Inhibition of p70/p85 S6 kinase activities in T cells by dexamethasone.
Glucocorticoids (GC) are potent immunosuppressive agents that interfere with interleukin-2 (IL-2)-dependent proliferation and IL-2 receptor signal transduction in T lymphocytes through complex mechanisms. Here we report that the basal activity, and IL-2- and phorbol ester-dependent activation of the p70/p85 S6 kinases (referred to collectively as pp70S6k) are inhibited by the glucocorticoid dexamethasone (Dex) in CTLL-20 cells. This Dex-induced inhibition is time- and dose-dependent, appears to be the consequence of pp70S6k dephosphorylation, and requires ongoing transcription. Attempts to establish a link between Dex action and those of known pp70S6k-regulating agents such as phosphatidylinositol 3-kinase, protein kinase A-stimulating agents, calyculin A-inhibited protein phosphatases, and rapamycin have been negative. Additional results with NIH3T3 cells suggest the existence of a T cell-specific blockade of pp70S6k by Dex. Implications are 2-fold: 1) pp70S6k inactivation may account for at least part of the immunosuppressive effects of GC in vivo, and 2) GC inactivation of pp70S6k is exerted through a novel, distinct mechanism that does not appear to be linked to any other known pp70S6k regulatory process.
Monfar
M
M
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Blenis
J
J
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology; D008387:Marine Toxins; D051379:Mice; D010080:Oxazoles / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011090:Polyenes / Q000494:pharmacology; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D016559:Tacrolimus / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D015056:1-Methyl-3-isobutylxanthine; D000893:Anti-Inflammatory Agents; D005576:Colforsin; D003907:Dexamethasone; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D007376:Interleukin-2; D008387:Marine Toxins; D010080:Oxazoles; D010703:Phorbol Esters; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D019893:Ribosomal Protein S6 Kinases; D020123:Sirolimus; D016559:Tacrolimus; D013755:Tetradecanoylphorbol Acetate; C059041:calyculin A