Molecular mechanisms of T lymphocyte activation: convergence of T cell antigen receptor and IL-1 receptor-induced signaling at the level of IL-2 genetranscription

Go-stimulation of murine EL-4 thymoma cells-carrying high numbers of TCR an d type I IL-1 receptors (IL-1R)-with anti-CD3 antibodies and IL-1 resulted in synergistic enhancement of IL-2 synthesis. While the extracellular signa l-regulated kinase (ERK) cascade was activated by both receptors, IL-1 pref erentially stimulated Jun-N-terminal kinases (JNK) and p38 mitogen-activate d kinase or microtubule-associated protein kinase (MAPK). Interruption of T CR- or IL-1R-stimulated ERK cascade by PD-98059, a specific inhibitor of MA P/ERK kinase (MEK), resulted in partial suppression of nuclear factor of ac tivated T cells activation and in complete inhibition of IL-1-stimulated NF kappa B activation. Suppression of activation of both MEK and p38 MAPK res ulted in significant inhibition of IL-2 gene expression. The results show t hat maximal activation of the IL-2 gene requires activation of at least two different protein kinase cascades, i.e. of the ERK and p38 pathways but pr esumably also that of JNK which converge at the level of the IL-2 promoter resulting in enhancement of its transcriptional activity.