Failure of cyclosporin A to induce transforming growth factor beta (TGF-beta) synthesis in activated peripheral blood lymphocytes.
Induction of transforming growth factor beta (TGF-beta) by the immunosuppressive drug cyclosporin A (CsA) in activated lymphocytes has been claimed to add to the renal pro-fibrotic effects of CsA. The aim of this study was to evaluate CsA-mediated TGF-beta induction in a larger number of lymphocyte preparations from different donors. Peripheral blood lymphocytes (PBL) were obtained from healthy blood donors. The cells were stimulated with phytohemagglutinin E (PHA) and phorbol ester (tetradecanoyl phorbol acetate, TPA) in the presence or absence of CsA. TGF-beta, interleukin-2 (IL-2) and cyclooxygenase-2 (Cox-2) mRNA were detected by Northern blot analysis or by real time reverse transcriptase-polymerase chain reaction (RT-PCR). TGF-beta and IL-2 protein were determined in the cellular supernatants by enzyme-linked immunosorbent assay. TGF-beta mRNA and protein were up-regulated when the cells were stimulated with PHA/TPA. Cyclosporin A at high concentrations (500 ng/mL) caused a transient increase in TGF-beta mRNA which was significant after 2 h. CsA did not induce sustained TGF-beta protein expression (24-72 h) in any of the preparations (n = 14), whereas the up-regulation of IL-2 mRNA and protein was prevented by CsA in the same preparations. Furthermore, up-regulation of Cox-2 mRNA was inhibited by CsA. Taken together, there was no evidence for TGF-beta as a clinically relevant mediator being induced by CsA in activated peripheral blood T-lymphocytes.
Goppelt-Struebe
Margarete
M
Medizinische Klinik IV, Universität Erlangen-Nürnberg, Loschgestrasse 8, Germany. goppelt-struebe@rzmail.uni-erlangen.de
Esslinger
Birgit
B
Kunzendorf
Ulrich
U
D000328:Adult; D015152:Blotting, Northern; D016572:Cyclosporine / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics
D007166:Immunosuppressive Agents; D007376:Interleukin-2; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D016572:Cyclosporine