International Immunology, Vol. 11, No. 9, 1479-1489,
September 1999
© 1999 Japanese Society for Immunology
Wortmannin inhibits translation of tumor necrosis factor-
in superantigen-activated T cells
Departament de Fisiologia and
1 Departament de Biologia Cellular, Facultat de Biologia, Universitat de Barcelona, Avenue Diagonal 645, 08028 Barcelona, Spain
2 Servei d'Immunologia, Hospital Clínic Provincial, Villarroel 170, 08036 Barcelona, Spain
Correspondence to: E. Espel
The superantigen toxic shock syndrome toxin (TSST)-1 can induce tumor necrosis factor (TNF)-
expression in T cells and monocytes, through different signaling pathways. We have stimulated peripheral blood mononuclear cells with TSST-1 and found that the major cell producers of TNF- as detected by cytofluorimetry and immunocytochemistry were CD4+ T lymphocytes. The expression of TNF- by CD4+ T cells can be inhibited by either, wortmannin (WN) or LY 294002, two phosphatidylinositol 3-kinase (PI 3-K) inhibitors. The inhibitory effect is not transcriptional as WN does not change the mRNA steady state of TNF- at any of the concentrations tested and LY 294002 when preincubated with mononuclear cells at its median inhibitory concentration (IC50 = 1.4 µM) significantly inhibited the expression of TNF- but not its mRNA. Immunoprecipitation of pulse-labeled intracellular TNF- 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- translation in human macrophages. In T cells, we have found that the p38 MAPK inhibitor SB 203580 significantly decreased the secretion of TNF- but not its mRNA. In addition, the combined use of WN and SB 203580 had an additive inhibitory effect on secretion of TNF-. Therefore, both PI 3-K and p38 MAPK signaling pathways control TNF- production in T cells.
Keywords: LY 294002, p38 mitogen-activated protein kinase, phosphatidylinositol 3-kinase, SB 203580, toxic shock syndrome toxin-1
The first two authors contributed equally to this work
Transmitting editor: C. Terhorst
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