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

@article{citeulike:713455, abstract = {The immunosuppressive effects of cyclosporin A (CsA) and FK506 are mediated through binding to immunophilins. Here we show that FK506-FKBP complex suppresses the activation of JNK and p38 pathways at a level upstream of mitogen-activated protein kinase (MAPK) kinase kinase (MAPKK-K) besides the calcineurin-NFAT pathway. A238L, a viral gene product that binds to immunophilin, also blocks activation of both pathways. In contrast, direct inhibitors of calcineurin, Cabin 1 and FR901725, suppress the activation of NFAT but not the JNK or p38 pathway. We further demonstrate that co-expression of a constitutively active NFAT and a constitutively active MEKK1 renders the interleukin-2 promoter in Jurkat T lymphocytes resistant to CsA and FK506, whereas Jurkat cells expressing a constitutively active NFAT alone are still sensitive to CsA or FK506. Therefore, CsA and FK506 exert their immunosuppressive effects through targeting both the calcineurin-dependent NFAT pathway and calcineurin-independent activation pathway for JNK and p38.}, address = {Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.}, author = {Matsuda, S. and Shibasaki, F. and Takehana, K. and Mori, H. and Nishida, E. and Koyasu, S.}, citeulike-article-id = {713455}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/11258483}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=11258483}, comment = {reaction 72}, issn = {1469-221X}, journal = {EMBO Rep}, keywords = {tcrmr-cabin}, month = {November}, number = {5}, pages = {428--434}, posted-at = {2006-06-28 12:04:11}, priority = {2}, title = {Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/11258483}, volume = {1}, year = {2000} }

TY - JOUR ID - citeulike:713455 L3 - citeulike-article-id:713455 N2 - The immunosuppressive effects of cyclosporin A (CsA) and FK506 are mediated through binding to immunophilins. Here we show that FK506-FKBP complex suppresses the activation of JNK and p38 pathways at a level upstream of mitogen-activated protein kinase (MAPK) kinase kinase (MAPKK-K) besides the calcineurin-NFAT pathway. A238L, a viral gene product that binds to immunophilin, also blocks activation of both pathways. In contrast, direct inhibitors of calcineurin, Cabin 1 and FR901725, suppress the activation of NFAT but not the JNK or p38 pathway. We further demonstrate that co-expression of a constitutively active NFAT and a constitutively active MEKK1 renders the interleukin-2 promoter in Jurkat T lymphocytes resistant to CsA and FK506, whereas Jurkat cells expressing a constitutively active NFAT alone are still sensitive to CsA or FK506. Therefore, CsA and FK506 exert their immunosuppressive effects through targeting both the calcineurin-dependent NFAT pathway and calcineurin-independent activation pathway for JNK and p38. IS - 5 JF - EMBO Rep SN - 1469-221X AD - Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan. EP - 434 TI - Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation. VL - 1 SP - 428 KW - tcrmr-cabin N1 - reaction 72 AU - Matsuda, S AU - Shibasaki, F AU - Takehana, K AU - Mori, H AU - Nishida, E AU - Koyasu, S PY - 2000/11// UR - http://view.ncbi.nlm.nih.gov/pubmed/11258483 ER -