Inhibition of T-lymphocyte activation by the immunosuppressive drug FK-506.
Nanamolar concentrations of the immunosuppressive drug FK-506 inhibit the induction of T-lymphocyte proliferation by the lectins concanavalin A (Con A) and phytohaemagglutinin (PHA). Activation by Con A is more sensitive to inhibition than the response to PHA. FK-506 inhibits an early Ca2+-dependent step in the activation process, and its effects are not reversible by the addition of recombinant interleukin-2 (IL-2) or lymphokine-rich culture supernatant. While the effects of suboptimal concentrations of FK-506 and cyclosporin A (CsA) are additive, FK-506 does not enhance the effects of optimal concentrations of CsA. Both drugs also have similar effects on the expression of specific mRNA in Con A-activated lymphocytes. A brief preincubation of unstimulated cells with FK-506 irreversibly inhibits their subsequent responsiveness to Con A. The mechanism of action of FK-506 thus resembles that of CsA, except that it is effective at two to three orders of magnitude lower concentrations and its effects are much less readily reversible.
Kay
J E
JE
Biochemistry Laboratory, School of Biological Sciences, University of Sussex, Brighton.
Benzie
C R
CR
Goodier
M R
MR
Wick
C J
CJ
Doe
S E
SE
D000818:Animals; D002478:Cells, Cultured; D003208:Concanavalin A; D003524:Cyclosporins / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects*; D010835:Phytohemagglutinins; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D013601:T-Lymphocytes / Q000187:drug effects*; D016559:Tacrolimus
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D010835:Phytohemagglutinins; D011725:Pyridines; D012333:RNA, Messenger; D011994:Recombinant Proteins; D003208:Concanavalin A; D016559:Tacrolimus