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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  • [1] CLOSE GENETIC AND PHYSICAL LINKAGE BETWEEN THE MURINE HEMATOPOIETIC GROWTH-FACTOR GENES GM-CSF AND MULTI-CSF (IL3)
    BARLOW, DP
    BUCAN, M
    LEHRACH, H
    HOGAN, BIM
    GOUGH, NM
    [J]. EMBO JOURNAL, 1987, 6 (03) : 617 - 623
  • [2] BENEDICT SH, 1987, J IMMUNOL, V139, P1694
  • [3] DIFFERENTIAL REGULATION OF COLONY-STIMULATING FACTORS AND INTERLEUKIN-2 PRODUCTION BY CYCLOSPORINE-A
    BICKEL, M
    TSUDA, H
    AMSTAD, P
    EVEQUOZ, V
    MERGENHAGEN, SE
    WAHL, SM
    PLUZNIK, DH
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (10) : 3274 - 3277
  • [4] CYCLOSPORIN-A - USEFULNESS, RISKS AND MECHANISM OF ACTION
    BRITTON, S
    PALACIOS, R
    [J]. IMMUNOLOGICAL REVIEWS, 1982, 65 : 5 - 22
  • [5] REGULATION OF EXPRESSION OF HUMAN GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR
    CHAN, JY
    SLAMON, DJ
    NIMER, SD
    GOLDE, DW
    GASSON, JC
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (22) : 8669 - 8673
  • [6] RECOMBINANT MURINE GM-CSF FROM ESCHERICHIA-COLI HAS BIOLOGICAL-ACTIVITY AND IS NEUTRALIZED BY A SPECIFIC ANTISERUM
    DELAMARTER, JF
    MERMOD, JJ
    LIANG, CM
    ELIASON, JF
    THATCHER, DR
    [J]. EMBO JOURNAL, 1985, 4 (10) : 2575 - 2581
  • [7] DUNN DE, 1987, J IMMUNOL, V139, P3942
  • [8] INDUCTION OF INTERLEUKIN-2 MESSENGER-RNA INHIBITED BY CYCLOSPORIN-A
    ELLIOTT, JF
    LIN, YA
    MIZEL, SB
    BLEACKLEY, RC
    HARNISH, DG
    PAETKAU, V
    [J]. SCIENCE, 1984, 226 (4681) : 1439 - 1441
  • [9] FARRAR WL, 1985, LYMPHOKINE RES, V4, P87
  • [10] FARRAR WL, 1986, J IMMUNOL, V137, P3836