OVEREXPRESSION OF MITOGEN-ACTIVATED PROTEIN-KINASE KINASE KINASE REVERSED CAMP INHIBITION OF NF-KAPPA-B IN T-CELLS

cAMP inhibits T cell activation by acting as an antagonist for selecti ve kinases and transcriptional factors. We have recently demonstrated that cAMP inhibited c-Jun N-terminal kinase (JNK) but left the mitogen -activated protein (MAP) kinase cascade almost unaffected in T lymphoc ytes. In accordance with recent reports, we also observed a selective suppression of nuclear factor NF-kappa B activation by cAMP. The possi ble link between the JNK cascade and NF-kappa B activation was demonst rated by the fact that the active form of MAP kinase kinase kinase (De lta MEKK), a constitutive activator of JNK, induced NF-kappa B but not AP-1, Oct, and NF-AT in T cells. In contrast, the induction of MAP ki nase kinase (MEK)-MAP kinase did not stimulate NF-kappa B activity. Th e specific activation of NF-kappa B by a single MEKK-JNK cascade was t hus unusual, given that the activation of other transcriptional elemen ts in T cells requires at least two signal pathways. This was further confirmed by the fact that cAMP inhibition of NF-kappa B activation wa s reversed by overexpression of Delta MEKK.