TY - JOUR
T1 - The cyclosporins inhibit lymphocyte activation at more than one site
AU - Gelfand, E. W.
AU - Cheung, R. K.
AU - Mills, G. B.
N1 - Copyright:
Copyright 2004 Elsevier B.V., All rights reserved.
PY - 1987
Y1 - 1987
N2 - Cyclosporin A (CsA), a potent immunosuppressive agent, acts primarily by inhibiting T cell function. Although several potential sites of action have been identified, the mechanisms whereby CsA mediates its immunosuppressive properties have not been fully delineated. We have examined the effects of the immunosuppressive cyclosporins, CsA, dihydrocyclosporin D, and cyclosporin G, and a nonimmunosuppressive analog, cyclosporin H, on early events associated with activation of human T cells. Interleukin 2 (IL 2) receptor expression, as measured by immunofluorescence, was unaffected by CsA. Despite this, in the continuous presence of CsA, exogenous IL 2 did not bypass CsA inhibition of phytohemagglutinin (PHA)-induced proliferation. Thus, one site of activity of CsA is on IL 2-induced proliferation of IL 2 receptor-expressing cells. In addition, several potential mechanisms for inhibiting IL 2 secretion were identified. Changes in cytosolic free Ca2+ ([Ca2+](i)), an obligatory event for PHA-induced IL 2 secretion, were inhibited by a 30-min preincubation with the immunosuppressive cyclosporins but not the inactive analog. In this action, the drug effects cannot be distinguished from that of Ca2+ channel blockers. The active compounds also resulted in membrane depolarization, an effect which may, in part, explain the reduction in PHA-induced changes in [Ca2+](i). These results identify multiple sites of action of the immunosuppressive cyclosporins, the combination of which likely accounts for their selective inhibition of T cell function in vitro and in vivo.
AB - Cyclosporin A (CsA), a potent immunosuppressive agent, acts primarily by inhibiting T cell function. Although several potential sites of action have been identified, the mechanisms whereby CsA mediates its immunosuppressive properties have not been fully delineated. We have examined the effects of the immunosuppressive cyclosporins, CsA, dihydrocyclosporin D, and cyclosporin G, and a nonimmunosuppressive analog, cyclosporin H, on early events associated with activation of human T cells. Interleukin 2 (IL 2) receptor expression, as measured by immunofluorescence, was unaffected by CsA. Despite this, in the continuous presence of CsA, exogenous IL 2 did not bypass CsA inhibition of phytohemagglutinin (PHA)-induced proliferation. Thus, one site of activity of CsA is on IL 2-induced proliferation of IL 2 receptor-expressing cells. In addition, several potential mechanisms for inhibiting IL 2 secretion were identified. Changes in cytosolic free Ca2+ ([Ca2+](i)), an obligatory event for PHA-induced IL 2 secretion, were inhibited by a 30-min preincubation with the immunosuppressive cyclosporins but not the inactive analog. In this action, the drug effects cannot be distinguished from that of Ca2+ channel blockers. The active compounds also resulted in membrane depolarization, an effect which may, in part, explain the reduction in PHA-induced changes in [Ca2+](i). These results identify multiple sites of action of the immunosuppressive cyclosporins, the combination of which likely accounts for their selective inhibition of T cell function in vitro and in vivo.
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M3 - Article
C2 - 3492542
AN - SCOPUS:0023110170
SN - 0022-1767
VL - 138
SP - 1115
EP - 1120
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -