M. Ramirez et al., Wortmannin inhibits translation of tumor necrosis factor-alpha in superantigen-activated T cells, INT IMMUNOL, 11(9), 1999, pp. 1479-1489
The superantigen toxic shock syndrome toxin (TSST)-1 can induce tumor necro
sis factor (TNF)-alpha expression in T cells and monocytes, through differe
nt signaling pathways, We have stimulated peripheral blood mononuclear cell
s with TSST-1 and found that the major cell producers of TNF-alpha as detec
ted by cytofluorimetry and immunocytochemistry were CD4(+) T lymphocytes, T
he expression of TNF-alpha by CD4(+) T cells can be inhibited by either, wo
rtmannin (WN) or LY 294002, two phosphatidylinositol 3-kinase (PI 3-K) inhi
bitors, The inhibitory effect is not transcriptional as WN does not change
the mRNA steady state of TNF-alpha at any of the concentrations tested and
LY 294002 when preincubated with mononuclear cells at its median inhibitory
concentration (IC50 = 1.4 mu M) significantly inhibited the expression of
TNF-alpha but not its mRNA, Immunoprecipitation of pulse-labeled intracellu
lar TNF-alpha showed a specific decrease in the synthesis of this cytokine
on cells treated with PI 3-K inhibitors, The p38 mitogen-activated protein
kinase (MAPK) is involved in control of TNF-alpha translation in human macr
ophages, In T cells, we have found that the p38 MAPK inhibitor SE 203580 si
gnificantly decreased the secretion of TNF-alpha but not its mRNA, In addit
ion, the combined use of WN and SE 203580 had an additive inhibitory effect
on secretion of TNF-alpha. Therefore, both PI 3-K and p38 MAPK signaling p
athways control TNF-alpha production in T cells.