Cyclosporin A inhibits late steps of T lymphocyte activation after transmembrane signaling.
The in vitro stimulation of murine splenic T lymphocytes with concanavalin A (Con A) produced interleukin 2 (IL2). The addition of cyclosporin A (CsA) to the culture resulted in complete inhibition of IL2 production. The Con A stimulation of T lymphocytes induced the breakdown of phosphatidylinositol into inositol trisphosphate and diacylglycerol, each of which could function as the second messengers in the subsequent signal transduction pathway. CsA did not inhibit the production of inositol (poly)phosphates. Further, CsA did not affect Ca2+-calmodulin functions; a) the redistribution of various cytoskeletal proteins as well as Con A-receptor aggregation, and b) the cytosolic Ca2+-calmodulin-dependent enzyme activities. Moreover, the activity of protein kinase C, which has been accepted to be the target of diacylglycerol, was not influenced in the presence of CsA. While the above steps of signal transduction are bypassed by synergy between calcium ionophore and phorbol ester, T lymphocyte activation which was induced by such stimuli was completely inhibited by CsA. These results indicate that CsA does not influence early steps of T lymphocyte activation as bypassed by calcium ionophore and phorbol ester, but rather inhibits later step(s) subsequent to the activation of protein kinase C and Ca2+-calmodulin.
Mizushima
Y
Y
Department of Oncogenesis, Institute for Cancer Research, Osaka.
Kosaka
H
H
Sakuma
S
S
Kanda
K
K
Itoh
K
K
Osugi
T
T
Mizushima
A
A
Hamaoka
T
T
Yoshida
H
H
Sobue
K
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000494:pharmacology; D002147:Calmodulin / Q000494:pharmacology; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008809:Mice, Inbred C3H; D009219:Myosin-Light-Chain Kinase / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011952:Receptors, Concanavalin A / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002147:Calmodulin; D003524:Cyclosporins; D007295:Inositol Phosphates; D007376:Interleukin-2; D011952:Receptors, Concanavalin A; D003208:Concanavalin A; D000001:Calcimycin; D011493:Protein Kinase C; D009219:Myosin-Light-Chain Kinase; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium