Rapamycin inhibits the phosphorylation of p70 S6 kinase in IL-2 and mitogen-activated human T cells.
Phosphorylation of 40S ribosomal protein S6 is regulated in part by the mitogen-activated p70 S6 kinase (p70s6k). Following the addition of IL-2 to the IL-2 dependent human cell line Kit225, or mitogenic activation of resting human T cells, a rapid phosphorylation of p70s6k was observed by immunoblotting. Rapamycin (RAP), a potent suppressor of T-cell proliferative responses, markedly inhibited the phosphorylation of p70s6k induced by IL-2 in Kit225 cells or by the mitogens added to resting T cells. Other immunosuppressants such as cyclosporin A or an FK506 analogue were without effect. Moreover, the effect of RAP was restricted to p70s6k; it did not inhibit the phosphorylation of p90rsk, another kinase which utilizes the S6 protein as a substrate. These data indicate for the first time that RAP may target the pathway leading to p70s6k phosphorylation during human T-cell proliferation.
Terada
N
N
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Lucas
J J
JJ
Szepesi
A
A
Franklin
R A
RA
Takase
K
K
Gelfand
E W
EW
D000595:Amino Acid Sequence; D000906:Antibodies; D002460:Cell Line; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D019319:Okadaic Acid; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D010835:Phytohemagglutinins; D011090:Polyenes / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology; D038601:Ribosomal Protein S6; D019893:Ribosomal Protein S6 Kinases; D012269:Ribosomal Proteins / Q000302:isolation & purification / Q000378:metabolism*; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology
D000906:Antibodies; D004988:Ethers, Cyclic; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010455:Peptides; D010835:Phytohemagglutinins; D011090:Polyenes; D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D038601:Ribosomal Protein S6; D012269:Ribosomal Proteins; D019319:Okadaic Acid; D015240:Phorbol 12,13-Dibutyrate; D015759:Ionomycin; D016572:Cyclosporine; D019893:Ribosomal Protein S6 Kinases; D010749:Phosphoprotein Phosphatases; D020123:Sirolimus; D016559:Tacrolimus