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Blood, 15 September 2007, Vol. 110, No. 6, pp. 1982-1988. Prepublished online as a Blood First Edition Paper on June 1, 2007; DOI 10.1182/blood-2006-06-031088. This Article Full Text (PDF) All Versions of this Article: blood-2006-06-031088v1 110/6/1982    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Marks, R. E. Articles by Gajewski, T. F Search for Related Content PubMed PubMed Citation Articles by Marks, R. E. Articles by Gajewski, T. F Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted June 22, 2006 Accepted April 11, 2007 Farnesyltransferase inhibitors inhibit T cell cytokine production at the post-transcriptional level Reinhard E. Marks*, Allen W. Ho, Christian Robbel, Todd Kuna, Seth Berk, and Thomas F Gajewski Dept. of Hematology/Oncology, University Hospital Freiburg, Freiburg, Germany Dept. of Pathology, University of Chicago, Chicago, IL, United States Dept. of Medicine, University of Chicago, Chicago, IL, United States * Corresponding author; email: reinhard.marks{at}uniklinik-freiburg.de. Several cytoplasmatic 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 (FTI) 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 signalling 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-, 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- production also was observed, correlating with reduced phosphorylation of p70S6K. These results indicate that FTIs inhibit T cell activation at the post-transcriptional level, and also suggest that they may have potential as novel immunosuppressive agents. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Zeiser, S. Youssef, J. Baker, N. Kambham, L. Steinman, and R. S. Negrin Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity Blood, December 15, 2007; 110(13): 4588 - 4598. [Abstract] [Full Text] [PDF]

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