The Chinese herbal remedy, T2, inhibits mitogen-induced cytokine gene transcription by T cells, but not initial signal transduction

Xuelian Tao, Laurie S. Davis, Keisuke Hashimoto, Peter E. Lipsky

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

T2, an extract of Tripterygium wilfordii Hook F, has been reported to be effective in the treatment of a variety of autoimmune diseases, including rheumatoid arthritis. Previous studies have shown that T2 inhibited mitogen- or antigen-induced proliferation of human peripheral blood T cells and B cells, IL-2 production by T cells and Ig production by B cells. In contrast, T2 did not affect monocyte functions, such as IL-1 production and antigen presentation. The current studies sought to localize the immunosuppressive action of T2 more precisely. Results show that T2 prevented [3H]-uridine uptake by mitogen-stimulated T cells and arrested them in the early GI phase of the cell cycle. The inhibitory effects of T2 could be partially overcome by costimulating PHA activated T cells with PMA and completely nullified by costimulation with PMA plus a monoclonal antibody to CD28. Moreover, T2 had no effect on expression of IL-2R or the transferrin receptor (CD71), but inhibited production of a number of cytokines, including IL-2 and IFN-γ by activated T cells. T2 suppressed IL-2 mRNA levels, but not IL-2R mRNA levels, in activated T cells. T2-mediated inhibition reflected suppression of IL-2 gene transcription as indicated by suppression of the expression of a reporter gene driven by the IL-2 promoter. T2 had little inhibitory effect on either IL-2 gene expression or cell cycle progression when added after initial mitogenic stimulation, indicating that an early step in the cascade of activation events was inhibited. However, initial activation events including protein tyrosine phosphorylation, the generation of diacylglycerol, IP3, and the translocation of protein kinase C were not inhibited by T2. Moreover, T2 did not inhibit the phosphatase activity of calcineurin. These results have localized the effect of T2 to a step in the T cell activation cascade after initial second messenger generation, tyrosine phosphorylation and protein kinase activation, but before IL-2 gene transcription.

Original languageEnglish (US)
Pages (from-to)316-325
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume276
Issue number1
StatePublished - Jan 1 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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