Xl. Tao et al., THE CHINESE HERBAL REMEDY, T2, INHIBITS MITOGEN-INDUCED CYTOKINE GENE-TRANSCRIPTION BY T-CELLS, BUT NOT INITIAL SIGNAL-TRANSDUCTION, The Journal of pharmacology and experimental therapeutics, 276(1), 1996, pp. 316-325
T2, an extract of Tripterygium wilfordii Hook F, has been reported to
be effective in the treatment of a variety of autoimmune diseases, inc
luding rheumatoid arthritis. Previous studies have shown that T2 inhib
ited mitogen- or antigen-induced proliferation of human peripheral blo
od T cells and B cells, 11-2 production by T cells and Ig production b
y B cells. In contrast, T2 did not affect monocyte functions, such as
IL-1 produciton and antigen presentation. The current studies sought t
o localize the immunosuppressive action of T2 more precisely. Results
show that T2 prevented [H-3]-uridine uptake by mitogen-stimulated T ce
lls and arrested them in the early G1 phase of the cell cycle. The inh
ibitory effects of T2 could be partially overcome by costimulating PHA
activated T cells with PFAA and completely nullified by costimulation
with PMA plus a monoclonal antibody to CD28. Moreover, T2 had no effe
ct on expression of IL-2R or the transferrin receptor (CD71), but inhi
bited production of a number of cytokines, including 1L-2 and IfN-gamm
a by activated T cells. T2 suppressed IL-2 mRNA levels, but not IL-2R
mRNA levels, in activated T cells. T2-mediated inhibition reflected su
ppression of IL-2 gene transcription as indicated by suppression of th
e expression of a reporter gene driven by the IL-2 promoter. T2 had li
ttle inhibitory effect on either IL-2 gene expression or cell cycle pr
ogression when added after initial mitogenic stimulation, indicating t
hat an early step in the cascade of activation events was inhibited. H
owever, initial activation events including protein tyrosine phosphory
lation, the generation of diacylglycerol, IP3, and the translocation o
f protein kinase C were not inhibited by T2. Moreover, T2 did not inhi
bit the phosphatase activity of calcineurin. These results have locali
zed the effect of T2 to a step in the T cell activation cascade after
initial second messenger generation, tyrosine phosphorylation and prot
ein kinase activation, but before IL-2 gene transcription.