title: Immunosuppressants FK506 and rapamycin have different effects on the biosynthesis of cytoplasmic actin during the early period of T cell activation.
abstract: FK506 and rapamycin are immunosuppressants that interfere with T cell activation. FK506 inhibits early events of T cell activation such as the induction of cytokine transcription, whereas rapamycin inhibits later interleukin 2 signalling events. However, both reagents either directly or indirectly reduce protein synthesis. Therefore a kinetic study was conducted in human primary T lymphocytes examining increased synthesis of proteins stimulated by either ionomycin+phorbol myristate acetate (PMA) or PMA alone. Three patterns of protein expression were observed. Synthesis of one group of proteins had enhanced synthesis with FK506, but reduced synthesis with rapamycin. A second group had reduced synthesis with rapamycin and either no change or a slight reduction with FK506 and a third group had reduction with both FK506 and rapamycin. One major protein of the first group, p42, had a rapid increase in synthesis that decreased by 8 h. Its synthesis was strongly enhanced by FK506, but reduced by rapamycin after ionomycin+PMA stimulation. In contrast, this protein was strongly induced by PMA alone in these cells and not affected by FK506 treatment, but still reduced by rapamycin. p42 was identified as cytoplasmic actin. mRNA levels of both gamma- and beta-actin were found to be enhanced with FK506 treatment suggesting that regulation of actin was at a transcriptional or post-transcriptional level. Results with actinomycin D indicated that FK506 is regulating actin biosynthesis at the post-transcriptional level. Rapamycin, however, appeared to be operating at the level of translation.
authors.affiliation: Molecular Hematology Branch, Section on Protein and RNA Biosynthesis, National Heart, Lung and Blood Institute, Bldg. 10, Room 7D18, Bethesda, MD 20892-21654, USA. smiyamot@ucdavis.edu
authors.forename: S
authors.initials: S
authors.lastname: Miyamoto
authors.forename: B
authors.initials: B
authors.lastname: Safer
mesh_terms: D000199:Actins / Q000096:biosynthesis*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015759:Ionomycin / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects*; D016559:Tacrolimus / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000199:Actins; D007166:Immunosuppressive Agents; D003609:Dactinomycin; D015759:Ionomycin; D003513:Cycloheximide; D013755:Tetradecanoylphorbol Acetate; D020123:Sirolimus; D016559:Tacrolimus