Farnesyltransferase inhibitors inhibit T-cell cytokine production at the posttranscriptional level

Autor: Thomas F. Gajewski, Christian Robbel, Allen W. Ho, Seth Berk, Reinhard Marks, Todd V. Kuna
Rok vydání: 2007
Předmět:
MAPK/ERK pathway
CD3 Complex
MAP Kinase Kinase 4
Pyridines
T-Lymphocytes
Farnesyltransferase
medicine.medical_treatment
Blotting
Western
Immunology
Protein Prenylation
Quinolones
Lymphocyte Activation
Biochemistry
Interferon-gamma
chemistry.chemical_compound
Methionine
Th2 Cells
CD28 Antigens
Piperidines
Prenylation
medicine
Farnesyltranstransferase
Humans
Enzyme Inhibitors
Phosphorylation
RNA Processing
Post-Transcriptional
Extracellular Signal-Regulated MAP Kinases
Cells
Cultured
Immunobiology
biology
Farnesyl Transferase Inhibitor
Antibodies
Monoclonal
Ribosomal Protein S6 Kinases
70-kDa
Ribonuclease
Pancreatic
Cell Biology
Hematology
HSP40 Heat-Shock Proteins
Th1 Cells
T cell cytokine production
Cell biology
Cytokine
chemistry
Ionomycin
biology.protein
Interleukin-2
Cytokine secretion
Interleukin-4
Zdroj: Blood. 110:1982-1988
ISSN: 1528-0020
0006-4971
Popis: 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-γ, 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-γ 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.
Databáze: OpenAIRE
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