Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level.
Several cytoplasmic proteins, such as GTPases of the Ras family, containing a C-terminal CAAX motif are prenylated by farnesyltransferase to facilitate localization to cellular membranes where activation occurs. Farnesyltransferase inhibitors (FTIs) interfere with this farnesylation process, thereby preventing proper membrane localization and rendering the proteins unavailable for activation. Currently, FTIs are being explored as antineoplastic agents for the treatment of several malignancies. However, since farnesylated proteins like Ras are also involved in intracellular signaling in lymphocytes, FTIs might interfere with T-cell activation. Based on this hypothesis we examined the effect of several FTIs on cytokine production in response to anti-CD3 + anti-CD28 monoclonal antibodies or PMA + ionomycin. Murine Th1 and Th2 clones, stimulated in the presence of FTIs, showed a dose-dependent reduction of lineage-specific cytokine secretion (IFN-gamma, IL-2, IL-4, IL-5). However, no inhibition of ERK or JNK MAP kinases was observed, nor was induction of cytokine mRNA affected. Rather, intracellular cytokine protein synthesis was blocked. Inhibition of human T-cell INF-gamma production also was observed, correlating with reduced phosphorylation of p70S6K. These results indicate that FTIs inhibit T-cell activation at the posttranscriptional level and also suggest that they may have potential as novel immunosuppressive agents.
Marks
Reinhard E
RE
Department of Pathology, University of Chicago, IL, USA. reinhard.marks@uniklinik-freiburg.de
Ho
Allen W
AW
Robbel
Christian
C
Kuna
Todd
T
Berk
Seth
S
Gajewski
Thomas F
TF
D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D017368:Protein Prenylation; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional; D012259:Ribonuclease, Pancreatic / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003986:Dibenzocycloheptenes
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D051231:Farnesyltranstransferase; D050956:HSP40 Heat-Shock Proteins; D007371:Interferon-gamma; D007376:Interleukin-2; D015847:Interleukin-4; D048670:MAP Kinase Kinase 4; D008715:Methionine; D010880:Piperidines; D011725:Pyridines; D015363:Quinolones; D012259:Ribonuclease, Pancreatic; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C107481:DNAJA1 protein, human; C096898:L 744832; C115354:lonafarnib; D003986:Dibenzocycloheptenes; C402769:tipifarnib