF-B
activation induced by various other inflammatory stimuli. The
suppression of TNF-induced NF-B activation by MTX correlated with
inhibition of IB
degradation, suppression of IB
phosphorylation, abrogation of IB kinase activation, and
inhibition of NF-B-dependent reporter gene expression. Because ecto
5' nucleotidase inhibitor (,
-methylene adenosine-5'-diphosphate)
blocked the effect of MTX, adenosine mimicked the effect of MTX, and
adenosine A2b receptor antagonist (3,7-dimethyl-1-propargylxanthine)
reversed the inhibitory effect of MTX, we suggest that MTX suppresses
NF-B activation by releasing adenosine. A partial reversal of
MTX-induced NF-B suppression by thymidine and folinic acid indicates
the role of the thymidylate synthase pathway also. Overall, our results
clearly demonstrate that MTX suppresses NF-B activation through the
release of adenosine, which may contribute to the role of MTX in
anti-inflammatory, immunomodulatory, and antiproliferative
effects.
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