Differential inhibition by cyclosporin A reveals two pathways for activation of lymphokine synthesis in T cells.
Two pathways for the activation of lymphokine synthesis in murine T cell clones and polyclonal T cell blast populations were identified. One was induced by ligands of the T cell receptor (TCR) and led to high production of GM-CSF, IFN-gamma, and IL-3. The other was induced by IL-2 and led to production of lower levels of GM-CSF and IFN-gamma with relatively little IL-3 synthesis. Cyclosporin A (CsA) markedly inhibited TCR-independent production of lymphokine mRNA and protein at concentrations where IL-2-dependent stimulation of lymphokine production and proliferation was unaffected. Stimulation of lymphokine synthesis by phorbol myristate acetate (PMA) and the Ca2+ ionophore ionomycin, or by ionomycin alone, mimicked the TCR-dependent response. PMA on its own was a preferential stimulus for GM-CSF production, but, whereas CsA did not inhibit PMA stimulation of polyclonal T cell blasts, T cell clones displayed a biphasic response in which CsA only inhibited stimulation by high PMA concentrations. The data suggest that Ca2(+)-independent (CsA-resistant) T cell activation induces synthesis of GM-CSF and IFN-gamma but is a poor stimulus for IL-3 production. On the other hand, when Ca2(+)-dependent (CsA-sensitive) pathways are activated by TCR binding or by a Ca2+ ionophore, production of high levels of all three lymphokines can be induced.
Kelso
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A
Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital Victoria, Australia.
Gough
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NM
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002999:Clone Cells; D003115:Colony-Stimulating Factors / Q000096:biosynthesis* / Q000378:metabolism; D003208:Concanavalin A / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000096:biosynthesis* / Q000378:metabolism; D007376:Interleukin-2 / Q000502:physiology*; D007377:Interleukin-3 / Q000096:biosynthesis* / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003115:Colony-Stimulating Factors; D003524:Cyclosporins; D006133:Growth Substances; D007376:Interleukin-2; D007377:Interleukin-3; D011948:Receptors, Antigen, T-Cell; D003208:Concanavalin A; D015759:Ionomycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D013755:Tetradecanoylphorbol Acetate