Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation

The immunosuppressive effects of cyclosporin A (CsA) and FK506 are mediated through binding to immunophilins. Here we show that FK506-FKBP complex sup presses the activation of JNK and p38 pathways at a level upstream of mitog en-activated protein kinase (MAPK) kinase kinase (MAPKK-K) besides the calc ineurin-NFAT pathway. A238L, a viral gene product that binds to immunophili n, also blocks activation of both pathways. In contrast, direct inhibitors of calcineurin, Cabin 1 and FR901725, suppress the activation of NFAT but n ot the JNK or p38 pathway. We further demonstrate that coexpression of a co nstitutively active NFAT and a constitutively active MEKK1 renders the inte rleukin-2 promoter in Jurkat T lymphocytes resistant to CsA and FK506, wher eas Jurkat cells expressing a constitutively active NFAT alone are still se nsitive to CsA or FK506. Therefore, CsA and FK506 exert their immunosuppres sive effects through targeting both the calcineurin-dependent NFAT pathway and calcineurin-independent activation pathway for JNK and p38.