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Multiple Sclerosis Research Center, Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37212
IL-12 is a macrophage-derived cytokine that induces proliferation,
cytokine production, and cytotoxic activity of T and NK cells.
Signaling through its receptor, IL-12 induces these cellular responses
by tyrosine phosphorylation and activation of Janus kinase-2 (Jak-2),
Tyk-2, Stat3, and Stat4. We have used tyrphostin B42 (AG490), a Jak-2
inhibitor, to determine the role of Jak-2 kinase in IL-12 signaling and
IL-12-induced T cell functions. Treatment of activated T cells with
tyrphostin B42 inhibited the IL-12-induced tyrosine phosphorylation and
activation of Jak-2 without affecting Tyk-2 kinase. In contrast,
treatment with tyrphostin A1 inhibited the tyrosine phosphorylation of
Tyk-2 but not that of Jak-2 kinase. Inhibition of either Jak-2 or Tyk-2
leads to a decrease in the IL-12-induced tyrosine phosphorylation of
Stat3, but not of Stat4, protein. While inhibition of Jak-2 lead to
programmed cell death, the inhibition of Jak-2 or Tyk-2 resulted a
decrease in IFN-
production. We have further tested the in vivo
effects of tyrphostin B42 in experimental allergic encephalomyelitis, a
Th1 cell-mediated autoimmune disease. In vivo treatment with tyrphostin
B42 decreased the proliferation and IFN- production of neural
Ag-specific T cells. Treatment of mice with tyrphostin B42 also reduced
the incidence and severity of active and passive EAE. These results
suggest that tyrphostin B42 prevents EAE by inhibiting IL-12 signaling
and IL-12-mediated Th1 differentiation in vivo.
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