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Department of Adult Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Harvard Medical School, Boston, MA 02115
IL-12 and IL-2 can stimulate mitogen- or CD3-activated T cells to
proliferate, produce IFN-
, and kill tumor cells. The magnitude of
these functional responses is greatly augmented when T cells are
activated by the combination of IL-12 and IL-2. Although peripheral
blood T cells are largely unresponsive to these cytokines without prior
activation, a small subset of CD8+ T cells
(CD8+CD18bright) is strongly activated by the
combination of IL-12 and IL-2. In this report we show that the
functional synergy between IL-12 and IL-2 in
CD8+CD18bright T cells correlates with the
activation of the stress kinases, p38 mitogen-activated protein (MAP)
kinase and stress-activated protein kinase (SAPK)/Jun N-terminal
kinase, but not with the activation of the extracellular
signal-regulated kinases. The functional synergy between IL-2 and IL-12
is also associated with a prominent increase in STAT1 and STAT3 serine
phosphorylation over that observed with IL-12 or IL-2 alone. By
contrast, STAT tyrosine phosphorylation is not augmented over that seen
with either cytokine alone. A specific inhibitor of p38 MAP kinase
completely inhibits the serine phosphorylation of STAT1 and STAT3
induced by IL-12 and IL-2 and abrogates the functional synergy between
IL-12 and IL-2 without affecting STAT tyrosine phosphorylation. This
suggests that p38 MAP kinase may play an important role in regulating
STAT serine phosphorylation in response to the combination of IL-12 and
IL-2. Furthermore, these findings indicate that the optimal activation
of T cells by IL-12 and IL-2 may depend on an interaction between the
p38 MAP kinase and Janus kinase/STAT signaling
pathways.
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