Mechanism of action of cyclosporin A. Effect on T-cell-binding of interleukin 1 and antagonizing effect of insulin.
Previous studies have shown that cyclosporin A (CyA) prevents the elaboration of the lymphokine leucocyte migration inhibitory factor (LIF). Since LIF production is interleukin 1 (IL-1)-dependent, we carried out experiments using partially and highly purified IL-1 preparations to study the effect of CyA. We found that (a) IL-1 was consistently depleted during a 1-h incubation with human blood T lymphocytes but not with B lymphocytes or erythrocytes; (b) the depletion could not be ascribed to pinocytosis, cell functions requiring active metabolism, or enzyme-mediated destruction of IL-1; (c) CyA, but not biologically inactive cyclosporin, antagonized the apparent absorption of IL-1; (d) T cells pre-exposed to CyA were rendered incapable of removing the monokine; and (e) CyA was capable of displacing IL-1 once absorbed by T cells. Because the putative binding of IL-1 showed saturability, reversibility (with CyA as a probe), and tissue specificity consistent with a known target for the monokine, we propose that IL-1 interacts with a receptor-like structure on T cells. Finally, we found that insulin interfered with the function of CyA at the very early macrophage-T-cell co-operative stage, even at physiological concentrations.
D000042:Absorption; D003524:Cyclosporins / Q000494:pharmacology*; D003571:Cytochalasin B / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors; D007329:Insulin Antagonists / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism*; D007961:Leukocyte Migration-Inhibitory Factors / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000378:metabolism*
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007329:Insulin Antagonists; D007375:Interleukin-1; D007961:Leukocyte Migration-Inhibitory Factors; D003571:Cytochalasin B