Comparison of the effects of FK-506, cyclosporin A and rapamycin on IL-2 production.
The immunosuppressive compounds FK-506, cyclosporin A (CsA) and rapamycin inhibit both the human and mouse mixed lymphocyte reactions (MLR) with IC50s of 2-5 x 10(-10) M for FK-506 and rapamycin and 10(-8) M for CsA. FK-506 and CsA were also potent inhibitors of A23187/PMA-stimulated IL-2 production by Jurkat and HuT-78 cells but had no effect on the response of mouse CTLL cells to IL-2. IC50 values for inhibition of IL-2 production closely matched those for inhibition of the MLR and both drugs were active only during the first 4-6 hr following stimulation. In contrast, rapamycin was a poor inhibitor of IL-2 production, although it inhibited cellular responses to IL-2. The IC50 values for these two activities indicated that neither alone accounted for rapamycin inhibition of the MLR. FK-506 and CsA affected IL-2 gene transcription in Jurkat cells by the same mechanism. Both inhibited the appearance of the transcription factor, NFAT, whereas rapamycin did not. The appearance of another transcription factor, NFK beta, was unaffected by all three drugs. The effects of FK-506 and CsA on IL-2 gene expression, therefore, are similar even though the two drugs act through distinct cytosolic receptors.
Henderson
D J
DJ
Dept. of Biochemistry, Fisons Pharmaceuticals plc, Loughborough, Leicestershire, U.K.
Naya
I
I
Bundick
R V
RV
Smith
G M
GM
Schmidt
J A
JA
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002460:Cell Line; D003524:Cyclosporins / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D007700:Kinetics; D007959:Lymphocyte Culture Test, Mixed; D011090:Polyenes / Q000494:pharmacology*; D020123:Sirolimus; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus
D000900:Anti-Bacterial Agents; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011090:Polyenes; D020123:Sirolimus; D016559:Tacrolimus