The functional synergy between IL-12 and IL-2 involves p38 mitogen-activated protein kinase and is associated with the augmentation of STAT serine phosphorylation

IL-12 and IL-2 can stimulate mitogen- or CD3-activated T cells to prolifera te, produce IFN-gamma, and kill tumor cells. The magnitude of these functio nal responses is greatly augmented when T cells are activated by the combin ation of IL-12 and IL-2. Although peripheral blood T cells are largely unre sponsive to these cytosines without prior activation, a small subset of CD8 (+) T cells (CD8(+)CD(18bright)) is strongly activated by the combination o f IL-12! and IL-2. In this report He show that the functional synergy betwe en IL-12 and IL-2 in CD8(+)CD18(bright) T cells correlates with the activat ion of the stress kinases, p38 mitogen-activated protein (MAP) kinase and s tress-activated protein kinase (SAPK)Jun N-terminal kinase, but not with th e 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 tryosine phosphorylation is not augmented ov er that seen with either cytokine alone, A specific inhibitor of p38 MAP ki nase completely inhibits the serine phosphorylation of STAT1 and STAT3 indu ced by IL-12 and IL-2 and abrogates the functional synergy between IL-12 an d IL-2 without affecting STAT tryosine phosphorylation, This suggests that p38 MAP kinase may play an important role in regulating STAT serine phospho rylation in response to the combination of IL-IZ and IL-2, Furthermore, the se 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.