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Calcineurin preferentially synergizes with PKC‐θ to activate JNK and IL‐2 promoter in T lymphocytes

Costimulation of the T cell receptor (TCR) and CD28 is required for optimal interleukin‐2 (IL‐2) induction. These signals, which can be replaced by the pharmacological agents phorbol ester (PMA) and Ca2+ ionophore, synergistically activate the mitogen‐activated protein kinase (MAPK) JNK. Cyclosporin A, an inhibitor of the Ca2+‐dependent phosphatase calcineurin which blocks IL‐2 induction, abrogates Ca2+‐triggered synergistic JNK activation. As protein kinase C (PKC) downregulation inhibits PMA+ionophore‐induced JNK activation, we examined whether a particular PKC isoform is preferentially involved in this response. We found that PKC‐θ but neither PKC‐α nor PKC‐ϵ participates in JNK activation, whereas all three PKCs lead to ERK MAPK activation. PKC‐θ specifically cooperates with calcineurin, and together their signals converge on (or upstream of) Rac leading to potent JNK activation. Similarly, calcineurin and PKC‐θ specifically synergize to induce transcription of reporters driven by the c‐jun and IL‐2 promoters. PKC‐θ and calcineurin are also partially responsible for the synergistic activation of JNK following TCR and CD28 ligation. Preferential cooperation between PKC‐θ and calcineurin is observed in Jurkat T cells but not in HeLa cells. These results indicate that PKC isozymes have distinct biological functions and suggest that synergistic JNK activation is an important function for PKC‐θ in T‐cell activation.