Differential Inhibition by Cyclosporin A Reveals Two Pathways for Activation of-Lympholune Synthesis in T Cells

被引:21
作者
Kelso, Anne [1 ]
Gough, Nicholas M. [1 ]
机构
[1] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia
基金
美国国家卫生研究院; 英国医学研究理事会;
关键词
Lymphokines; T lymphocyte activation; cyclosporin A;
D O I
10.3109/08977198909029126
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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-y 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.
引用
收藏
页码:165 / 177
页数:13
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