Rapamycin selectively inhibits IL-2-driven activation of p70 S6 kinase during T-cell proliferation.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | T cells; in vitro |
| Journal | Nature |
| Year | 1992 |
| Peer reviewed | Yes |
| Source | DOI 10.1038/358070a0 · PMID 1614535 |
The macrolide rapamycin induces cell cycle G1 arrest in yeast and in mammalian cells, which suggests that an evolutionarily conserved, rapamycin-sensitive pathway may regulate entry into S phase. In mammals, rapamycin inhibits interleukin-2 receptor-induced S phase entry and subsequent T-cell proliferation, resulting in immunosuppression. Here we show that interleukin-2 selectively stimulates the phosphorylation and activation of p70 S6 kinase but not the erk-encoded MAP kinases and rsk-encoded S6 kinases. Rapamycin completely and rapidly inhibits interleukin-2-induced phosphorylation and activation of p70 S6 kinase at concentrations comparable to those blocking S phase entry of T cells (0.05-0.2 nM). The structurally related macrolide FK506 competitively antagonizes the actions of rapamycin, indicating that these effects are mediated by FKBP, which binds the transition-state mimic structure common to both rapamycin and FK506 (refs 4, 6, 9-11). The selective blockade of the p70 S6 kinase activation cascade by the rapamycin-FKBP complex implicates this signalling pathway in the regulation of T cell entry into S phase.
| Intervention | Rapamycin |
| Target | p70 S6 kinase (IL-2 signaling) |
| Model | T cells; in vitro |
| Effect | Rapamycin selectively inhibits IL-2-induced activation of p70 S6 kinase (basis of immunosuppression) |