Cyclosporin A regulates the expression of HLA-DR on human monocytes by two different mechanisms.
Cyclosporin A (CsA), but not its nonimmunosuppressive analog cyclosporin H (CsH), inhibited the expression of HLA-DR in human monocytes. Induction of HLA-DR by interferon (IFN)-gamma in fresh monocytes was also inhibited by CsA and not by CsH. However, when monocytes were pretreated with either CsA or CsH for 16 hr prior to the addition of IFN-gamma, HLA-DR expression was increased, probably because of a cyclosporin-induced increase in the number of IFN-gamma receptors. Down-regulation of the HLA-DR mRNA by CsA was found to be dependent on continuous protein synthesis. IFN-alpha also inhibited the IFN-gamma-induced HLA-DR mRNA expression and showed synergy with CsA at low concentrations but not at high concentrations of the drugs. A common mechanistic element in the pathways of CsA and IFN-alpha is proposed.
Yonish-Rouach
E
E
Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel.
Fischer
D G
DG
Rubinstein
M
M
D003513:Cycloheximide / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D006684:HLA-DR Antigens / Q000032:analysis* / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D011971:Receptors, Immunologic / Q000032:analysis / Q000187:drug effects; D017471:Receptors, Interferon
D003524:Cyclosporins; D006684:HLA-DR Antigens; D007370:Interferon Type I; D007376:Interleukin-2; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D017471:Receptors, Interferon; D007371:Interferon-gamma; D003513:Cycloheximide