Distinct mechanisms of suppression of murine T cell activation by the related macrolides FK-506 and rapamycin.
FK-506 and the structurally related macrolide rapamycin (RAP) were investigated in comparison with cyclosporin A (CsA) for their immunosuppressive effects on murine T cells. All three agents suppressed the proliferation of splenic T cells triggered by lectins or antibodies to CD3 and Ly-6C. FK-506 or CsA also inhibited proliferation, IL-2 production, and IL-2R expression in splenic T cells activated with ionomycin + PMA. However, RAP minimally affected IL-2 production and IL-2R expression in these cells, although it reduced proliferation. Similarly, FK-506 and CsA, but not RAP, suppressed IL-2 production by activated DO.11.10 T hybridoma cells. In such a system, as well as in normal T cells stimulated with high ionomycin concentrations, FK-506 and CsA enhanced proliferation, indicating that they both abrogate negative signals associated with T cell activation. On the contrary, RAP diminished the autonomous proliferation of hybridoma cells, whereas FK-506 and CsA had little effect. The proliferative response induced in D10.G4 cells by IL-1 + ionomycin but not that induced by IL-1 + PMA was sensitive to inhibition by FK-506 and CsA. In contrast, RAP inhibited equally well both types of stimulation. Finally, T cell proliferation driven by IL-2 or IL-4 was found to be relatively resistant to FK-506 or CsA but sensitive to RAP. Altogether, these data demonstrate that FK-506 and CsA alter similar calcium-associated events of T cell activation and block T cell proliferation primarily by suppressing lymphokine production. RAP interferes with a different set of events and inhibits T cells by impairing their response to growth-promoting lymphokines.
Dumont
F J
FJ
Department of Immunology Research, Merck Sharp and Dohme Research Laboratories, Rahway, NJ 07065.
Staruch
M J
MJ
Koprak
S L
SL
Melino
M R
MR
Sigal
N H
NH
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D006825:Hybridomas; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011090:Polyenes / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D020123:Sirolimus; D016559:Tacrolimus; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011090:Polyenes; D015375:Receptors, Interleukin-2; D015847:Interleukin-4; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus; D016559:Tacrolimus